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【结 构 式】

【分子编号】10180

【品名】Thiourea

【CA登记号】62-56-6

【 分 子 式 】CH4N2S

【 分 子 量 】76.12224

【元素组成】C 15.78% H 5.3% N 36.8% S 42.12%
与该中间体有关的原料药合成路线共 137 条
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合成路线1

该中间体在本合成路线中的序号：(A)

The protection of the amino group of ethyl 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (I) with trityl chloride (B) by means of triethylamine in CH2Cl2 gives ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetate (II), which is hydrolyzed to the corresponding acid (III) with NaOH in refluxing dioxane-water. The condensation of (III) with 7-aminocephalosporanic acid (IV) by means of dicyclohexylcarbodiimide in CH2Cl2 containing triethylamine affords 7-(2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]cephalosporanic acid (V). The elimination of the trityl group is performed with hot 55% formic acid yielding the corresponding free acid, which is finally treated with NaHCO3 in water.

参考文献 中间体
合成目标
【1】 Neuman, M.; Castaner, J.; HR-756. Drugs Fut 1978, 3, 10, 749.
【2】 Heymes, R.; Lutz, A. (Aventis Pharma SA); Oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acid processes for preparing them and pharmaceutical compositions incorporating them. BE 0850662; ES 455089; ES 466539; GB 1580621; GB 1580623; JP 52102293; JP 5247013 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(B) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(I) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(II) 39963 ethyl 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate C27H25N3O3S 详情 详情
(III) 25058 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid 64485-90-1 C25H21N3O3S 详情 详情
(IV) 22747 (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C10H12N2O5S 详情 详情
(V) 39964 (6R,7R)-3-[(acetoxy)methyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C35H31N5O7S2 详情 详情
(VI) 39961 ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate C6H8ClNO4 详情 详情
(VII) 39962 ethyl 4-chloro-2-(methoxyimino)-3-oxobutanoate C7H10ClNO4 详情 详情
(VIII) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(IX) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(X) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

By condensation of 3-dimethylaminopropyl chloride (I) with thiourea (II) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Weetman, D.F.; Castaner, J.; Dimaprit. Drugs Fut 1978, 3, 4, 273.
【2】 Kartinos, N.J. (Baxter International Inc.); Gamma-Dimethylaminopropyl isothiourea and acid addition salts thereof. US 3116327 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24581 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine 5407-04-5 C5H12ClN 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The condensation of 6-methylpyridine-3-carboxaldehyde (I) with malonic acid (II) by means of piperidine in refluxing pyridine gives 3-(6-methyl-3-pyridyl)acrylic acid (III), which is esterified with ethanol and H2SO4 as usual to afford ethyl 3-(6-methyl-3-pyridyl)acrylate (IV). The reduction of (IV) with H2 over Pd/C in ethanol affords ethyl 3-(6-methyl-3-pyridyl)propionate (V), which is cyclized with ethyl formate (VI) and thiourea (VII) by means of Na in ether-ethanol yielding 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (VIII). The methylation of (VIII) with methyl iodide and NaOH in hot water gives 5-(6-methyl-3-pyridyl-methyl)-2-methylthio-4-pyrimidone (IX), which is finally condensed with 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (X) in refluxing pyridine.

参考文献 中间体
合成目标
【1】 Brown, T.H.; Ife, R.J. (SmithKline Beecham plc); Pyrimidine compounds. DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141 .
【2】 de Angelis, L.; Serradell, M.N.; Castaner, J.; Blancafort, P.; SKF-93,479. Drugs Fut 1982, 7, 3, 175.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22949 6-methylnicotinaldehyde C7H7NO 详情 详情
(II) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(III) 22950 (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid C9H9NO2 详情 详情
(IV) 36446 ethyl (E)-3-(6-methyl-3-pyridinyl)-2-propenoate C11H13NO2 详情 详情
(V) 22951 ethyl 3-(6-methyl-3-pyridinyl)propanoate C11H15NO2 详情 详情
(VI) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(VII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 36447 5-[(6-methyl-3-pyridinyl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H11N3OS 详情 详情
(IX) 36448 5-[(6-methyl-3-pyridinyl)methyl]-2-(methylsulfanyl)-4(3H)-pyrimidinone C12H13N3OS 详情 详情
(X) 13851 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine C10H18N2OS 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

The reaction of 1-methylcyclohexylmethanol (II) with 4-chloronitrobenzene (III) by means of NaH in hot DMSO gives 4-(1-methylcyclohexylmethoxylnitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 4-(1-methylcyclohexylmethoxylaniline (IV). Diazotation of (IV) with NaNO2 and HCl in water affords a solution of the corresponding diazonium chloride (V), which is condensed with methyl acrylate (VI) by means of Cu2O affording methyl 2-chloro-3-[4-(1-methylcyclohexylmethoxyl)phenyl]propionate (VII). The cyclization of (VII) with thiourea (VIII) by means of sodium acetate in hot 2-methoxyethanol gives 2-imino-5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidin-4-one (IX), which is finally hydrolyzed with HCl in refluxing 2-methoxyethanol - water.

参考文献 中间体
合成目标
【1】 Kawamatsu, Y.; Mizuno, K.; Sugiyama, Y.; Imamiya, E.; Fujita, T.; Sohda, T.; Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull 1982, 30, 10, 3580.
【2】 Nohria, V.; Castaner, J.; Serradell, M.N.; Ciglitazone. Drugs Fut 1984, 9, 4, 258.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34173 (1-methylcyclohexyl)methanol C8H16O 详情 详情
(II) 13909 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene 100-00-5 C6H4ClNO2 详情 详情
(III) 34174 1-[(1-methylcyclohexyl)methoxy]-4-nitrobenzene; (1-methylcyclohexyl)methyl 4-nitrophenyl ether C14H19NO3 详情 详情
(IV) 34175 4-[(1-methylcyclohexyl)methoxy]phenylamine; 4-[(1-methylcyclohexyl)methoxy]aniline C14H21NO 详情 详情
(V) 34176 4-[(1-methylcyclohexyl)methoxy]benzenediazonium chloride C14H19ClN2O 详情 详情
(VI) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(VII) 34177 methyl 2-chloro-3-[4-[(1-methylcyclohexyl)methoxy]phenyl]propanoate C18H25ClO3 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IX) 34178 2-imino-5-[4-[(1-methylcyclohexyl)methoxy]benzyl]-1,3-thiazolidin-4-one C18H24N2O2S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

By cyclization of (VIII) with methyl 2-(methanesulfonyloxy)-3-[4-(1-methylcyclohexylmethoxy)phenyl]propionate (X) by means of sodium acetate in hot 2-methoxyethanol, followed by hydrolysis with HCl in ethanol water.

参考文献 中间体
合成目标
【1】 Fujita, T.; Kawamatsu, Y.; Thiazolidine derivatives. EP 0008203; US 4287200; US 4340605; US 4438141; US 4444779 .
【2】 Nohria, V.; Castaner, J.; Serradell, M.N.; Ciglitazone. Drugs Fut 1984, 9, 4, 258.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(X) 34179 　 C21H32O4S 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The synthesis of [14C]-labeled cefepime has been reported: The cyclization of [14C]-thiourea (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid ethyl ester (II) in ethanol gives 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid ethyl ester (III), which is hydrolyzed with NaOH in methanol to the corresponding free acid (IV). The esterification of (IV) with 1-hydroxybenzotriazole (V) by means of dicyclohexylcarbodiimide in THF affords the corresponding active ester (VI), which is condensed with 7-amino-3-(1-methylpyrrolidiniomethyl)-3-cephem-4-carboxylate (VII) by means of NaOH in THF-water and isolated as the sulfate salt (VIII). Finally, this compound is treated with triethylamine in N-methyl-2-pyrrolidone.

参考文献 中间体
合成目标
【1】 Swigor, J.E.; Standridge, R.T.; Synthesis of 7-[alpha-(2-amino-[2-14C]thiazol-4-yl)-alpha-(Z)-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride ([14C]cefepime hydrochloride). J Label Compd Radiopharm 1993, 33, 8, 759.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 44602 thiourea CH4N2S 详情 详情
(II) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(III) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(III) 44603 ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate C8H11N3O3S 详情 详情
(IV) 10183 (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetic acid；2-(2-Amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid 66338-96-3 C5H5N3O3S 详情 详情
(IV) 44604 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid C5H5N3O3S 详情 详情
(V) 10184 1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol 2592-95-2 C6H5N3O 详情 详情
(VI) 10185 1-(2-Amino-1,3-thiazol-4-yl)-2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime C11H8N6O3S 详情 详情
(VI) 44605 1-(2-amino-1,3-thiazol-4-yl)-2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime C11H8N6O3S 详情 详情
(VII) 10186 (6R,7R)-7-amino-3-[(1-methyltetrahydro-1H-pyrrolium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H19N3O3S 详情 详情
(VIII) 10187 1-[((6R,7R)-7-[[2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methyltetrahydro-1H-pyrrolium C19H25N6O5S2 详情 详情
(VIII) 44606 1-[((6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium C19H25N6O5S2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VII)

The cyclization of ethyl 3-(3,4-ethylenedioxyphenyl)propionate (V), ethyl formate (VI) and thiourea (VII) by means of Na in ether and ethanol gives 5-(3,4-methylenedioxyphenyl)-2-thiouracil (VIII), which by reaction with methyl iodide and NaOH in ethanol-water is converted into 5-(3,4-methylenedioxybenzyl)-2-methylthio-4-pyrimidone (IX). Finally, this compound is condensed with (IV) by heating at 150 C.

参考文献 中间体
合成目标
【1】 Brown, T.H.; DE 2660563 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Oxmetidine hydrochloride. Drugs Fut 1982, 7, 10, 749.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 34071 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]-1-ethanamine; 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethylamine C7H13N3S 详情 详情
(V) 37083 ethyl 3-(1,3-benzodioxol-5-yl)propanoate C12H14O4 详情 详情
(VII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 37084 5-(1,3-benzodioxol-5-ylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10N2O3S 详情 详情
(IX) 37085 5-(1,3-benzodioxol-5-ylmethyl)-2-(methylsulfanyl)-4(1H)-pyrimidinone C13H12N2O3S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

Reaction of o-chlorobenzyl chloride (I) with thiourea (A) in refluxing ethanol affords the isothiourea hydrochloride (II), which is treated with chlorine gas in aqueous solution equal or lower at 10 C to afford the corresponding sulfonyl chloride (III). Exposure of (III) to liquid ammonia smoothly converts (III) to the sulfonamide (IV), which is converted to the sodium salt monohydrate with ethanolic sodium hydroxide.

参考文献 中间体
合成目标
【1】 Dubey, A.; Hall, I.H.; Wyrick, S.D.; Structure-activity studies on antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates and benzylsulfonamides. J Pharm Sci 1984, 73, 374-377.
【2】 Wyrick, S.D.; Hall, I.H.; o-Chlorobenzylsulfonamide Sodium Salt. Drugs Fut 1985, 10, 4, 277.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 10205 1-Chloro-2-(chloromethyl)benzene; 2-Chlorobenzyl chloride 611-19-8 C7H6Cl2 详情 详情
(II) 29105 1-([[amino(imino)methyl]sulfanyl]methyl)-2-chlorobenzene C8H9ClN2S 详情 详情
(III) 29106 (2-chlorophenyl)methanesulfonyl chloride C7H6Cl2O2S 详情 详情
(IV) 29107 (2-chlorophenyl)methanesulfonamide C7H8ClNO2S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(B)

The reaction of 7-beta-(D-5-phthalimido-5-carboxylvaleramido)-3-hydroxy-methyl-3-cephem-4-carboxylic acid (I) with diketene in CH2Cl2 gives the 3-(3-oxobutyryloxy)methyl derivative (II), which is treated with triethylamine-N,N-dimethylaniline, dimethyldichlososilane and PCl5 to obtain 7-beta-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (III).The acylation of (III) with 4-chloro-3-oxobutyryl chloride (A) and triethylamine in CH2Cl2 affords the amide (IV), which is condensed with thiourea (B) by means of NaHCO3 in acetone yielding the thiazole derivative (V). Finally, this compound is condensed with 5-mercapto-1-[2-(N,N-dimethylamino)ethyl-1H-tetrazole (VI) by means of NaHCO3 in hot water.

参考文献 中间体
合成目标
【1】 Tsushima, S.; et al. (Takeda Chemical Industries, Ltd.); Novel 3-acyloxymethyl-cephem compounds useful as intermediates for preparing cephalosporin antibiotics. DE 2607064; ES 459261; FR 2301528; GB 1544103; US 4245088 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(A) 15696 4-chloro-3-oxobutanoyl chloride C4H4Cl2O2 详情 详情
(I) 33220 (6R,7R)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C22H21N3O9S 详情 详情
(II) 33221 (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C26H25N3O11S 详情 详情
(III) 15748 (6R,7R)-3-[(acetoacetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C12H14N2O6S 详情 详情
(IV) 33222 (6R,7R)-3-[(acetoacetoxy)methyl]-7-[(4-chloro-3-oxobutanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H17ClN2O8S 详情 详情
(V) 33223 (6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H18N4O7S2 详情 详情
(VI) 33224 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 61607-68-9 C5H11N5S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(B)

The condensation of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (VII) with the mercaptane (VI) by means of NaHCO3 in hot water gives 7-beta-amino-3-[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (VIII), which is then condensed with 2-aminothiazol-4-ylacetic acid (IX) by means of N-hydroxysuccinimide and dicyclohexylcarbodiimide in THF. The free amino group of (VIII) is acylated with Cl2 and diketene giving the 4-chloro-3-oxobutyramido derivative (X), which is finally cyclized with thiourea (B) by means of NaHCO3 in acetone.

参考文献 中间体
合成目标
【1】 Numata, M.; et al. (Takeda Chemical Industries, Ltd.); 7-Alpha-(2-aminothiazole)acetamidocephalosporins. DE 2461478; FR 2255077; GB 1491018; NL 7416609; US 4080498; US 4421912; US 4517361 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Roberts, P.J.; Cefotiam. Drugs Fut 1979, 4, 6, 400.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 33224 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazole-5-thiol; 1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 61607-68-9 C5H11N5S 详情 详情
(VII) 33225 (6R,7R)-7-(acetoacetamido)-3-[(acetoxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H16N2O7S 详情 详情
(VIII) 33226 (6R,7R)-7-amino-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C13H19N7O3S2 详情 详情
(IX) 33228 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid C5H6N2O2S 详情 详情
(X) 33227 (6R,7R)-7-[(4-chloro-3-oxobutanoyl)amino]-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H22ClN7O5S2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(A)

The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water.

参考文献 中间体
合成目标
【1】 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17.
【2】 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 .
【3】 Ochiai, M.; et al. (Takeda Chemical Industries, Ltd.); Thiazolylacetamido cephasloporin type compounds. DE 2556736; ES 464772; FR 2294690; GB 1536283; NL 7514811; US 4098888 .
【4】 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(V) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VI) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(VII) 32659 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride 75532-64-8 C8H7Cl2N3O3S 详情 详情
(VIII) 32660 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H20N2O5S 详情 详情
(IX) 32661 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H26ClN5O8S2 详情 详情
(X) 32662 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C20H25N5O7S2 详情 详情
(XI) 29686 (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H17N5O7S2 详情 详情
(XII) 28420 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 13183-79-4 C2H4N4S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(A)

The condensation of (VII) or the free acid (VI) by means of pyridine or isobutyl chloroformate, respectively, with 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIII) gives 7-[alpha-(2-chloroacetylamidothiazol-4-yl)-alpha-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (XIV), which is finally desacylated with thiourea (A) and benzyltriethylammonium bromide as before.

参考文献 中间体
合成目标
【1】 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17.
【2】 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 .
【3】 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(VII) 32659 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride 75532-64-8 C8H7Cl2N3O3S 详情 详情
(XIII) 32663 (6R,7R)-7-amino-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 24209-38-9 C10H12N6O3S2 详情 详情
(XIV) 32664 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C18H18ClN9O6S3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

A new direct synthesis of thalidomide has been reported: Reaction of the commercially available N-phthaloyl-L-glutamic acid (I) with either urea (II) or thiourea (III) under microwave irradiation (1000 W output) provides thalidomide in 63 or 85% yield, respectively.

参考文献 中间体
合成目标
【1】 Vazquez-Tato, M.P.; Pacios-Lopez, B.; Martinez, M.M.; Gonzalez-Bando, C.; Seijas, J.A.; Microwave promoted synthesis of a rehabilitated drug: Thalidomide. Synthesis (Stuttgart) 2001, 7, 999.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54082 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioic acid 2301-52-2 C13H11NO6 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VIII)

The reaction of 2,3-dichlorobenzoic acid (I) with oxalyl chloride in dichloromethane gives the acyl chloride (II), which is condensed with labeled copper cyanide (III) by means of KI in refluxing xylene to yield the 2,3-dichlorobenzoyl cyanide (IV). The condensation of (IV) with labeled aminoguanidine (V) by means of sulfuric acid in acetonitrile/water affords adduct (VI), which is finally cyclized by refluxing under the conditions of the preceding reaction to provide the target labeled diaminotriazine. The intermediate labeled copper cyanide (III) has been obtained by reaction of CuSO4 with labeled potassium cyanide (VII) and Na2S2O5 in hot water. The intermediate labeled aminoguanidine (V) has been obtained by methylation of thiourea (VIII) with dimethyl sulfate in boiling water to give S-methylisothiourea (IX), which is finally treated with hydrazine (X) and NaOH in water.

参考文献 中间体
合成目标
【1】 Manning, C.O.; et al.; Synthesis of stable isotopically labelled versions of lamotrigine and its methylated metabolite. J Label Compd Radiopharm 2002, 45, 7, 611.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 24007 2,3-dichlorobenzoic acid 50-45-3 C7H4Cl2O2 详情 详情
(II) 24008 2,3-dichlorobenzoyl chloride 2905-60-4 C7H3Cl3O 详情 详情
(III) 56856 Copper (I) cyanide; Cuprous cyanide 544-92-3 CCuN 详情 详情
(III) 56861 cyanocopper CCuN 详情 详情
(IV) 24009 2-(2,3-dichlorophenyl)-2-oxoacetonitrile; 2,3-Dichlorobenzoylcyanide 77668-42-9 C8H3Cl2NO 详情 详情
(IV) 56862 2-(2,3-dichlorophenyl)-2-oxoacetonitrile C8H3Cl2NO 详情 详情
(V) 56857 　 CH6N4 详情 详情
(V) 56866 　 CH6N4 详情 详情
(VI) 56858 1,2-dichloro-3-{cyano[(Z)-2-(diaminomethylene)hydrazono]methyl}benzene C9H7Cl2N5 详情 详情
(VI) 56867 1,2-dichloro-3-{cyano[(Z)-2-(diaminomethylene)hydrazono]methyl}benzene C9H7Cl2N5 详情 详情
(VII) 56859 Potassium cyanide 151-50-8 CKN 详情 详情
(VII) 56860 cyanopotassium CKN 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 56863 thiourea CH4N2S 详情 详情
(IX) 10272 [[Amino(imino)methyl]sulfanyl]methane 2986-19-8 C2H6N2S 详情 详情
(IX) 56864 {[amino(imino)methyl]sulfanyl}methane C2H6N2S 详情 详情
(X) 27344 hydrazine 302-01-2 H4N2 详情 详情
(X) 56865 hydrazine H4N2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VI)

This compound can be obtained by three related ways: 1) The carboxylation of 3-ethoxy-4-pentyloxyiodobenzene (I) with CO2 and butyllithium in ether gives 3-ethoxy-4-pentyloxybenzoic acid (II), which is reduced with LiAlH4 in refluxing ether to yield the corresponding benzyl alcohol (III). The controlled oxidation of (III) with pyridinium chlorochromate in dichloromethane affords 3-ethoxy-4-pentyloxybenazldehyde (IV), which is treated wtih NaCN and acetic acid - water giving 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetonitrile (V). Finally, this compound is cyclized with thiourea (VI) and HCl in 2-methoxyethanol. 2) The alkylation of ethyl-vanilline (VII) with c and K2CO3 in hot DMF gives aldehyde (IV), which by reaction with NaCH in methanol - HCl yields the cyanohydrine (V). The reaction of (V) with SOCl2 in refluxing CHCl3 affords 2-chloro-2-(3-ethoxy-5-pentyloxyphenyl)acetonitrile (VIII), which is finally cyclized with thiourea (VI) in ethylene glycol monomethyl ether - HCl at 110 C in refluxing ethanol - HCl. 3) The cyclization of 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetic acid (IX) with thiourea (VI) under acidic conditions gives 5-(3-ethoxy-4-pentyloxyphenyl)-2-iminothiazolidin-4-one (X), which is then hydrolyzed to the desired product.

参考文献 中间体
合成目标
【1】 Awata, T.; Maenaka, T.; Kawamatsu, Y. (Senju Pharmaceuticals Co., Ltd.); Ophthalmic topical agent for remedy of diseases of iris and ciliary body. EP 0170237; JP 1986043114; US 4602026 .
【2】 Kawamatsu, Y.; Yamamoto, Y. (Senju Pharmaceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.); Thiazolidine derivs. and their production and use. EP 0033617 .
【3】 Imanishi, M.; Imamiya, E.; Kawamatsu, Y.; Hayashi, N.; Synthesis of 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-[5-14C]thiazolidinedione ([14C]CT-112). J Takeda Res Lab 1983, 42, 3/4, 238-40.
【4】 Tawada, H.; Mizuno, K.; Meguro, K.; Sohda, T.; Imamiya, E.; Kawamatsu, Y.; Yamamoto, Y.; Studies on antidiabetic agents. III. 5-Arylthiazolidine-2,4-diones as potent aldose reductase inhibitors. Chem Pharm Bull 1982, 30, 10, 3601-16.
【5】 Prous, J.; Castaner, J.; CT-112. Drugs Fut 1991, 16, 10, 895.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10398 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether C13H19IO2 详情 详情
(II) 10399 3-Ethoxy-4-(pentyloxy)benzoic acid C14H20O4 详情 详情
(III) 10400 [3-Ethoxy-4-(pentyloxy)phenyl]methanol C14H22O3 详情 详情
(IV) 10401 3-Ethoxy-4-(pentyloxy)benzaldehyde C14H20O3 详情 详情
(V) 10402 2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetonitrile C15H21NO3 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 10404 Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde 121-32-4 C9H10O3 详情 详情
(VIII) 10405 2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile C15H20ClNO2 详情 详情
(IX) 10406 2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetic acid C15H22O5 详情 详情
(X) 10407 5-[3-Ethoxy-4-(pentyloxy)phenyl]-2-imino-1,3-thiazolidin-4-one C16H22N2O3S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VIII)

The condensation of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (I) with 4-bromoacetoacetyl bromide (II) by means of trimethylsilylacetamide in ethyl acetate gives benzhydryl 7-(4-bromoaceto-acetamido)-3-vinyl-3-cephem-4-carboxylate (III), which by reaction with NaNO2 - acetic acid in dichloromethane and then with urea is converted to benzhydryl 7-[4-bromo-2-(hydroxyimino)acetoacetamido]-3-vinyl-3-cephem-4 carboxylate (IV). The cyclization of (IV) with thiourea in dimethylacetamide affords benzhydryl 7-[2-(2-aminothiazol-4-yl) (hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (V), which is finally hydrolyzed with trifluoroacetic acid - anisole as usual.

参考文献 中间体
合成目标
【1】 Kawabata, K.; Masugi, T.; Takaya, T.; Taksugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Syn-isomer of 7-substd.-3-vinyl-3-cephem cpds., pr. EP 0105459; ES 8600309; ES 8800235; US 4559334 .
【2】 Castaner, J.; Prous, J.; FK-482. Drugs Fut 1988, 13, 3, 224.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22001 benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O3S 详情 详情
(II) 15619 5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid C6H8O5S 详情 详情
(III) 22003 benzhydryl (6R,7R)-7-[(4-bromo-3-oxobutanoyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C26H23BrN2O5S 详情 详情
(IV) 22004 benzhydryl (6R,7R)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C26H22BrN3O6S 详情 详情
(V) 22005 benzhydryl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C27H23N5O5S2 详情 详情
(VI) 63021 N-(trimethylsilyl)acetamide 13435-12-6 C5H13NOSi 详情 详情
(VII) 19310 urea 57-13-6 CH4N2O 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The cyclization of p-methoxyacetophenone (I) with thiourea (II) by means of SO2Cl2 gives 4-(p-methoxyphenyl)-2-aminothiazole (III), which is then reacted with ethoxalyl chloride (IV) in presence of a base to afford F-1865.

参考文献 中间体
合成目标
【1】 Casadio, S.; Cousse, H.; Tarayre, J.P.; Mouzin, G. (Pierre Fabre SA.); 4-Phenyl-2-thiazolyloxamate derivs., method for their preparation and their application in the treatment of asthma. EP 0006368; ES 481633; FR 2429210; JP 55002684; US 4246271 .
【2】 Tarayre, J.P.; Bonnaud, B.; TIOXAMAST. Drugs Fut 1990, 15, 5, 469.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 11042 4-(4-Methoxy-phenyl)-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-ylamine; 4-(4-methoxyphenyl)-1,3-thiazol-2-amine 2104-04-3 C10H10N2OS 详情 详情
(IV) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

6-Chloronicotinic acid (I) is reacted with thiourea (II) to give 6-mercaptonicotinic acid (III) This is oxidized to the disulfide with iodine or hydrogen peroxide.

参考文献 中间体
合成目标
【1】 Grassetti, D.R.; et al.; The effects of some disulfides and thiols on the carbohydrate metabolism of Ehrlich ascites tumor. J Med Chem 1967, 10, 6, 1170.
【2】 Grassetti, D.R.; CPDS. Drugs Fut 1986, 11, 7, 559.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12996 6-Chloronicotinic acid 5326-23-8 C6H4ClNO2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 24687 6-sulfanylnicotinic acid C6H5NO2S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

This compound can be prepared in several different ways: 1) The reaction of benzhydryl bromide (I) with thiourea (II) in refluxing water gives diphenyl - methanethiol (III), which is condensed with chloroacetic acid (A) by means of NaOH in hot water yielding (benzhydrylthio)acetic acid (IV). The esterification of (IV) with ethanol and H2SO4 affords the corresponding ethyl ester (V), which is treated with hydroxylamine hydrochloride and KOH in methanol to give benzhydrylthioacetohydroxamic acid (VI). Finally, this compound is oxidized with H2O2 in acetic acid. 2) Compound (III) can also be obtained by reaction of benzhydrol (VII) with thiourea and aqueous 48% HBr at 100 C. 3) Compound (IV) can be oxidized with H2O2 in water to give benzhydrylsulfinylacetic acid (VIII), which is methylated with dimethyl sulfate and NaHCO3 in water to the corresponding methyl ester (IX). Finally, this compound is treated with hydroxylamine and NaOH in water

参考文献 中间体
合成目标
【1】 Lafon, L. (Laboratoires L. Lafon); New benzhydrysulphinyl derivatives. DE 2642511; FR 2326181; GB 1520812; JP 52046058; US 4066686 .
【2】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(I) 12079 Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 776-74-9 C13H11Br 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 32695 diphenylmethanethiol; benzhydrylhydrosulfide C13H12S 详情 详情
(IV) 11848 2-(Benzhydrylsulfanyl)acetic acid C15H14O2S 详情 详情
(V) 32696 ethyl 2-(benzhydrylsulfanyl)acetate C17H18O2S 详情 详情
(VI) 32697 2-(benzhydrylsulfanyl)-N-hydroxyacetamide 63547-44-4 C15H15NO2S 详情 详情
(VII) 11845 Diphenylmethanol; Benzhydrol 91-01-0 C13H12O 详情 详情
(VIII) 11851 2-(Benzhydrylsulfinyl)acetic acid C15H14O3S 详情 详情
(IX) 11852 methyl 2-(benzhydrylsulfinyl)acetate C16H16O3S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(III)

The bromination of 1-allylhexahydro-4H-azepin-4-one (I) with Br2 in acetic acid gives 1-allyl-5-bromohexahydro-4H-azepin-4-one (II), which is cyclized with thiourea (III) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Griss, G.; et al. (Boehringer Ingelheim GmbH); 2-Amino-4,5,7,8-tetrahydro-6H-thiazolo or oxazolo[5,4-d]azepines and salts. ES 396454; FR 2102192; GB 1321509; NL 7111176; US 3804849 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Thorpe, P.J.; B-HT-920. Drugs Fut 1980, 5, 10, 481.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32702 1-allyl-4-azepanone C9H15NO 详情 详情
(II) 32703 1-allyl-5-bromo-4-azepanone C9H14BrNO 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线21

该中间体在本合成路线中的序号：(V)

1) The methanolysis of 3-(acetoxymethyl)-7-[4-chloro-3-oxo-2(Z)-(methoxyimino)butyrylamidol-3-cephem-4-carboxylic acid (I) with methanol and NaHCO3 gives the corresponding 3-(methoxymethyl) derivative (II), which is esterified with 1-iodoethylisopropyl carbonate (III) by means of dicyclohexylamine in DMA to afford the corresponding ester (IV). Finally, this compound is cyclized with thiourea (V) and methyl iodide in a phosphate buffer.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 .
【2】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370.
【3】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
27347 N,N-dicyclohexylamine 101-83-7 C12H23N 详情 详情
(I) 21554 (6R,7R)-3-[(acetoxy)methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C15H16ClN3O8S 详情 详情
(II) 21555 (6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H16ClN3O7S 详情 详情
(III) 15685 1-iodoethyl isopropyl carbonate C6H11IO3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 21558 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C15H17N5O6S2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(V)

2) The free acid (II) can be cyclized with thiourea in a similar way as before to give 7-[2 (2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem 4-carboxylic acid (VI), which is finally esterified with the iodoester (III) as before.

参考文献 中间体
合成目标
【1】 Fujimoto, K.; Nakayama, E.; Nakao, H. (Sankyo Co., Ltd.); Process for preparing 3-alkoxymethylcephalosporin derivatives. DE 3244457 .
【2】 Castaner, J.; Serradell, M.N.; Cefpodoxime Proxetil. Drugs Fut 1988, 13, 1, 16.
【3】 Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M.; Studies on orally active cephalosporin esters. J Antibiot 1987, 40, 3, 370.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21554 (6R,7R)-3-[(acetoxy)methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C15H16ClN3O8S 详情 详情
(II) 21555 (6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H16ClN3O7S 详情 详情
(III) 15685 1-iodoethyl isopropyl carbonate C6H11IO3 详情 详情
(IV) 21559 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C20H26ClN3O10S 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IV)

The condensation of 7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid (II) by means of PCl5 and HMDS in dichloromethane gives the butyramide (III), which is cyclized with thiourea (IV) by means of Na-OAc in water to yield the thiazol derivative (IV). Finally, the carboxy group of (IV) is esterified with 1-iodoethyl isopropyl carbonate (VI) by means of DBU in DMA to afford the target cefpodoxime proxetil.

参考文献 中间体
合成目标
【1】 Kumar, Y.; Nizar, H.; Tewari, N.; Rai, B.P.; Aryan, R.C. (Ranbaxy Laboratories Ltd.); Process for the preparation of cefpodoxime acid. WO 0283634 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 43811 (6R,7R)-7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C9H12N2O4S 详情 详情
(II) 58114 4-bromo-2-(methoxyimino)-3-oxobutanoic acid;(Z)-4-bromo-2-(methoxyimino)-3-oxobutanoic acid C5H6BrNO4 详情 详情
(III) 58115 (6R,7R)-7-{[4-bromo-2-(methoxyimino)-3-oxobutanoyl]amino}-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H16BrN3O7S 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 21558 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C15H17N5O6S2 详情 详情
(VI) 58116 isopropyl 3-iodobutanoate C7H13IO2 详情 详情

合成路线24

该中间体在本合成路线中的序号：

Synthesis of intermediate (I): 1a) Dimethyl acetonedicarboxylate (IV) is treated with MgCl2 and triethylamine, giving the corresponding magnesium complex (V), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (VI). The reduction of (VI) with NaBH4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (VII), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the OH group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (VIII). The hydrolysis of (VIII) with aqueous NaOH in toluene gives the corresponding diacid (IX), which is selectively esterified with benzyl alcohol in acidic medium yielding (I). 1b) The reaction of methyl 2-(2-aminothiazol-4-yl)acetate (X) with beozyloxycarbonyl chloride and NaHCO3 gives the protected compound (XI), which is condensed with methyl 3-methoxyacrylate (XII) by means of sodium methoxide in DMF to yield dimethyl ester (VIII), already obtained.

参考文献 中间体
合成目标
【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(IV) 22692 dimethyl 3-oxopentanedioate 1830-54-2 C7H10O5 详情 详情
(V) 22693 Bis(3-Hydroxy-2-pentenoic acid dimethyl ester) magnesium salt C14H18MgO10 详情 详情
(VI) 22694 dimethyl (E)-2-(2-amino-1,3-thiazol-4-yl)-3-hydroxy-2-pentenedioate C10H12N2O5S 详情 详情
(VII) 22695 dimethyl 2-(2-amino-1,3-thiazol-4-yl)-3-hydroxypentanedioate C10H14N2O5S 详情 详情
(VIII) 22696 dimethyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C18H18N2O6S 详情 详情
(IX) 22697 (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioic acid C16H14N2O6S 详情 详情
(X) 22698 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate 64987-16-2 C6H8N2O2S 详情 详情
(XI) 22699 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate C14H14N2O4S 详情 详情
(XII) 22700 methyl (E)-3-methoxy-2-propenoate 34846-90-7 C5H8O3 详情 详情

合成路线25

该中间体在本合成路线中的序号：

Synthesis of intermediate (I): 1c) The bromination of diketene (XIII) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (XIV), which by cyclization with thiourea by means of K2CO3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (XV). The reaction of (XV) with benzyloxycarbonyl chloride and pyridine affords the protected compound (XVI), which is formylated with diphenyl methyl formiate (XVII) and NaH to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (XVIII) The Wittig condensation of (XVIII) with benzyl triphenylphosphoranylidene acetate (XIX) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (XX), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.

参考文献 中间体
合成目标
【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(XIII) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(XIV) 22715 benzhydryl 4-bromo-3-oxobutanoate C17H15BrO3 详情 详情
(XV) 22716 benzhydryl 2-amino-1,3-thiazole-4-carboxylate C17H14N2O2S 详情 详情
(XVI) 22717 benzhydryl 2-[[(benzyloxy)carbonyl]amino]-1,3-thiazole-4-carboxylate C25H20N2O4S 详情 详情
(XVII) 22718 benzhydryl formate C14H12O2 详情 详情
(XVIII) 22719 benzhydryl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-hydroxy-2-propenoate C27H22N2O5S 详情 详情
(XIX) 22668 benzyl 2-(triphenylphosphoranylidene)acetate C27H23O2P 详情 详情
(XX) 22721 1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C36H30N2O6S 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

This compound can be obtained by two related ways: 1) The condensation of benzhydrol (I) with chloroacetic acid (II) by means of thiourea (III) in concentrated hydrobromic acid at 95 C gives 2-(diphenylmethylthio)acetic acid (IV), which by reaction with SOCl2 in refluxing benzene is converted into the acid chloride (V). The reaction of (V) with ammonium hydroxide in water - methylene chloride affords 2-(diphenylmethylthio)acetamide (VI), which is finally oxidized with hydrogen peroxide. 2) Acid (IV) can also be oxidized with hydrogen peroxide to give 2-(diphenylmethylsulfinyl)acetic acid (VII), which is methylated with dimethylsulfate and NaHCO3 to the corresponding methyl ester (VIII). Finally, this compound is treated with ammonia in anhydrous methanol.

参考文献 中间体
合成目标
【1】 Lafon, L. (Laboratoires L. Lafon); Acetamide derivs. DE 2809625; FR 2385693; US 4177290 .
【2】 Prous, J.; Castaner, J.; MODAFINIL. Drugs Fut 1990, 15, 2, 130.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11845 Diphenylmethanol; Benzhydrol 91-01-0 C13H12O 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(IV) 11848 2-(Benzhydrylsulfanyl)acetic acid C15H14O2S 详情 详情
(V) 11849 2-(Benzhydrylsulfanyl)acetyl chloride C15H13ClOS 详情 详情
(VI) 11850 2-(Benzhydrylsulfanyl)acetamide C15H15NOS 详情 详情
(VII) 11851 2-(Benzhydrylsulfinyl)acetic acid C15H14O3S 详情 详情
(VIII) 11852 methyl 2-(benzhydrylsulfinyl)acetate C16H16O3S 详情 详情

合成路线27

该中间体在本合成路线中的序号：(II)

This compound can be obtained in two related ways: 1) The cyclization of 4-acetamidocyclohexanone (I) with thiourea (II) by means of Br2 in hot acetic acid gives 6-acetamido-2-amino-4,5,6,7-tetrahydrobenzothiazole (III), which by hydrolysis with refluxing aqueous HBr yields racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (racemic IV). Optical resolution with L-(+)-tartaric acid affords the (S)-(-)-isomer (IV), which is finally treated with propionaldehyde and LiBH4. 2) The reaction of 4-aminocyclohexanol (V) with phthalic anhydride (VI) in toluene gives the phthalimido derivative (VII), which is oxidized with potassium dichromate - H2SO4 to the corresponding cyclohexanone (VIII). The cyclization of (VIII) with thiourea (II) and Br2 as before affords 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole (IX), which is deprotected with hydrazine in refluxing ethanol yielding racemic (IV), already obtained.

参考文献 中间体
合成目标
【1】 Griss, G. et al. (Dr. Karl Thomae GmbH); Tetrahydrobenzothiazoles, their preparation and their use as intermediates or as medicines. AU 8551544; DE 3447075; DE 3508947; EP 0186087; ES 8707513; ES 8707514; ES 8707515; JP 1986155377; US 4731374 .
【2】 Schneider, C.S.; Mierau, J.; J. Dopamine autoreceptor agonists: Resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine. J Med Chem 1987, 30, 3, 494.
【3】 De Angelis, L.; Pramipexole Hydrochloride. Drugs Fut 1992, 17, 4, 291.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11895 N-(4-Oxocyclohexyl)acetamide 27514-08-5 C8H13NO2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 11897 N-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)acetamide 104617-51-8 C9H13N3OS 详情 详情
(IV) 11898 (6S)-2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-ylamine; (6S)-4,5,6,7-Tetrahydro-1,3-benzothiazole-2,6-diamine C7H11N3S 详情 详情
(V) 11899 4-Aminocyclohexanol; trans-4-Aminocyclohexanol 27489-62-9 C6H13NO 详情 详情
(VI) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(VII) 11901 2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione 104618-31-7 C14H15NO3 详情 详情
(VIII) 11902 2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione C14H13NO3 详情 详情
(IX) 11903 2-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)-1H-isoindole-1,3(2H)-dione C15H13N3O2S 详情 详情

合成路线28

该中间体在本合成路线中的序号：(A)

The bromination of 2'-deoxyadenosine (VIII) with Br2 in dioxane - water by means of CaCO3 or sodium acetate gives 8-bromo-2'-deoxyadenosine (IX), which by reaction with triphenylmethyl chloride in pyridine - DMF is converted into 8-bromo-2'-deoxy-5'-O-triphenylmethyladenosine (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords 8-bromo-5'-O-triphenylmethyl-3'-O-(p-toluenesulfonyl)-2'-deoxyadenosine (XI), which by reaction with thiourea (A) in refluxing butanol and treatment with propanol-ammonia-water is converted into 2',3'-dideoxy-8-mercapto-8,3'-anhydroadenosine (XII). Finally, this compound is desulfurized by treatment with Raney-Ni in refluxing water.

参考文献 中间体
合成目标
【1】 Morio, I.; Masakatsu, K.; Nucleosides and nucleotides. XLIV. Purine cyclonucleosides. 2. Synthesis of cyclonucleosides having 8,3'-O- and -S-anhydro linkage derived from 2'-deoxyadenosine. Chem Pharm Bull 1970, 18, 12, 2441-46.
【2】 Castaner, J.; Hopkins, S.J.; Serradell, M.N.; Blancafort, P.; 2',3'-Dideoxyadenosine. Drugs Fut 1982, 7, 4, 244.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 18061 (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol 958-09-8 C10H13N5O3 详情 详情
(IX) 36386 (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol C10H12BrN5O3 详情 详情
(X) 36387 (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanol C29H26BrN5O3 详情 详情
(XI) 36388 (2R,3S,5R)-5-(6-amino-8-bromo-9H-purin-9-yl)-2-[(trityloxy)methyl]tetrahydro-3-furanyl 4-methylbenzenesulfonate C36H32BrN5O5S 详情 详情
(XII) 36389 [(1S,12S,13R)-7-amino-14-oxa-11-thia-2,4,6,9-tetraazatetracyclo[10.2.1.0(2,10).0(3,8)]pentadeca-3,5,7,9-tetraen-13-yl]methanol C10H11N5O2S 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IV)

The methylation of ethyl 2-(hydroxyimino)-3-oxobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 2-(methoxyimino)-3-oxobutyrate (II), which is brominated with Br2 in CHCl3 yielding ethyl 4-bromo-2-(methoxyimino)-3-oxobutyrate (III). The cyclization of (III) with thiourea (IV) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (V), which is acylated with chloroacetyl chloride (VI) in DMA to give the corresponding N-chloroacetyl derivative (VII). The hydrolysis of (VII) with KOH in ethanol-water affords 2-(2-chloroacetamidothiazol-4-yl)-2-(methoxyimino)acetic acid (VIII), which is condensed with desacetoxycephalosporanic acid (IX) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) in THF yielding 7beta-[2-(2-chloroacetamidothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]desacetoxycephalosporanic acid (X). The deprotection of (X) with sodium acetate in THF gives the free acid (XI), which is finally esterified with pivaloyloxymethyl bromide (XII) by means of NaHCO3 in ethyl acetate-DMSO.

参考文献 中间体
合成目标
【1】 Ochiai, M.; Morimoto, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Cephalosporin derivatives, process for their preparation and medicines containing them. DE 2715385 .
【2】 Nakao, H.; Sugawara, S. (Sankyo Co., Ltd.); Cephalosporin derivatives for oral administration. DE 3020625 .
【3】 Prous, J.; Castaner, J.; CEFETAMET PIVOXIL < Prop INNM >. Drugs Fut 1989, 14, 5, 420.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VIII) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(IX) 20861 (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ADCA 22252-43-3 C8H10N2O3S 详情 详情
(X) 20862 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H16ClN5O6S2 详情 详情
(XI) 20863 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H15N5O5S2 详情 详情
(XII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情

合成路线30

该中间体在本合成路线中的序号：(II)

The reaction of 3-(chloromethyl)pyridine (I) with thiourea (II) in ethanol gives S-(3-pyridylmethyl)isothiourea (III), which is condensed with 4-chlorobutyl bromide (IV) by means of NaOH in dichloromethane to yield 3-(4-chlorobutylsulfanylmethyl)pyridine (V). The careful oxidation of (V) with MCPBA in dichloromethane affords the corresponding sulfoxide (VI), which is cyclized by means of potassium tert-butoxide in THF, providing a mixture of cis- and trans-2-(3-pyridyl)tetrahydrothiopyran S-oxide (VII + VIII). This mixture can be separated by conventional methods; however, when this mixture (VII + VIII), or either (VII) or (VIII) separately, are treated with NaNH2 and methyl isothiocyanate, only the target (1RS,2RS)-compound is obtained. Alternatively, the mixture (VII + VIII) or either (VII) or (VIII) can also be treated with potassium tert-butoxide, CS2 and methyl iodide to yield the (1RS,2RS)-dithioester (IX), which is finally converted into the target compound by reaction with methylamine.

参考文献 中间体
合成目标
【1】 Aloup, J.C.; Farge, D.; James, C.; Mondot, S.; Cavero, I.; 2-(3-PYRIDYL)-TETRAHYDROTHIOPYRAN-2-CARBOTHIOAMIDE DERIVATIVES AND ANALOGUES: A NOVEL FAMILY OF POTENT POTASSIUM CHANNEL OPENERS. Drugs Fut 1990, 15, 11, 1097.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 44408 3-([[amino(imino)methyl]sulfanyl]methyl)pyridine C7H9N3S 详情 详情
(IV) 16141 1-bromo-4-chlorobutane 6940-78-9 C4H8BrCl 详情 详情
(V) 44409 4-chlorobutyl 3-pyridinylmethyl sulfide; 3-[[(4-chlorobutyl)sulfanyl]methyl]pyridine C10H14ClNS 详情 详情
(VI) 44410 3-[[(4-chlorobutyl)sulfinyl]methyl]pyridine; 4-chlorobutyl 3-pyridinylmethyl sulfoxide C10H14ClNOS 详情 详情
(VII) 44412 (2R)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2H)-one C10H13NOS 详情 详情
(VIII) 44411 (2R)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2H)-one C10H13NOS 详情 详情
(IX) 44413 methyl (2S)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate C12H15NOS3 详情 详情

合成路线31

该中间体在本合成路线中的序号：(X)

The synthesis of metabolites M-III, M-IV and M-V of pioglitazone has been reported: a) Synthesis of metabolite M-IV: The reduction of 5-acetyl-2-methylpyridine (I) with NaBH4 in cooled ethanol gives the corresponding 1-hydroxyethyl derivative (II), which is protected with chloromethyl methyl ether and NaH in DMF yielding the methoxymethyl ether (III). The hydroxymethylation of (III) with aqueous formaldehyde at 150-60 C affords the ethanol (IV), which is condensed with 4-fluoronitrobenzene (V) by means of NaH in cooled DMF giving 5-[1-(methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine (VI). The reduction of the nitro group of (VI) with H2 over Pd/C in ethyl acetate yields the corresponding amino compound (VII), which is diazotized with NaNO2 in aqueous HBr and condensed with methyl acrylate (VIII) by means of Cu2O to afford the 2-bromopropionate derivative (IX). The cyclization of (IX) with thiourea (X) by means of sodium acetate in refluxing ethanol gives the intermediate iminothiazolidinone (XI), which without isolation, is treated with refluxing 2N HCl to give metabolite M-IV. b) Synthesis of metabolite M-III: By oxidation of metabolite M-IV with the pyridine.sulfur trioxide complex in ethanol/dichloromethane/triethylamine

参考文献 中间体
合成目标
【1】 Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
M-IV 63861 5-(4-{2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy}benzyl)-1,3-thiazolidine-2,4-dione C19H20N2O4S 详情 详情
M-III 63862 5-{4-[2-(5-acetyl-2-piperidinyl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione C19H24N2O4S 详情 详情
(I) 14149 1-(6-Methyl-3-pyridinyl)-1-ethanone C8H9NO 详情 详情
(II) 14150 1-(6-Methyl-3-pyridinyl)-1-ethanol C8H11NO 详情 详情
(III) 14151 5-[1-(Methoxymethoxy)ethyl]-2-methylpyridine; Methoxymethyl 1-(6-methyl-3-pyridinyl)ethyl ether C10H15NO2 详情 详情
(IV) 14152 2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]-1-ethanol C11H17NO3 详情 详情
(V) 14153 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene 350-46-9 C6H4FNO2 详情 详情
(VI) 14154 2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethyl 4-nitrophenyl ether; 5-[1-(Methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine C17H20N2O5 详情 详情
(VII) 14155 4-(2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)aniline; 4-(2-[5-[1-(Methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)phenylamine C17H22N2O3 详情 详情
(VIII) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(IX) 14157 methyl 2-bromo-3-[4-(2-[5-[1-(methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)phenyl]propanoate C21H26BrNO5 详情 详情
(X) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XI) 14159 2-Imino-5-[4-(2-[5-[1-(methoxymethoxy)ethyl]-2-pyridinyl]ethoxy)benzyl]-1,3-thiazolan-4-one C21H25N3O4S 详情 详情

合成路线32

该中间体在本合成路线中的序号：(X)

c) Synthesis of metabolite M-V: The reduction of 6-methylpyridine-3-carboxylic acid methyl ester (XII) with LiAlH4 in THF gives the corresponding hydroxymethyl derivative (XIII), which is protected with chloromethyl methyl ether as before yielding the methoxymethoxymethyl compound (XIV). Hydroxymethylation of (XIV) with formaldehyde as described affords the ethanol derivative (XV), which is condensed with 4-fluoronitrobenzene (V) as before giving 5-(hydroxymethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (XVI). The deprotection of (XVI) with HCl in refluxing methanol yields the hydroxymethyl compound (XVII), which is treated with SOCl2 in refluxing chloroform to afford the chloromethyl compound (XVIII). The reaction of (XVIII) with KCN in hot DMF gives the corresponding cyanomethyl derivative (XIX), which by reduction of the NO2 group with H2 over Pd/C in ethyl acetate yields the amino derivative (XX). The diazotation of (XX) with NaNO2 in aqueous HBr followed by condensation with methyl acrylate as before affords the 2-bromopropionate (XXI), which is cyclized with thiourea (X) as reported to give iminothiazolidinone derivative (XXII). Finally, the hydrolysis of the cyano gives Metabolite M-V.

参考文献 中间体
合成目标
【1】 Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
M-V 63863 2-[6-(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-3-pyridinyl]acetic acid C19H18N2O5S 详情 详情
(V) 14153 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene 350-46-9 C6H4FNO2 详情 详情
(VIII) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(X) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XII) 14160 methyl 6-methylnicotinate 5470-70-2 C8H9NO2 详情 详情
(XIII) 14161 (6-Methyl-3-pyridinyl)methanol C7H9NO 详情 详情
(XIV) 14162 Methoxymethyl (6-methyl-3-pyridinyl)methyl ether; 5-[(Methoxymethoxy)methyl]-2-methylpyridine C9H13NO2 详情 详情
(XV) 14163 2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]-1-ethanol C10H15NO3 详情 详情
(XVI) 14164 5-[(Methoxymethoxy)methyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-[5-[(Methoxymethoxy)methyl]-2-pyridinyl]ethyl 4-nitrophenyl ether C16H18N2O5 详情 详情
(XVII) 14165 [6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]methanol C14H14N2O4 详情 详情
(XVIII) 14166 2-[5-(Chloromethyl)-2-pyridinyl]ethyl 4-nitrophenyl ether; 5-(Chloromethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine C14H13ClN2O3 详情 详情
(XIX) 14167 2-[6-[2-(4-Nitrophenoxy)ethyl]-3-pyridinyl]acetonitrile C15H13N3O3 详情 详情
(XX) 14168 2-[6-[2-(4-Aminophenoxy)ethyl]-3-pyridinyl]acetonitrile C15H15N3O 详情 详情
(XXI) 14169 methyl 2-bromo-3-(4-[2-[5-(cyanomethyl)-2-pyridinyl]ethoxy]phenyl)propanoate C19H19BrN2O3 详情 详情
(XXII) 14170 2-[6-(2-[4-[(2-Imino-4-oxo-1,3-thiazolan-5-yl)methyl]phenoxy]ethyl)-3-pyridinyl]acetonitrile C19H18N4O2S 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VII)

The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluoronitrobenzene (II) by means of NaH in DMF gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (III), which is reduced with H2 over Pd/C in methanol to yield the corresponding aniline (IV). The reaction of (IV) with NaNO2/HBr and methyl acrylate (V) in acetone/methanol affords the 2-bromopropionate derivative (VI), which is cyclized with thiourea (VII) by means of NaOAc in refluxing ethanol to provide the 2-imino-4-thiazolidinone (VIII). Finally, this compound is hydrolyzed with refluxing 2N HCl.

参考文献 中间体
合成目标
【1】 Meguro, K.; Fujita, T. (Takeda Chemical Industries, Ltd.); Thiazolidinedione derivs., their production and use. EP 0193256; ES 8705886; JP 1986267580; US 4687777 .
【2】 Sohda, T.; Momose, Y.; Meguro, K.; Kawamatsu, Y.; Sugiyama, Y.; Ikeda, H.; Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneim-Forsch Drug Res 1990, 40, 1, 37.
【3】 Prous, J.; Castaner, J.; PIOGLITAZONE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1990, 15, 11, 1080.
【4】 Meguro, K.; Momose, Y.; Sohda, T.; Oi, S.; Ikeda, H.; Hatanaka, C.; Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds. Chem Pharm Bull 1991, 39, 6, 1440-5.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14139 2-(5-Ethyl-2-pyridinyl)-1-ethanol 5223-06-3 C9H13NO 详情 详情
(II) 14153 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene 350-46-9 C6H4FNO2 详情 详情
(III) 62867 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-(5-ethyl-2-pyridinyl)ethyl 4-nitrophenyl ether C15H16N2O3 详情 详情
(IV) 62868 4-[2-(5-ethyl-2-pyridinyl)ethoxy]aniline; 4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenylamine C15H18N2O 详情 详情
(V) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(VI) 62869 methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}propanoate C19H22BrNO3 详情 详情
(VII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 62870 5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-2-imino-1,3-thiazolidin-4-one C19H21N3O2S 详情 详情

合成路线34

该中间体在本合成路线中的序号：(I)

Treatment of thiourea (I) with iodomethane provided S-methylthiouronium iodide (II). This was further condensed with N-methylpiperazine (III) to afford the intermediate piperazine-1-carboxamidine (IV)

参考文献 中间体
合成目标
【1】 Miller, A.A.; Nobbs, M.S.; Hyde, R.M.; Leach, M.J. (Glaxo Wellcome plc); Pharmacologically active CNS cpds.. AU 8945964; EP 0372934; EP 0713703; EP 0715851; EP 0727212; EP 0727213; EP 0727214; JP 1990202876; US 5587380; US 5597828; US 5635507; US 5684005 .
【2】 Patel, R.; Packham, T.W.; Germain, A.L.; Barras, J.R.; Milne, D.J. (GlaxoSmithKline plc); Process of preparing 2,3,5-trihalobenzaldehyde. WO 9507877 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(II) 62329 　 C3H10N2S 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 62330 　 C7H18N4 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XII)

3) The condensation of 4-chloro-2(Z)-(methoxyimino)-3-oxobutyric acid (IX) with 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylate (X) by means of POCl3 in DMF gives the corresponding acetamide (XI), which is then cyclized with thiourea by means of sodium acetate in water to obtain compound (VII). Finally, this compound is treated with H2SO4 to give FK-037.

参考文献 中间体
合成目标
【1】 Sakane, K.; Kawabata, K.; Ohki, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of cephalosporin cpd. JP 1992173792 .
【2】 Prous, J.; Graul, A.; Castaner, J.; FK-037. Drugs Fut 1994, 19, 4, 325.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 15075 (6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C19H22N8O6S2 详情 详情
(IX) 15077 4-chloro-2-(methoxyimino)-3-oxobutyric acid C5H6ClNO4 详情 详情
(X) 15078 (6R,7R)-7-amino-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H17N5O4S 详情 详情
(XI) 15079 (6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H21ClN6O7S 详情 详情
(XII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线36

该中间体在本合成路线中的序号：(XXIV)

2) The condensation of 7-(formamido)-3-(hydroxymethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XV) with trichloromethyl chloroformate and dimethylamine in THF gives the corresponding dimethylcarbamoyloxy derivative (XVI), which is hydrolyzed with trifluoroacetic acid and anisole to the corresponding acid (as Na salt) (XVII). The esterification of (XVII) with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF as before affords the corresponding ester (XVIII), which is deformylated with HCl in methanol/THF to the 7-amino derivative (XIX). The acylation of (XIX) with 4-bromo-3-oxobutyryl bromide (XX) (obtained from diketene (XXI) with Br2) by means of bis(trimethylsilyl)acetamide in dichloromethane affords the 7-(4-bromo-3-oxobutyramido)-derivative (XXII), which is treated with NaNO2 and acetic acid to obtain the hydroxyimino compound (XXIII). Finally, this compound is cyclized with thiourea in dimethylacetamide. 3) The 7-amino cephem derivative (XIX) can also be acylated with 4-chloro-3-oxobutyryl chloride (XXV) (obtained from diketene (XXI) with Cl2) to yield the 7-(4-chloro-3-oxobutyramido)-derivative (XXVI), which is treated with amyl nitrite and acetyl chloride to afford the hydroxyimino compound (XXVII). Finally, this compound is cyclized with thiourea as before.

参考文献 中间体
合成目标
【1】 Negi, S.; et al.; Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins. J Antibiot 1994, 47, 12, 1507-25.
【2】 Fromtling, R.A.; Castaner, J.; E-1101. Drugs Fut 1995, 20, 8, 766.
【3】 Negi, S.; Yamanaka, M.; Katsu, K.; Sugiyama, I.; Komatu, Y.; Kamata, A.; Tsuruoka, A.; Machida, Y. (Eisai Co., Ltd.); 7-Acyl-3-(substd. carbamoyloxy)cephem cpds., use thereof and process for their preparation. EP 0484966; EP 0761671; JP 1992178392; JP 1992282388; JP 1993311173; JP 1993311174; JP 1994092969; JP 1998067784; US 5559225; US 5587473; US 5604217 .
【4】 Negi, S.; Yamanaka, M.; Sugiyama, I.; et al.; E1101, a new oral cephalosporin: I. Synthesis and structure-activity relations of 3-substituted carbamoyloxymethyl cephems. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 894.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
42918 Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene 503-38-8 C2Cl4O2 详情 详情
(XIV) 15685 1-iodoethyl isopropyl carbonate C6H11IO3 详情 详情
(XV) 15686 benzhydryl 7-(formylamino)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O5S 详情 详情
(XVI) 64676 diphenylmethyl 3-({[(dimethylamino)carbonyl]oxy}methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C25H25N3O6S 详情 详情
(XVII) 15687 7-(Formamido)-3-(N,N-dimethylcarbamoyloxy)-3-cephem-4-carboxylic acid sodium salt C12H14N3NaO6S 详情 详情
(XVIII) 15689 1-[(isopropoxycarbonyl)oxy]ethyl 3-([[(dimethylamino)carbonyl]oxy]methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H25N3O9S 详情 详情
(XIX) 15690 1-[(isopropoxycarbonyl)oxy]ethyl 7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H25N3O8S 详情 详情
(XX) 15691 4-bromo-3-oxobutanoyl bromide C4H4Br2O2 详情 详情
(XXI) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(XXII) 15693 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-bromo-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28BrN3O10S 详情 详情
(XXIII) 64677 1-({[(1-methylethyl)oxy]carbonyl}oxy)ethyl 7-{[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino}-3-({[(dimethylamino)carbonyl]oxy}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27BrN4O11S 详情 详情
(XXIV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXV) 15696 4-chloro-3-oxobutanoyl chloride C4H4Cl2O2 详情 详情
(XXVI) 15697 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-chloro-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28ClN3O10S 详情 详情
(XXVII) 15698 1-[(isopropoxycarbonyl)oxy]ethyl 7-[[4-chloro-2-(hydroxyimino)-3-oxobutanoyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27ClN4O11S 详情 详情

合成路线37

该中间体在本合成路线中的序号：(V)

The synthesis of [14C]-labeled E-1101 has been reported: (6R,7R)-7-Amino-3-(N,N-dimethylcarbamoyloxymethyl)-3-cephem-4-carboxyli c acid 1-(isopropoxycarbonyloxy)ethyl ester (I) is a diastereomeric mixture (Ia and Ib) due to the asymmetric carbon in the ester group. These isomers are separated by crystallization in THF and submitted separately to the following reaction sequence: The reaction of (Ia) and (Ib) with diketene (II) and Br2 gives the 4-bromo-3-oxobutyrylamides (IIIa and IIIb), which by oxidation with acetyl chloride and butylnitrite in dichloromethane yield the hydroxyimino derivatives (IVa and IVb). The cyclization of (IVa) and (IVb) with [14C]-labeled thiourea (V) in dimethylacetamide affords the two labeled diastereomeric E-1101 compounds (VIa and VIb), which are finally mixed equimolecularly to obtain the labeled E-1101 racemic at the ester group.

参考文献 中间体
合成目标
【1】 Uemura, Y.; Komatsu, Y.; Negi, S.; Tsuruoka, A.; Synthesis of a radiolabelled new oral cephalosporin, E1101. J Label Compd Radiopharm 1996, 38, 1, 1.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Ia) 15699 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H25N3O8S 详情 详情
(Ib) 15700 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7S)-7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H25N3O8S 详情 详情
(IIIa) 15702 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[(4-bromo-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28BrN3O10S 详情 详情
(IIIb) 15703 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7S)-7-[(4-bromo-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28BrN3O10S 详情 详情
(IVa) 15704 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27BrN4O11S 详情 详情
(IVb) 15705 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7S)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27BrN4O11S 详情 详情
(VIa) 15707 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H28N6O10S2 详情 详情
(VIb) 15708 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7S)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H28N6O10S2 详情 详情
(VIa) 45262 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H28N6O10S2 详情 详情
(VIb) 45263 1-[(isopropoxycarbonyl)oxy]ethyl (6R,7S)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H28N6O10S2 详情 详情
(II) 15701 2,4-oxetanedione C3H2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线38

该中间体在本合成路线中的序号：(IX)

The esterification of indole-2-carboxylic acid (I) with benzyl alcohol and CDI gives the corresponding benzyl ester (II), which is alkylated with methyl bromoacetate (III) by means of NaH in DMF yielding 1-(methoxycarbonylmethyl)-1H-indole-2-carboxylic acid benzyl ester (IV). The debenzylation of (IV) with H2 over Pd/C in ethanol/DMF affords the free acid (V), which is condensed with 4-(2-chlorophenyl)thiazol-2-amine (VI) by means of benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in DMF to give the carboxamide (VII). Finally, the ester group of (VII) is hydrolyzed with NaOH or KOH in methanol/water.

参考文献 中间体
合成目标
【1】 Bras, J.-P.; Frehel, D.; Gully, D.; Valette, G. (Sanofi-Synthélabo ); Heterocyclic derivs. of acylaminothiazole, their preparation and pharmaceutical compsns. containing them. EP 0432040; FR 2655344; FR 2661677; JP 1991279374; JP 1998130147; US 5189049 .
【2】 Radisson, J. (Sanofi-Synthelabo ); Method for preparing lintitript potassium salt. FR 2781227; WO 0005233 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(I) 25226 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid 1477-50-5 C9H7NO2 详情 详情
(II) 34572 benzyl 1H-indole-2-carboxylate C16H13NO2 详情 详情
(III) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(IV) 34573 benzyl 1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate C19H17NO4 详情 详情
(V) 34574 1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylic acid C12H11NO4 详情 详情
(VI) 34575 4-(2-chlorophenyl)-1,3-thiazol-2-ylamine; 4-(2-chlorophenyl)-1,3-thiazol-2-amine C9H7ClN2S 详情 详情
(VII) 34576 methyl 2-[2-([[4-(2-chlorophenyl)-1,3-thiazol-2-yl]amino]carbonyl)-1H-indol-1-yl]acetate C21H16ClN3O3S 详情 详情
(VIII) 34577 2-bromo-1-(2-chlorophenyl)-1-ethanone C8H6BrClO 详情 详情
(IX) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线39

该中间体在本合成路线中的序号：(XII)

The condensation of ethyl 2-bromo-3-methylbutyrate (IX) with phenylacetonitrile (X) by means of activated Zn in THF gives the ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (XI), which is cyclized with thiourea (XII) by means of sodium ethoxide in refluxing ethanol yielding 6-benzyl-5-isopropyl-2-thioracil (XIII). The desulfurization of (XIII) with a refluxing solution of 10% chloroacetic acid in water affords the corresponding uracil (XIV), which is finally alkylated with chloromethyl ethyl ether (II) and BSA in chloroform.

参考文献 中间体
合成目标
【1】 Larsen, D.K.; et al.; Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem 1996, 39, 12, 2427.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 13149 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether 3188-13-4 C3H7ClO 详情 详情
(IX) 27032 2-Bromoisovalerianic acid ethyl ester; ethyl 2-bromo-3-methylbutanoate 609-12-1 C7H13BrO2 详情 详情
(X) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(XI) 27033 ethyl 2-isopropyl-3-oxo-4-phenylbutanoate C15H20O3 详情 详情
(XII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XIII) 27034 6-benzyl-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C14H16N2OS 详情 详情
(XIV) 27035 6-benzyl-5-isopropyl-2,4(1H,3H)-pyrimidinedione C14H16N2O2 详情 详情

合成路线40

该中间体在本合成路线中的序号：

The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII), which is condensed with benzothiazolone (VIII) by means of DCC, HOBT and triethylamine in DMF yielding the correponding amide (IX). Finally, this compound is reduced with borane/THF yielding the target compound.

参考文献 中间体
合成目标
【1】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915.
【2】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275.
【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276.
【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 .
【5】 Castañer, J.; Graul, A.; Viozan. Drugs Fut 2000, 25, 2, 165.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(I) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 25939 3-sulfanyl-1-propanol 19721-22-3 C3H8OS 详情 详情
(III) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(IV) 25940 2-benzyl-1,3-oxathiane C11H14OS 详情 详情
(V) 25941 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol C11H16OS 详情 详情
(VI) 25942 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid C13H18O3S 详情 详情
(VII) 25943 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid C13H18O5S 详情 详情
(VIII) 25944 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one C9H10N2O2S 详情 详情
(IX) 25945 N-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide C22H26N2O6S2 详情 详情

合成路线41

该中间体在本合成路线中的序号：

The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII).The condensation of sulfonylacetic acid (VII) with dimethoxybenzothiazole derivative (X) by means of DCC, HOBT and triethylamine in DMF gives the corresponding amide (XI), which is reduced with borane/THF yielding intermediate (XII). Finally, this compound is demethylated with concentrated HBr or HCl.

参考文献 中间体
合成目标
【1】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275.
【2】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276.
【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915.
【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(I) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 25939 3-sulfanyl-1-propanol 19721-22-3 C3H8OS 详情 详情
(III) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(IV) 25940 2-benzyl-1,3-oxathiane C11H14OS 详情 详情
(V) 25941 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol C11H16OS 详情 详情
(VI) 25942 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid C13H18O3S 详情 详情
(VII) 25943 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid C13H18O5S 详情 详情
(X) 25946 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethylamine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-1-ethanamine C11H14N2O2S 详情 详情
(XI) 25947 N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide C24H30N2O6S2 详情 详情
(XII) 25948 N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)amine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)-1-ethanamine C24H32N2O5S2 详情 详情

合成路线42

该中间体在本合成路线中的序号：

Treatment of 3-nitro-7-hydroxyquinoline (I) with NaH and benzyl bromide (A) provides benzyloxyderivative (II), which is reduced with SnCl4 in HCl/EtOH to yield (III). Amine (III) is then converted into (IV) via the diazonium salt by treatment with NaNO2 in HCl followed by reaction with methyl acrylate (B) in presence of CuO. Cyclization of (IV) with thiourea in 2-methoxyethanol in presence of NaOAc affords imino-thiazolidinone (V), which is finally hydrolyzed with HCl and EtOH.

参考文献 中间体
合成目标
【1】 Nomura, Y.; Sakuma, S.; Masui, S. (Nippon Chemiphar Co., Ltd.); Quinoline deriv.. EP 0787725; JP 1997100280; US 5693651; WO 9612719 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(B) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(I) 41511 3-nitro-7-quinolinol C9H6N2O3 详情 详情
(II) 41512 7-(benzyloxy)-3-nitroquinoline; benzyl 3-nitro-7-quinolinyl ether C16H12N2O3 详情 详情
(III) 41513 7-(benzyloxy)-3-quinolinamine; 7-(benzyloxy)-3-quinolinylamine C16H14N2O 详情 详情
(IV) 41514 methyl 3-[7-(benzyloxy)-3-quinolinyl]-2-chloropropanoate C20H18ClNO3 详情 详情
(V) 41515 5-[[7-(benzyloxy)-3-quinolinyl]methyl]-2-imino-1,3-thiazolidin-4-one C20H17N3O2S 详情 详情

合成路线43

该中间体在本合成路线中的序号：(XI)

2) An alternative method starting from aniline (VII) employed the Meerwein arylation of methyl acrylate (IX) with the intermediate diazonium salt (VIII) in the presence of cuprous oxide. The resulting bromoester (X) was cyclized with thiourea (XI) in Et2O, followed by hydrolysis with HCl in sulfolane to afford (XIII). Finally, acid (XIII) was coupled to benzylamine (V) in the presence of (EtO)2POCN and Et3N.

参考文献 中间体
合成目标
【1】 Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(V) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(VII) 21927 methyl 5-amino-2-methoxybenzoate C9H11NO3 详情 详情
(VIII) 21928 methyl 5-(1lambda(5)-diazynyl)-2-methoxybenzoate C9H10N2O3 详情 详情
(IX) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(X) 21930 methyl 5-(2-bromo-3-methoxy-3-oxopropyl)-2-methoxybenzoate C13H15BrO5 详情 详情
(XI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XII) 21932 methyl 5-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoate C13H14N2O4S 详情 详情
(XIII) 21933 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoic acid C12H11NO5S 详情 详情

合成路线44

该中间体在本合成路线中的序号：(VII)

Condensation of pyruvic aldehyde dimethyl acetal (V) with dimethylformamide dimethyl acetal produced enamino ketone (VI). Cyclization of (VI) with thiourea (VII), followed by methylation with iodomethane furnished the (methylsulfanyl)pyrimidine (VIII). Acid hydrolysis of the dimethyl acetal gave rise to aldehyde (IX). Cyclohexanedione monoketal (X) was converted to oxime (XI) and then hydrogenated to give amine (XII). This was condensed with aldehyde (IX) yielding imine (XIII). Reaction of imine (XIII) with sulfonyl isocyanide (IV) gave rise to imidazole (XIV). The methylsulfanyl group of (XIV) was then oxidized to sulfone (XV) employing oxone®. Further displacement of the methylsulfonyl group of (XV) with NaOMe produced the methoxy pyrimidine (XVI). After ketal (XVI) hydrolysis, reduction of the resulting ketone (XVII) with NaBH4 furnished the title alcohol.

参考文献 中间体
合成目标
【1】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 .
【2】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 .
【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
(V) 25433 1,1-dimethoxyacetone 6342-56-9 C5H10O3 详情 详情
(VI) 25434 (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one C8H15NO3 详情 详情
(VII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 41422 methoxy[2-(methylsulfanyl)-4-pyrimidinyl]methyl methyl ether; 4-(dimethoxymethyl)-2-(methylsulfanyl)pyrimidine C8H12N2O2S 详情 详情
(IX) 41423 2-(methylsulfanyl)-4-pyrimidinecarbaldehyde C6H6N2OS 详情 详情
(X) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(XI) 41424 1,4-dioxaspiro[4.5]decan-8-one oxime C8H13NO3 详情 详情
(XII) 41425 1,4-dioxaspiro[4.5]dec-8-ylamine; 1,4-dioxaspiro[4.5]decan-8-amine C8H15NO2 详情 详情
(XIII) 41426 N-(1,4-dioxaspiro[4.5]dec-8-yl)-N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]amine; N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]-1,4-dioxaspiro[4.5]decan-8-amine C14H19N3O2S 详情 详情
(XIV) 41427 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfide C22H23FN4O2S 详情 详情
(XV) 41428 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfonyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfone C22H23FN4O4S 详情 详情
(XVI) 41429 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl ether; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-methoxypyrimidine C22H23FN4O3 详情 详情
(XVII) 41430 4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanone C20H19FN4O2 详情 详情

合成路线45

该中间体在本合成路线中的序号：(XXIII)

4-Cyclohexylbutyric acid (XVIII) was converted to the corresponding acid chloride (XIX) with SOCl2. Subsequent Friedel-Crafts condensation with 2,5-dimethoxychlorobenzene (XX) yielded ketone (XXI). After bromination of (XXI) in CH2Cl2, the resulting bromoketone (XXII) was condensed with thiourea (XXIII), providing aminothiazole (XXIV). This amine was coupled with indole acid (XV) by means of BOP to give amide (XXV). The title compound was then obtained by deprotection of the tert-butyl ester with trifluoroacetic acid. In a related alternative procedure, coupling of aminothiazole (XXIV) with indole acid (XVII) gave amide (XXVI). The methyl ester was then deprotected by hydrolysis with K2CO3 in aqueous butanol.

参考文献 中间体
合成目标
【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情
(XVIII) 32926 4-cyclohexylbutyric acid 4441-63-8 C10H18O2 详情 详情
(XIX) 32927 4-cyclohexylbutanoyl chloride C10H17ClO 详情 详情
(XX) 32928 2-chloro-1,4-dimethoxybenzene; 2-chloro-4-methoxyphenyl methyl ether 2100-42-7 C8H9ClO2 详情 详情
(XXI) 32929 1-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-1-butanone C18H25ClO3 详情 详情
(XXII) 32930 2-bromo-1-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-1-butanone C18H24BrClO3 详情 详情
(XXIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXIV) 32931 4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-amine; 4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-ylamine C19H25ClN2O2S 详情 详情
(XXV) 32932 tert-butyl 2-[2-([[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]amino]carbonyl)-5,7-dimethyl-1H-indol-1-yl]acetate C36H44ClN3O5S 详情 详情
(XXVI) 32933 methyl 2-[2-([[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]amino]carbonyl)-5,7-dimethyl-1H-indol-1-yl]acetate C33H38ClN3O5S 详情 详情

合成路线46

该中间体在本合成路线中的序号：(III)

Diazotization of 4,4'-diaminodiphenylmethane (I) with NaNO2 and HCl, followed by copper-catalyzed coupling with methyl acrylate afforded the alpha,alpha'-dichloro diester (II). Subsequent cyclization of (II) with thiourea (III) in refluxing EtOH produced the bis(iminothiazolidinone) (IV). Finally, acid hydrolysis of (IV) yielded the title compound.

参考文献 中间体
合成目标
【1】 Niigata, K.; Takahashi, T.; Iwaoka, K.; Yoneda, T.; Noshiro, O.; Koike, R. (Yamanouchi Pharmaceutical Co., Ltd.); Bisheterocyclic cpd.. EP 0533933; JP 1992511153; WO 9200967 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(I) 36325 4-(4-aminobenzyl)phenylamine; 4-(4-aminobenzyl)aniline 101-77-9 C13H14N2 详情 详情
(II) 36324 methyl 2-chloro-3-[4-[4-(2-chloro-3-methoxy-3-oxopropyl)benzyl]phenyl]propanoate C21H22Cl2O4 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 36326 2-imino-5-(4-[4-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]benzyl]benzyl)-1,3-thiazolidin-4-one C21H20N4O2S2 详情 详情

合成路线47

该中间体在本合成路线中的序号：(VII)

Wittig reaction of phosphonium bromide (I) with 4-methoxy-3-nitrobenzaldehyde (II) in the presence of NaOMe provided an approximately equimolecular mixture of Z- and E-stilbenes (III) and (IV), from which the E-isomer was isolated by crystallization. Stilbene (IV) was converted to bromohydrin (V) by treatment with N-bromosuccinimide in aqueous DMSO. Further Swern oxidation of (V) with DMSO-trifluoroacetic anhydride (TFAA) yielded bromoketone (VI), which was then cyclized with thiourea (VII) in the presence of K2CO3 in DMF to give aminothiazole (VIII). Finally, the nitro of (VIII) group was reduced to the target amine by treatment with Zn in AcOH.

参考文献 中间体
合成目标
【1】 Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y.; Nihei, Y.; Suga, Y.; Morinaga, Y.; Akiyama, Y.; Tsuji, T.; Syntheses and antitumor activity of cis-restricted combretastatins: 5-Membered heterocyclic analogues. Bioorg Med Chem Lett 1998, 8, 22, 3153.
【2】 Suga, Y.; Ohsumi, K.; Fukuda, Y.; Nihei, Y.; Hatanaka, T.; Tsuji, T.; Nakagawa, R.; Morrinaga, Y.; Ohishi, K.; Akiyama, Y.; Novel combretastatin analogue effective against murine solid tumors: Design and structure-activity relationships. J Med Chem 1998, 41, 16, 3022.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19866 triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide C28H28BrO3P 详情 详情
(II) 18225 4-METHOXY-3-NITROBENZALDEHYDE 31680-08-7 C8H7NO4 详情 详情
(III) 28720 2,3-dimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(Z)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene C18H19NO6 详情 详情
(IV) 18226 2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene C18H19NO6 详情 详情
(V) 18226 2,3-dimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]phenyl methyl ether; 1,2,3-trimethoxy-5-[(E)-2-(4-methoxy-3-nitrophenyl)ethenyl]benzene C18H19NO6 详情 详情
(V) 19870 2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanol C18H20BrNO7 详情 详情
(VI) 19871 2-bromo-2-(4-methoxy-3-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-1-ethanone C18H18BrNO7 详情 详情
(VII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VIII) 19873 5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-amine; 5-(4-methoxy-3-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-thiazol-2-ylamine C19H19N3O6S 详情 详情

合成路线48

该中间体在本合成路线中的序号：(VI)

The N-alkylation of N-(tert-butoxycarbonyl)glycine (I) with benzyl bromide (II) by means of NaH in THF gives N-benzyl-N-(tert-butoxycarbonyl)glycine (III), which is condensed with 4-aminoacetophenone (IV) by means of isobutyl chloroformate and TEA in dichloromethane yielding the corresponding glycinamide (V). The cyclization of (V) with thiourea (VI) by means of I2 in refluxing isopropanol affords, after work up, the N-benzyl-glycinamide (VII), which is finally acylated with pyridine-4-carbonyl chloride by means of TEA and DMAP in dichloromethane.

参考文献 中间体
合成目标
【1】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 27846 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid C14H19NO4 详情 详情
(IV) 27847 1-(4-aminophenyl)-1-ethanone 99-92-3 C8H9NO 详情 详情
(V) 27848 tert-butyl 2-(4-acetylanilino)-2-oxoethyl(benzyl)carbamate C22H26N2O4 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 27849 N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-2-(benzylamino)acetamide C18H18N4OS 详情 详情
(VIII) 27850 isonicotinoyl chloride 39178-35-3 C6H4ClNO 详情 详情

合成路线49

该中间体在本合成路线中的序号：(X)

The condensation of 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3,4-dihydrobenzofuran-3-ylmethyl methanesulfonate (I) with 2-(methylamino)ethanol (II) by heating at 120 C gives the tertiary amine (III), which is treated with SOCl2 in benzene yielding the chloroethylamino compound (IV). The condensation of (IV) with 4-nitrophenol (V) by means of K2CO3 in hot DMF affords the 4-nitrophenoxy compound (VI), which is reduced with H2 over Pd/C in ethyl acetate to the corresponding 4-aminophenoxy compound (VII). The condensation of (VII) with ethyl acrylate (VIII) by means of NaNO2 and HBr in methanol/water gives the 2-bromopropionic ester (IX), which is cyclized with thiourea (X) by means of NaOAc in refluxing ethanol yielding the thiazolidinedione (XI). Finally, this compound is debenzylated with HCl in hot acetic acid.

参考文献 中间体
合成目标
【1】 Casturi, S.R.; Lohray, V.B.; Kallam, A.R.; Pingali, H.; Ramanujam, R.; Alla, S.R. (Dr. Reddy's Research Foundation); Cpds. having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compsns. containing them. US 5925656 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 26455 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran C24H32O3S 详情 详情
(II) 13324 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol 109-83-1 C3H9NO 详情 详情
(III) 26456 2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]-1-ethanol C24H33NO3 详情 详情
(IV) 26457 N-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]-2-chloro-N-methyl-1-ethanamine C24H32ClNO2 详情 详情
(V) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(VI) 26458 N-[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl]-N-methyl-2-(4-nitrophenoxy)-1-ethanamine C30H36N2O5 详情 详情
(VII) 26459 4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]aniline C30H38N2O3 详情 详情
(VIII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(IX) 26460 ethyl 3-(4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]phenyl)-2-bromopropanoate C35H44BrNO5 详情 详情
(X) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XI) 26461 5-(4-[2-[[[5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methyl](methyl)amino]ethoxy]benzyl)-1,3-thiazolidine-2,4-dione C34H40N2O5S 详情 详情

合成路线50

该中间体在本合成路线中的序号：(V)

Addition of methylmagnesium iodide to nitrile (I), followed by hydrolytic treatment, provided ketone (II), which was brominated in CHCl3-MeOH to give bromomethyl ketone (III). Alkylation of thiourea (V) with 3-(dimethylamino)propyl chloride (IV) produced S-alkyl isothiourea (VI). After hydrolysis of (VI) with NaOEt, the intermediate thiol (VII) was condensed with bromoketone (III) to yield the required thioether, which was finally converted to the citrate salt.

参考文献 中间体
合成目标
【1】 Harris, P.J.; Heal, D.J. (The Boots Company plc); 1-Arylcycloalkyl sulphides, sulphoxides and sulphones for the treatment of depression, anxiety and Parkinson's disease. EP 0715620; JP 1996510222; US 5652271; WO 9426704 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27478 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile C11H9Cl2N 详情 详情
(II) 27479 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone C12H12Cl2O 详情 详情
(III) 27480 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone C12H11BrCl2O 详情 详情
(IV) 24581 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine 5407-04-5 C5H12ClN 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 27481 1-[[amino(imino)methyl]sulfanyl]-3-(dimethylamino)propane C6H15N3S 详情 详情
(VII) 27482 N,N-Dimethyl-N-(3-sulfanylpropyl)amine sodium salt C5H12NNaS 详情 详情

合成路线51

该中间体在本合成路线中的序号：(V)

Friedel Crafts condensation of benzothiophene (I) with p-fluorobenzoyl chloride (II) yielded the benzoyl benzothiophene (III). Then, substitution of the fluorine atom of (III) with 2-(1-piperidinyl)ethanethiol (VI) (obtained from b-chloroethylpiperidine (IV) and thiourea (V)), afforded sulfide (VII). Finally, deprotection of the methyl ethers of (VII) with BBr3 in cold 1,2-dichloroethane furnished the target compound.

参考文献 中间体
合成目标
【1】 Glasebrook, A.W.; Schmid, C.R.; Duke, K.M.; Sluka, J.P.; Novel nonsteroidal selective estrogen receptor modulators. Carbon and heteroatom replacement of oxygen in the ethoxypiperidine region of raloxifene. Bioorg Med Chem Lett 1999, 9, 4, 523.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10121 4-(6-Methoxy-1-benzothiophen-2-yl)phenyl methyl ether; 6-Methoxy-2-(4-methoxyphenyl)-1-benzothiophene 63675-74-1 C16H14O2S 详情 详情
(II) 17263 4-fluorobenzoyl chloride 403-43-0 C7H4ClFO 详情 详情
(III) 21916 (4-fluorophenyl)[6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]methanone C23H17FO3S 详情 详情
(IV) 10117 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine 1932-03-2 C7H14ClN 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 21919 2-(1-piperidinyl)ethylhydrosulfide; 2-(1-piperidinyl)-1-ethanethiol C7H15NS 详情 详情
(VII) 21920 [6-methoxy-2-(4-methoxyphenyl)-1-benzothiophen-3-yl](4-[[2-(1-piperidinyl)ethyl]sulfanyl]phenyl)methanone C30H31NO3S2 详情 详情

合成路线52

该中间体在本合成路线中的序号：(IV)

The reaction of 2-phenylacetonitrile (I) with 2-bromo-3-methylbutyric acid ethyl ester (II) by means of Zn in THF gives the ketoester (III), which is cyclized with thiourea (IV) by means of sodium ethoxide in ethanol yielding 6-benzyl-5-isopropyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally, this compound is treated with chloromethyl methyl sulfide (VI) and K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Vig, R.; Mao, C.; Venkatachalam, T.K.; Tuel-Ahlgren, L.; Sudbeck, E.A.; Uckun, F.M.; 5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series. Bioorg Med Chem Lett 1998, 8, 12, 1461.
【2】 Sudbeck, E.A.; Mao, C.; Vig, R.; Venkatachalam, T.K.; Tuel-Ahlgren, L.; Uckun, F.M.; Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother 1998, 42, 12, 3225.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(II) 27032 2-Bromoisovalerianic acid ethyl ester; ethyl 2-bromo-3-methylbutanoate 609-12-1 C7H13BrO2 详情 详情
(III) 27033 ethyl 2-isopropyl-3-oxo-4-phenylbutanoate C15H20O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 27034 6-benzyl-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C14H16N2OS 详情 详情
(VI) 27701 chloro(methylsulfanyl)methane 2373-51-5 C2H5ClS 详情 详情

合成路线53

该中间体在本合成路线中的序号：(IV)

1,3-Cyclohexanedione (I) was brominated in cold water, and the resulting 2-bromo-1,3-cyclohexanedione (II) was condensed with 2-aminopyridine (III) in boiling EtOH to afford the dihydropyridobenzimidazolone (IV). Further bromination in concentrated HBr at 70 C gave bromoketone (V), which was finally condensed with thiourea (VI) in EtOH to yield the target tetracyclic compound.

参考文献 中间体
合成目标
【1】 Yoo, H.Y.; Chung, K.J.; Chai, J.P.; Chang, M.S.; Kim, S.G.; Choi, W.S.; Kim, Y.H.; Chun, J.K.; Chung, Y.K.; Kim, Y.H.; Paek, J.H.; Seo, K.H.; Kang, D.P. (Yung-Jin Pharmaceutical Co., Ltd.); Heterocycle-fused thiazole derivs.. EP 0843681; JP 1998508877; WO 9703076 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(II) 21027 2-bromo-1,3-cyclohexanedione C6H7BrO2 详情 详情
(III) 11305 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine 504-29-0 C5H6N2 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 21029 7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one C11H10N2O 详情 详情
(V) 21030 8-bromo-7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one C11H9BrN2O 详情 详情

合成路线54

该中间体在本合成路线中的序号：(III)

The cyclization of methyl acetoacetate (I), 2-methoxybenzaldehyde (II) and thiourea (III) by means of HCl in refluxing ethanol gives the tetrahydropyrimidine (IV), which is finally cyclized with chloroacetic acid (V) and benzaldehyde (VI) by means of sodium acetate in a refluxing mixture of acetic acid and acetic anhydride.

参考文献 中间体
合成目标
【1】 Kelicen, P.; Ertan, M.; Demirdamar, R.; Krebs, B.; Tozkoparan, B.; Lage, M.; Condensed heterocyclic compounds: Synthesis and antiinflammatory activity of novel thiazolo[3,2-a]pyrimidines. Arch Pharm 1998, 331, 6, 201.
【2】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 27432 methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H16N2O3S 详情 详情
(V) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线55

该中间体在本合成路线中的序号：

The reaction of succinic anhydride (I) with the lithium salt of the chiral oxazolidinone (II) in THF gives 3-(hydroxysucccinyl)-4(S)-isopropyloxazolidin-2-one (III), which is treated successively with oxalyl chloride, CH2N2 and HBr to yield the bromomethyl derivative (IV). The cyclization of (IV) with thiourea in refluxing isopropanol affords the 2-aminothiazol derivative (V), which is protected with 2,2,2-trichloroethyl chloroformate by means of DIEA and DMAP in dichloromethane giving the carbamate (VI). The reaction of (VI) with tert-butyl 2-bromoacetate (VII) by means of sodium hexamethyldisilazane (NaHMDS) in THF yields the chiral butyrate (VIII), which is hydrolyzed with TFA in dichloromethane to the chiral butyric acid (IX). The condensation of (IX) with the intermediate amine (X) by means of BOP-PF6 and DIEA in DMF affords the corresponding amide (XI), which is treated with magnesium methoxide in methanol to eliminate the oxazolidinone group (the chiral inductor) providing the methyl ester (XII). The hydrolysis of (XII) with NaOH, followed by condensation with amine (XIII) (J Org Chem 1988, 53: 6109; J Med Chem 1993, 36: 449) gives the protected intermediate (XIV), which is finally deprotected by reaction with Zn/HCl in aqueous dioxane.

参考文献 中间体
合成目标
【1】 Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
13664 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate 17341-93-4 C3H2Cl4O2 详情 详情
(I) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情
(II) 29533 [(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]lithium C6H10LiNO2 详情 详情
(III) 29534 4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutyric acid C10H15NO5 详情 详情
(IV) 29535 5-bromo-1-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-1,4-pentanedione C11H16BrNO4 详情 详情
(V) 29536 (4S)-3-[3-(2-amino-1,3-thiazol-4-yl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one C12H17N3O3S 详情 详情
(VI) 29537 2,2,2-trichloroethyl 4-[3-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-1,3-thiazol-2-ylcarbamate C15H18Cl3N3O5S 详情 详情
(VII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VIII) 29538 tert-butyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate C21H28Cl3N3O7S 详情 详情
(IX) 29539 (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butyric acid C17H20Cl3N3O7S 详情 详情
(X) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XI) 29541 2,2,2-trichloroethyl 4-((2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-2-[[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-1,3-thiazol-2-ylcarbamate C34H45Cl3N6O7S 详情 详情
(XII) 29542 methyl (2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxo-2-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate C29H38Cl3N5O6S 详情 详情
(XIII) 29543 (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol C14H29NO2 详情 详情
(XIV) 29544 2,2,2-trichloroethyl 4-[(2R)-2-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxobutyl]-1,3-thiazol-2-ylcarbamate C42H63Cl3N6O7S 详情 详情

合成路线56

该中间体在本合成路线中的序号：(XVI)

The thiazole ring formation by cyclization of (XV) with thiourea (XVI) gives intermediate (XVII), which is finally deprotected with methanesulfonic acid in dichloromethane.

参考文献 中间体
合成目标
【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 31617 (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65BrN4O6 详情 详情
(XVI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XVII) 31618 (2R)-2-[(2-amino-1,3-thiazol-4-yl)methyl]-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C42H66N6O5S 详情 详情

合成路线57

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(3,5-dimethylphenyl)acetonitrile (I) with ethyl 2-bromo-3-methylbutyrate (II) by means of Zn in THF gives the beta-ketoester (III), which is cyclized with thiourea (IV) by means of sodium ethoxide in ethanol yielding the thioxopyrimidinone (V). Finally, this compound is condensed with choromethyl methyl sulfide by means of K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Vig, R.; Mao, C.; Venkatachalam, T.K.; Tuel-Ahlgren, L.; Sudbeck, E.A.; Uckun, F.M.; 5-Alkyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-ones as potent non-nucleoside reverse transcriptase inhibitors of S-DABO series. Bioorg Med Chem Lett 1998, 8, 12, 1461.
【2】 Sudbeck, E.A.; Mao, C.; Vig, R.; Venkatachalam, T.K.; Tuel-Ahlgren, L.; Uckun, F.M.; Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother 1998, 42, 12, 3225.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30213 2-(3,5-dimethylphenyl)acetonitrile 39101-54-7 C10H11N 详情 详情
(II) 27032 2-Bromoisovalerianic acid ethyl ester; ethyl 2-bromo-3-methylbutanoate 609-12-1 C7H13BrO2 详情 详情
(III) 30214 ethyl 4-(3,5-dimethylphenyl)-2-isopropyl-3-oxobutanoate C17H24O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 30215 6-(3,5-dimethylbenzyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C16H20N2OS 详情 详情
(VI) 27701 chloro(methylsulfanyl)methane 2373-51-5 C2H5ClS 详情 详情

合成路线58

该中间体在本合成路线中的序号：(VI)

In an alternative procedure, pyrimidinone (I) is alkylated with 4-(2-bromoethoxy)nitrobenzene (II) to produce (III). Reduction of nitro compound (III) by catalytic hydrogenation affords aniline (IV). After diazotization of amine (IV), the resultant diazonium salt is coupled to ethyl acrylate in the presence of CuI, yielding the 2-bromo-3-arylpropionate (V). Cyclization of bromo ester (V) with thiourea (VI) furnishes the iminothiazolidinone (VII), which is finally hydrolyzed under acidic conditions to the target thiazolidinedione.

参考文献 中间体
合成目标
【1】 Lohray, V.B.; Lohray, B.B.; Ramanujam, R.; Chakrabarti, R.; Gurram, R.M.; Paraselli, R.B.; Pakala, S.K.S. (Dr. Reddy's Research Foundation); Heterocyclic cpds., process for their preparation and pharmaceutical compsns. containing them and their use in the treatment of diabetes and related diseases. EP 0958296; US 5885997; US 5985884; US 6372750; US 6573268; WO 9741097 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63395 2-ethyl-6-methyl-4(3H)-pyrimidinone C7H10N2O 详情 详情
(II) 63398 1-[(2-bromoethyl)oxy]-4-nitrobenzene; 2-bromoethyl 4-nitrophenyl ether 13288-06-7 C8H8BrNO3 详情 详情
(III) 63399 2-ethyl-6-methyl-3-{2-[(4-nitrophenyl)oxy]ethyl}-4(3H)-pyrimidinone C15H17N3O4 详情 详情
(IV) 63400 3-{2-[(4-aminophenyl)oxy]ethyl}-2-ethyl-6-methyl-4(3H)-pyrimidinone C15H19N3O2 详情 详情
(V) 63401 ethyl 2-bromo-3-[4-({2-[2-ethyl-4-methyl-6-oxo-1(6H)-pyrimidinyl]ethyl}oxy)phenyl]propanoate C20H25BrN2O4 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 63402 2-ethyl-3-[2-({4-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]phenyl}oxy)ethyl]-6-methyl-4(3H)-pyrimidinone C19H22N4O3S 详情 详情

合成路线59

该中间体在本合成路线中的序号：(III)

Bromination of 4'-chloropropiophenone (I) afforded bromoketone (II). This was cyclized with thiourea (III) to produce the target 4-arylthiazole.

参考文献 中间体
合成目标
【1】 Hatanaka, Y.; Yamaguchi, K.; Kobori, T.; Tsuji, T.; Goda, K.; Yada, M.; 4-Phenylthiazole derivatives inhibit IL-6 secretion in osteoblastic cells and suppress bone weight loss in ovariectomized mice. Bioorg Med Chem Lett 1999, 9, 7, 957.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29196 1-(4-Chlorophenyl)-1-propanone; 4-Chloropropiophenone 6285-05-8 C9H9ClO 详情 详情
(II) 29197 2-bromo-1-(4-chlorophenyl)-1-propanone C9H8BrClO 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线60

该中间体在本合成路线中的序号：(V)

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,4,5-Trimethoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Shams, G.; Feller, D.R.; Zheng, W.; Konkar, A.A.; Miller, D.D.; Nikulin, V.I.; Vansal, S.S.; 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel selective beta3-adrenoceptor agonists. J Med Chem 1999, 42, 12, 2287.
【2】 Miller, D.D.; Feller, D.R. (Molecular Design International, Inc. ); beta3-Adrenoreceptor agonists, agonist compsns. and methods of using. EP 1023269; WO 9916752 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(II) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(III) 35230 2-(3-oxobutyl)-1H-isoindole-1,3(2H)-dione C12H11NO3 详情 详情
(IV) 35231 2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione C12H10BrNO3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 35232 2-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione C13H11N3O2S 详情 详情
(VII) 35233 4-(2-aminoethyl)-1,3-thiazol-2-amine; 4-(2-aminoethyl)-1,3-thiazol-2-ylamine C5H9N3S 详情 详情
(VIII) 25349 2-(3,4,5-trimethoxyphenyl)acetic acid 937-52-0 C11H14O5 详情 详情
(IX) 35238 2-(3,4,5-trimethoxyphenyl)acetyl chloride C11H13ClO4 详情 详情
(X) 35239 N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide C16H21N3O4S 详情 详情
(XI) 35240 4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-amine; 4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine C16H19N3O3S 详情 详情

合成路线61

该中间体在本合成路线中的序号：(V)

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,5-Diiodo-4-methoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Shams, G.; Feller, D.R.; Zheng, W.; Konkar, A.A.; Miller, D.D.; Nikulin, V.I.; Vansal, S.S.; 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel selective beta3-adrenoceptor agonists. J Med Chem 1999, 42, 12, 2287.
【2】 Miller, D.D.; Feller, D.R. (Molecular Design International, Inc. ); beta3-Adrenoreceptor agonists, agonist compsns. and methods of using. EP 1023269; WO 9916752 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(II) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(III) 35230 2-(3-oxobutyl)-1H-isoindole-1,3(2H)-dione C12H11NO3 详情 详情
(IV) 35231 2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione C12H10BrNO3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 35232 2-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione C13H11N3O2S 详情 详情
(VII) 35233 4-(2-aminoethyl)-1,3-thiazol-2-amine; 4-(2-aminoethyl)-1,3-thiazol-2-ylamine C5H9N3S 详情 详情
(VIII) 35234 2-(3,5-diiodo-4-methoxyphenyl)acetic acid C9H8I2O3 详情 详情
(IX) 35235 2-(3,5-diiodo-4-methoxyphenyl)acetyl chloride C9H7ClI2O2 详情 详情
(X) 35236 N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,5-diiodo-4-methoxyphenyl)acetamide C14H15I2N3O2S 详情 详情
(XI) 35237 4-(3,5-diiodo-4-methoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-amine; 4-(3,5-diiodo-4-methoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine C14H13I2N3OS 详情 详情

合成路线62

该中间体在本合成路线中的序号：(III)

The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.

参考文献 中间体
合成目标
【1】 DE 2921316 .
【2】 Serradell, M.N.; Blancafort, P.; Castañer, J.; Ceftazidime. Drugs Fut 1981, 6, 10, 612.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 29669 Pyridine 110-86-1 C5H5N 详情 详情
(I) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情
(V) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(VI) 37478 ethyl 2-(hydroxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate C26H23N3O3S 详情 详情
(VII) 34947 tert-butyl 2-bromo-2-methylpropanoate 23877-12-5 C8H15BrO2 详情 详情
(VIII) 37479 tert-butyl 2-[([(Z)-2-ethoxy-2-oxo-1-[2-(tritylamino)-1,3-thiazol-4-yl]ethylidene]amino)oxy]-2-methylpropanoate C34H37N3O5S 详情 详情
(IX) 29047 2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid C32H33N3O5S 详情 详情
(X) 32660 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H20N2O5S 详情 详情
(XI) 37480 tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C46H51N5O9S2 详情 详情
(XII) 37481 (6R,7R)-3-[(acetoxy)methyl]-7-([2-(2-amino-1,3-thiazol-4-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C19H21N5O9S2 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

The cyclization of N-[5-(2-chloroacetyl)furan-2-ylmethylacetamide (I) with thiourea (II) in ethanol gives the thiazole (III), which is condensed with benzoyl isothiocyanate (IV) in acetone to yield the benzoylthiourea (V). The hydrolysis of (V) with NaOH in aqueous methanol affords the thiourea (VI), which is treated with methyl iodide in methanol to give the S-methylisothiourea (VII). Finally, this compound is condensed with 2-ethoxybenzylamine (VIII) in EtOH/AcOH.

参考文献 中间体
合成目标
【1】 Matsumoto, Y.; Takasugi, H.; Ohno, M.; Sakane, K.; Ishikawa, H.; Nishino, S.; Morinaga, C.; Katsura, Y.; Anti-Helicobacter pylori Agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles. J Med Chem 1999, 42, 15, 2920.
【2】 Katsura, Y.; Ohno, M.; Nishino, S.; Tomishi, T.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Furylthiazoles and their use as H2-receptor antagonists and antimicrobials. JP 1997507222; WO 9518126 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38248 N-[[5-(2-chloroacetyl)-2-furyl]methyl]acetamide C9H10ClNO3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 38249 N-[[5-(2-amino-1,3-thiazol-4-yl)-2-furyl]methyl]acetamide C10H11N3O2S 详情 详情
(IV) 23530 benzoyl isothiocyanate 532-55-8 C8H5NOS 详情 详情
(V) 38250 N-[[5-(2-[[(benzoylamino)carbothioyl]amino]-1,3-thiazol-4-yl)-2-furyl]methyl]acetamide C18H16N4O3S2 详情 详情
(VI) 38251 N-[(5-[2-[(aminocarbothioyl)amino]-1,3-thiazol-4-yl]-2-furyl)methyl]acetamide C11H12N4O2S2 详情 详情
(VII) 38252 4-[5-[(acetamido)methyl]-2-furyl]-2-[[(Z)-amino(methylsulfanyl)methylidene]amino]-1,3-thiazole C12H14N4O2S2 详情 详情
(VIII) 38253 2-ethoxybenzylamine; (2-ethoxyphenyl)methanamine C9H13NO 详情 详情

合成路线64

该中间体在本合成路线中的序号：(A)

Reaction of 2-chloro-5-ispropylpyridine (VII) with thiourea (A) in aqueous HCl gives 5-isopropyl- pyridine-2-thiol (VIII), which is chlorinated with chlorine in acetic acid to yield 5-isopropylpyridine-2-sulfochloride (IX). This compound is converted into 5-isopropylpyridine-2-sulfonamide potassium salt (X).

参考文献 中间体
合成目标
【1】 Breu, V.; Burri, K.; Cassal, J.-M.; Clozel, M.; Hirth, G.; Loffler, B.-M.; Muller, M.; Neidhart, W.; Ramuz, H. (F. Hoffmann-La Roche AG); Novel sulfonamides. EP 0799209; JP 1998509182; WO 9619459 .
【2】 Spurr, P. (F. Hoffmann-La Roche AG); Process for the preparation of 2,5-disubstd. pyridines. EP 0897914 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 62973 2-chloro-5-isopropylpyridine C8H10ClN 详情 详情
(VIII) 62974 5-isopropyl-2-pyridinethiol; 5-isopropyl-2-pyridinylhydrosulfide C8H11NS 详情 详情
(IX) 62975 5-isopropyl-2-pyridinesulfonyl chloride C8H10ClNO2S 详情 详情
(X) 50142 　 C8H11KN2O2S 详情 详情

合成路线65

该中间体在本合成路线中的序号：(VIII)

3-Acetylbenzonitrile (I) was protected as the ethylene ketal (II) employing ethylene glycol and boron trifluoride etherate. Reduction of the cyano group of (II) with LiAlH4 gave amine (III), and further ketal hydrolysis provided 3-acetylbenzylamine (IV). This was acetylated using acetyl chloride and Et3N to yield the intermediate amide (V). Alternatively, intermediate (V) was obtained by addition of methylmagnesium bromide to N-(3-cyanobenzyl)acetamide (VI). Bromination of (V) in dioxan furnished the bromoacetophenone (VII). This was cyclized to the aminothiazole (IX) by treatment with thiourea (VIII) in refluxing ethanol. Condensation of (IX) with benzoyl isothiocyanate (X) provided the benzoyl thiourea (XI). After selective hydrolysis of the benzoyl group of (XI) with NaOH in MeOH-H2O at 60 C, the resulting thiourea (XII) was methylated with iodomethane yielding S-methylisothiourea (XIII). Finally, displacement of the methylthio group with 2-methoxyetylamine (XIV) furnished the title guanidinothiazole.

参考文献 中间体
合成目标
【1】 Katsura, Y.; Tomishi, T.; Inoue, Y.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Guanidino thiazoles and their use as H2-receptor antagonist. EP 0545376; JP 1994321921; US 5532258 .
【2】 Inoue, Y.; Morinaga, C.; Ishikawa, H.; Takasugi, H.; Tomishi, T.; Matsumoto, Y.; Katsura, Y.; Sakane, K.; Anti-Helicobacter pylori agents.4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives. J Med Chem 2000, 43, 17, 3315.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
33623 bromo(methyl)magnesium 75-16-1 CH3BrMg 详情 详情
(I) 17992 m-Cyanoacetophenone; 3-acetylbenzonitrile 6136-68-1 C9H7NO 详情 详情
(II) 34665 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile C11H11NO2 详情 详情
(III) 34673 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine; [3-(2-methyl-1,3-dioxolan-2-yl)phenyl]methanamine C11H15NO2 详情 详情
(IV) 34666 1-[3-(aminomethyl)phenyl]-1-ethanone C9H11NO 详情 详情
(V) 34674 N-(3-acetylbenzyl)acetamide C11H13NO2 详情 详情
(VI) 34667 N-(3-cyanobenzyl)acetamide C10H10N2O 详情 详情
(VII) 34668 N-[3-(2-bromoacetyl)benzyl]acetamide C11H12BrNO2 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IX) 34669 N-[3-(2-amino-1,3-thiazol-4-yl)benzyl]acetamide C12H13N3OS 详情 详情
(X) 23530 benzoyl isothiocyanate 532-55-8 C8H5NOS 详情 详情
(XI) 34670 N-[3-(2-[[(benzoylamino)carbothioyl]amino]-1,3-thiazol-4-yl)benzyl]acetamide C20H18N4O2S2 详情 详情
(XII) 34671 N-(3-[2-[(aminocarbothioyl)amino]-1,3-thiazol-4-yl]benzyl)acetamide C13H14N4OS2 详情 详情
(XIII) 34672 4-[3-[(acetamido)methyl]phenyl]-2-[[(E)-amino(methylsulfanyl)methylidene]amino]-1,3-thiazole C14H16N4OS2 详情 详情
(XIV) 34675 2-methoxyethylamine; 2-methoxy-1-ethanamine 109-85-3 C3H9NO 详情 详情

合成路线66

该中间体在本合成路线中的序号：(II)

The condensation of 1,3-dichloroacetone (I) with thiourea (II) provided 2-amino-4-(chloromethyl)thiazole (III). Further displacement of the chlorine atom of (III) with N-Boc-2-mercaptoethylamine (IV) gave thioether (V). Thiocyanation of the thiazole ring of (V) using thiocyanogen, generated from KSCN and Br2, provided (VI). Reductive cleavage of the thiocyanate group of (VI) with NaBH4 gave rise to the mercaptothiazole (VII), which was subsequently coupled with the chlorocephem (VIII) to yield adduct (IX). Incorporation of a N-Boc-alanine unit to (IX) to afford (XI) was then achieved by condensation with N-Boc-alanine pentafluorophenyl ester (X) in 1,2-dichloroethane. Finally, the protecting groups of (XI) were cleaved by treatment with trifluoroacetic acid in the presence of triethylsilane.

参考文献 中间体
合成目标
【1】 Glinka, T.; Price, M.; Halas, S.; Calkins,T.; Frith, R.; Nudelman, G.; Whitehead, C.; Cho, A.; Hecker, S.; Ludwikow, M.; Chamberland, S.; Crawford, J.; Lee, V.; Design, synthesis and in vitro antibacterial properties of novel 3-heteroarylthio cephems with anti-MRSA activity: Amino acid prodrug approach to solubility improvement. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F391.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 33078 4-(chloromethyl)-1,3-thiazol-2-amine; 4-(chloromethyl)-1,3-thiazol-2-ylamine C4H5ClN2S 详情 详情
(IV) 33079 tert-butyl 2-sulfanylethylcarbamate C7H15NO2S 详情 详情
(V) 33080 tert-butyl 2-[[(2-amino-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate C11H19N3O2S2 详情 详情
(VI) 33081 tert-butyl 2-([[2-amino-5-(cyanosulfanyl)-1,3-thiazol-4-yl]methyl]sulfanyl)ethylcarbamate C12H18N4O2S3 详情 详情
(VII) 33082 tert-butyl 2-[[(2-amino-5-sulfanyl-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate C11H19N3O2S3 详情 详情
(VIII) 33083 benzyl 3-chloro-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C57H43Cl2N5O5S2 详情 详情
(IX) 33084 benzyl 3-([2-amino-4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C68H61ClN8O7S5 详情 详情
(X) 33085 2,3,4,5,6-pentafluorophenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate C14H14F5NO4 详情 详情
(XI) 33086 benzyl 3-[[4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-5-yl]sulfanyl]-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; benzyl 3-[[4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-5-yl]sulfanyl]-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C76H74ClN9O10S5 详情 详情

合成路线67

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclopentyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线68

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclopentyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线69

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with malonic acid monoethyl ester potassium salt (III) to yield 4´(2,6-difluorophenyl)-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with cyclopentyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(IV) 51830 ethyl 4-(2,6-difluorophenyl)-3-oxopentanoate C13H14F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51831 6-[1-(2,6-difluorophenyl)ethyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VII) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线70

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4´(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with cyclopentyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线71

该中间体在本合成路线中的序号：(II)

Thiazolidinedione (III) was prepared by condensation of chloroacetic acid (I) with thiourea (II). Alkylation of the potassium salt of (III) with 4-methoxyphenacyl bromide (IV) furnished the 3-phenacyl thiazolidinedione (V). Finally, aldol condensation of (V) with flavone-6-carboxaldehyde (VI) in the presence of NaOAc in HOAc provided the title compound.

参考文献 中间体
合成目标
【1】 Altanlar, N.; Ayhan-Killergil, G.; Synthesis of 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl(methylenyl]thiazolidine-2,4-diones and evaluation of their antimicrobial activity. Arzneim-Forsch Drug Res 2000, 50, 2, 154.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(IV) 21991 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone 2632-13-5 C9H9BrO2 详情 详情
(V) 50131 3-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione C12H11NO4S 详情 详情
(VI) 50132 4-oxo-2-phenyl-4H-chromene-6-carbaldehyde C16H10O3 详情 详情

合成路线72

该中间体在本合成路线中的序号：(VI)

Palladium-catalyzed coupling of 5-bromopyrimidine (I) with ethyl acrylate (II) afforded pyrimidinyl acrylate (III), which was hydrogenated over Pd/C to give (IV). Claisen condensation of (IV) with ethyl formate furnished oxoester (V). This was then cyclized with thiourea (VI) to produce the intermediate thiouracil (VII).

参考文献 中间体
合成目标
【1】 Hickey, D.M.B.; Boyd, H.F.; Flynn, S.T.; et al.; 2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2000, 10, 4, 395.
【2】 Pinto, I.L.; Ife, R.J.; Hickey, D.M.B.; Smith, S.A.; Leach, C.A.; Porter, R.A. (SmithKline Beecham plc); Pyrimidinone cpds. and pharmaceutical compsns. containing them. EP 1028955; WO 9924420 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38987 5-bromopyrimidine 4595-59-9 C4H3BrN2 详情 详情
(II) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(III) 38988 ethyl (E)-3-(5-pyrimidinyl)-2-propenoate C9H10N2O2 详情 详情
(IV) 38989 ethyl 3-(5-pyrimidinyl)propanoate C9H12N2O2 详情 详情
(V) 38990 ethyl (Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate C10H12N2O3 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 38991 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C9H8N4OS 详情 详情

合成路线73

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with methyl chloride to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情

合成路线74

该中间体在本合成路线中的序号：(VI)

The Knoevenagel condensation of 1-methylpyrazole-4-carboxaldehyde (I) with malonic acid afforded the pyrazolylacrylic acid (II), which was further esterified with methanol and sulfuric acid, yielding ester (III). Catalytic hydrogenation of the unsaturated ester (III) in the presence of Pd/C gave the pyrazolylpropionate (IV). Claisen condensation of ester (IV) with methyl formate by using potassium tert-butoxide produced the (hydroxymethylene)propionate (V), which was subsequently cyclized with thiourea (VI) to furnish the thiouracil derivative (VII). Alkylation of (VII) with 4-fluorobenzyl chloride (VIII) gave rise to the thioether (IX). Regioselective alkylation of pyrimidine (IX) with tert-butyl iodoacetate produced the pyrimidinylacetate (X). The tert-butyl ester of (X) was then cleaved with trifluoroacetic acid yielding carboxylic acid (XI).

参考文献 中间体
合成目标
【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst .
【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 53042 1-methyl-1H-pyrazole-4-carbaldehyde n/a C5H6N2O 详情 详情
(II) 53043 (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoic acid n/a C7H8N2O2 详情 详情
(III) 53044 methyl (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoate n/a C8H10N2O2 详情 详情
(IV) 53045 methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate n/a C8H12N2O2 详情 详情
(V) 53046 methyl (Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate n/a C9H12N2O3 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VII) 53047 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone n/a C9H10N4OS 详情 详情
(VIII) 12354 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene 352-11-4 C7H6ClF 详情 详情
(IX) 53048 2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone n/a C16H15FN4OS 详情 详情
(X) 53049 tert-butyl 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetate n/a C22H25FN4O3S 详情 详情
(XI) 53050 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid n/a C18H17FN4O3S 详情 详情

合成路线75

该中间体在本合成路线中的序号：(II)

Condensation between ethyl 2-oxocyclopentanecarboxylate (I) and thiourea (II) gives rise to the thiouracil derivative (III) (1,2). This is then alkylated with 4-fluorobenzyl chloride (IV) to yield thioether (V). Subsequent alkylation of (V) with tert-butyl iodoacetate (VI) furnishes adduct (VII). Further acidic cleavage of the tert-butyl ester group of (VII) leads to carboxylic acid (VIII) (2,3). Alternatively, intermediate (VIII) is prepared by alkylation of (V) with triflate (IX), followed by alkaline hydrolysis of the resultant methyl ester (X)

参考文献 中间体
合成目标
【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067.
【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 .
【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29947 ethyl 2-oxocyclopentanecarboxylate 611-10-9 C8H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 63490 2-sulfanyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one C7H8N2OS 详情 详情
(IV) 12354 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene 352-11-4 C7H6ClF 详情 详情
(V) 63491 2-{[(4-fluorophenyl)methyl]sulfanyl}-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one C14H13FN2OS 详情 详情
(VI) 24735 tert-Butyl 2-iodoacetate C6H11IO2 详情 详情
(VII) 63492 1,1-dimethylethyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate C20H23FN2O3S 详情 详情
(VIII) 63494 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid C16H15FN2O3S 详情 详情
(IX) 63493 methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate C4H5F3O5S 详情 详情
(X) 63495 methyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate C17H17FN2O3S 详情 详情

合成路线76

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with cyclopentyl chloride (IV) in alkaline medium afforded the required 2-(cyclopentylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51791 methyl (Z)-3-hydroxy-4-phenyl-2-butenoate C11H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线77

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with sec-butyl chloride (IV) in alkaline medium afforded the required 2-(sec-butylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线78

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with methyl chloride (IV) in alkaline medium afforded the required 2-(methylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51791 methyl (Z)-3-hydroxy-4-phenyl-2-butenoate C11H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 51798 methyl chloride; Monochloromethane; Artic; Chloromethane 74-87-3 CH3Cl 详情 详情

合成路线79

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51791 methyl (Z)-3-hydroxy-4-phenyl-2-butenoate C11H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线80

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isobutyl chloride (IV) in alkaline medium afforded the required 2-(isobutylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51791 methyl (Z)-3-hydroxy-4-phenyl-2-butenoate C11H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线81

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with sec-butyl chloride (IV) in alkaline medium afforded the required 2-(sec-butylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21791 4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]phenylamine; 4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]aniline C12H17ClN2S 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线82

该中间体在本合成路线中的序号：(II)

When 4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with cyclohexyl chloride (IV) in alkaline medium afforded the required 2-(cyclohexylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51791 methyl (Z)-3-hydroxy-4-phenyl-2-butenoate C11H12O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51793 6-benzyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H10N2OS 详情 详情
(IV) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线83

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with methyl chloride (IV) in alkaline medium afforded the required 2-(methylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51798 methyl chloride; Monochloromethane; Artic; Chloromethane 74-87-3 CH3Cl 详情 详情

合成路线84

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线85

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with isobutyl chloride (IV) in alkaline medium afforded the required 2-(isobutylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线86

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with sec-butyl chloride (IV) in alkaline medium afforded the required 2-(sec-butylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线87

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with ciclopentyl chloride (IV) in alkaline medium afforded the required 2-(ciclopentylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线88

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with cyclohexyl chloride (IV) in alkaline medium afforded the required 2-(cyclohexylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线89

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with allyl chloride (IV) in alkaline medium afforded the required 2-(allylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 13235 Allyl chloride; 3-Chloro-1-propene 107-05-1 C3H5Cl 详情 详情

合成路线90

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with 1-chloro-but-2-ene (IV) in alkaline medium afforded the required 2-but-2-enylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 36218 (E)-1-chloro-2-butene C4H7Cl 详情 详情

合成路线91

该中间体在本合成路线中的序号：(II)

When 4-(3-methylphenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of the compound (III) with 1-chloro-3-methyl-but-2-ene (IV) in alkaline medium afforded the required 2-(3-methyl-but-2-enylthio)-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51787 methyl (Z)-3-hydroxy-4-(3-methylphenyl)-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51801 6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51796 Prenyl Chloride; 1-Chloro-3-methyl-2-butene 503-60-6 C5H9Cl 详情 详情

合成路线92

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with methyl chloride (IV) in alkaline medium afforded the required 2-(methylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51798 methyl chloride; Monochloromethane; Artic; Chloromethane 74-87-3 CH3Cl 详情 详情

合成路线93

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线94

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isobutyl chloride (IV) in alkaline medium afforded the required 2-(isobutylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线95

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with sec-butyl chloride (IV) in alkaline medium afforded the required 2-(sec-butylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线96

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-phenyl-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-benzyl-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with ciclohexyl chloride (IV) in alkaline medium afforded the required 2-(cyclohexylthio)-5-methyl-6-benzyl-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51789 methyl (Z)-3-hydroxy-2-methyl-4-phenyl-2-butenoate C12H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51800 6-benzyl-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H12N2OS 详情 详情
(IV) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线97

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with methyl chloride (IV) in alkaline medium afforded the required 2-(sec-methylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 51798 methyl chloride; Monochloromethane; Artic; Chloromethane 74-87-3 CH3Cl 详情 详情

合成路线98

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isopropyl chloride (IV) in alkaline medium afforded the required 2-(isopropylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线99

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with isobutyl chloride (IV) in alkaline medium afforded the required 2-(isobutylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线100

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with sec-butyl chloride (IV) in alkaline medium afforded the required 2-(sec-butylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线101

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with cyclopentyl chloride (IV) in alkaline medium afforded the required 2-(cyclopentylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 51794 1-Chlorocyclopentane; Chlorocyclopentane; cyclopentyl chloride 930-28-9 C5H9Cl 详情 详情

合成路线102

该中间体在本合成路线中的序号：(II)

When 2-methyl-4-(3-methylphenyl)-3-oxobutanoic acid methyl ester (I) were reacted with thiourea (II), in the presence of sodium methoxide, condensation occurred with formation of 5-methyl-3,4-dihydro-6-(3-methylbenzyl)-4-oxo-2-thioxopyrimidine (III). Reaction of compound (III) with cyclohexyl chloride (IV) in alkaline medium afforded the required 2-(cyclohexylthio)-5-methyl-6-(3-methylbenzyl)-3,4-dihydro-4-oxopyrimidine

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51785 methyl (Z)-3-hydroxy-2-methyl-4-(3-methylphenyl)-2-butenoate C13H16O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51799 5-methyl-6-(3-methylbenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H14N2OS 详情 详情
(IV) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线103

该中间体在本合成路线中的序号：(II)

Condensation of 4-(1-naphthylmethyl)-3-oxobutanoic acid methyl ester (I) with thiourea (II) followed by alkylation of the thioxo group of compound (III) with sec-butyl iodide (IV) led to the formation of target compound

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51808 methyl (Z)-3-hydroxy-4-(1-naphthyl)-2-butenoate C15H14O3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 51806 6-(1-naphthylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C15H12N2OS 详情 详情
(IV) 51807 2-iodobutane; sec-Butyl iodide 513-48-4 C4H9I 详情 详情

合成路线104

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(1-naphthyl)acetonitrile (I) with 2-bromobutyric acid ethyl ester (II) by means of K2CO3 gives 2-ethyl-4-(!-naphthyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) by means of NaOMe yielding 5-ethyl-6-(1-naphthylmethyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is condensed with methylsulfanylmethyl iodide (VI) to afford the title pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18587 2-(1-naphthyl)acetonitrile 132-75-2 C12H9N 详情 详情
(II) 36668 ethyl 2-bromobutanoate 533-68-6 C6H11BrO2 详情 详情
(III) 51802 ethyl 2-ethyl-4-(1-naphthyl)-3-oxobutanoate C18H20O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51803 5-ethyl-6-(1-naphthylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C17H16N2OS 详情 详情
(VI) 51805 iodomethyl methyl sulfide; iodo(methylsulfanyl)methane C2H5IS 详情 详情

合成路线105

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(1-naphthyl)acetonitrile (I) with 2-bromobutyric acid ethyl ester (II) by means of K2CO3 gives 2-ethyl-4-(!-naphthyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) by means of NaOMe yielding 5-ethyl-6-(1-naphthylmethyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is condensed with ethylsulfanylmethyl iodide (VI) to afford the title pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18587 2-(1-naphthyl)acetonitrile 132-75-2 C12H9N 详情 详情
(II) 36668 ethyl 2-bromobutanoate 533-68-6 C6H11BrO2 详情 详情
(III) 51802 ethyl 2-ethyl-4-(1-naphthyl)-3-oxobutanoate C18H20O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51803 5-ethyl-6-(1-naphthylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C17H16N2OS 详情 详情
(VI) 51804 ethyl iodomethyl sulfide; 1-[(iodomethyl)sulfanyl]ethane C3H7IS 详情 详情

合成路线106

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with methyl chloride by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情

合成路线107

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isopropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线108

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with butyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 51818 n-Butyl chloride; Butyl chloride; N-Propylcarbinyl chloride; 1-Chlorobutane 109-69-3 C4H9Cl 详情 详情

合成路线109

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with malonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isobutyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线110

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with 1-ethylpropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线111

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with lmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclohexyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(III) 51810 ethyl 4-(2,6-difluorophenyl)-3-oxobutanoate C12H12F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51811 6-(2,6-difluorobenzyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C11H8F2N2OS 详情 详情
(VI) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线112

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with methyl chloride by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情

合成路线113

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isopropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线114

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with butyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 51818 n-Butyl chloride; Butyl chloride; N-Propylcarbinyl chloride; 1-Chlorobutane 109-69-3 C4H9Cl 详情 详情

合成路线115

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methylmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with isobutyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 13624 1-Chloro-2-methylpropane; Isobutyl chloride 513-36-0 C4H9Cl 详情 详情

合成路线116

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methyllmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)-2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with 1-ethylpropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线117

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-methyllmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--2-methyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with cyclohexyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(III) 51814 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxobutanoate C13H14F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51815 6-(2,6-difluorobenzyl)-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C12H10F2N2OS 详情 详情
(VI) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线118

该中间体在本合成路线中的序号：(IV)

The condensation of 2-(2,6-difluorophenyl)acetic acid (I) with 2-ethyllmalonic acid monoethyl ester sodium salt (II) gives 4-(2,6-difluorophenyl)--2-ethyl-3-oxobutyric acid ethyl ester (III), which is cyclized with thiourea (IV) to yield 6-(2,6-difluorobenzyl)-5-ethyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (V). Finally this compound is reacted with 1-ethylpropyl chloride (VI) by means of K2CO3 to afford the target pyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51812 potassium 2-(ethoxycarbonyl)butanoate C7H11KO4 详情 详情
(III) 51816 ethyl 4-(2,6-difluorophenyl)-2-ethyl-3-oxobutanoate C14H16F2O3 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 51817 6-(2,6-difluorobenzyl)-5-ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VI) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线119

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with isopropyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情

合成路线120

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with butyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 51818 n-Butyl chloride; Butyl chloride; N-Propylcarbinyl chloride; 1-Chlorobutane 109-69-3 C4H9Cl 详情 详情

合成路线121

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with isobutyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 13924 2-Butyl-4-chloro-5-(hydroxymethyl)imidazole; (2-Butyl-4-chloro-1H-imidazol-5-yl)methanol 79047-41-9 C8H13ClN2O 详情 详情

合成路线122

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with 1-methylpropyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 51797 1-methylpropyl chloride; 2-Chlorobutane; 1-Chloro-1-methylpropane; Sec-Butyl Chloride 78-86-4 C4H9Cl 详情 详情

合成路线123

该中间体在本合成路线中的序号：(V)

The methylation of 2-(2,6-difluorophenyl)acetic acid (I) with Me-Cl and LDA in THF/HMPA gives 2-(2,6-difluorophenyl)propionic acid (II), which is condensed with 2-methylmalonic acid monoethyl ester potassium salt (III) to yield 4´(2,6-difluorophenyl)-2-methyl-3-oxopentanoic acid (IV). The cyclization of (IV) with thiourea (V) affords 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one (VI), which is finally alkylated with cyclohexyl chloride (VII) to provide the target pyrimidinone derivative.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51809 2,6-Difluorophenylacetic acid 85068-28-6 C8H6F2O2 详情 详情
(II) 51820 2-(2,6-difluorophenyl)propionic acid C9H8F2O2 详情 详情
(III) 51813 potassium 3-ethoxy-2-methyl-3-oxopropanoate C6H9KO4 详情 详情
(IV) 51821 ethyl 4-(2,6-difluorophenyl)-2-methyl-3-oxopentanoate C14H16F2O3 详情 详情
(V) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(VI) 51822 6-[1-(2,6-difluorophenyl)ethyl]-5-methyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C13H12F2N2OS 详情 详情
(VII) 51795 chlorocyclohexane; Hexahydrochlorobenzene; Cyclohexyl chloride 542-18-7 C6H11Cl 详情 详情

合成路线124

该中间体在本合成路线中的序号：(III)

Condensation of 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (I) with dimethylformamide-dimethylacetal gives the enamino ketone (II). This is cyclized with thiourea (III) in the presence of NaOEt to produce the pyrimidine-2-thione (IV). Finally, S-alkylation of (IV) with 2-(methylsulfinyl)benzyl chloride (V) yields the target compound.

参考文献 中间体
合成目标
【1】 Wagner, G.K.; Laufer, S.A.; From imidazoles to pyrimidines: New inhibitors of cytokine release. J Med Chem 2002, 45, 13, 2733.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37912 2-(4-fluorophenyl)-1-(4-pyridinyl)-1-ethanone C13H10FNO 详情 详情
(II) 59069 (Z)-3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridinyl)-2-propen-1-one C16H15FN2O 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 59070 5-(4-fluorophenyl)-4-(4-pyridinyl)-2(1H)-pyrimidinethione C15H10FN3S 详情 详情
(V) 59071 2-(chloromethyl)phenyl methyl sulfoxide; [2-(chloromethyl)phenyl](methyl)oxo-lambda~4~-sulfane C8H9ClOS 详情 详情

合成路线125

该中间体在本合成路线中的序号：(II)

Condensation of the pyridyl enaminone (I) with thiourea (II) in the presence of NaOEt gives 2-mercapto-4-(pyridin-2-yl)pyrimidine (III), which is alkylated with iodomethane, producing the corresponding methylsulfanyl pyrimidine (IV). Subsequent displacement of the methylsulfanyl group of (IV) with hydrazine leads to the hydrazino pyrimidine (V). Rhodium acetate-catalyzed coupling between 3-diazo-2,4-pentanedione (VI) and 4-chlorophenol (VII) furnishes the chlorophenyl ether (VIII). The tile pyrazole derivative is finally obtained by condensation between hydrazine (V) and diketone (VIII) in the presence of p-toluenesulfonic acid in boiling EtOH.

参考文献 中间体
合成目标
【1】 Hirth, B.H.; Kane, J.L. Jr.; Janjigian, A.D.; et al.; Discovery of TNF-alpha induced apoptosis inhibitors with activity in a murine model of multiple sclerosis: Pyrazole series. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 273.
【2】 Hirth, B.H.; Sneddon, S.F.; Kane, J.L.; Vinick, F.; Qiao, S.; Nahill, S.R. (Genzyme Corp.); Modulators of TNF-alpha signaling. WO 0187849 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 58385 (E)-3-(dimethylamino)-1-(2-pyridinyl)-2-propen-1-one C10H12N2O 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 58386 4-(2-pyridinyl)-2-pyrimidinylhydrosulfide; 4-(2-pyridinyl)-2-pyrimidinethiol C9H7N3S 详情 详情
(IV) 58387 2-(methylsulfanyl)-4-(2-pyridinyl)pyrimidine; methyl 4-(2-pyridinyl)-2-pyrimidinyl sulfide C10H9N3S 详情 详情
(V) 58388 2-hydrazino-4-(2-pyridinyl)pyrimidine C9H9N5 详情 详情
(VI) 58389 　 C5H6N2O2 详情 详情
(VII) 35543 4-chlorophenol 106-48-9 C6H5ClO 详情 详情
(VIII) 58390 3-(4-chlorophenoxy)-2,4-pentanedione; 3-(4-chlorophenoxy)pentane-2,4-dione C11H11ClO3 详情 详情

合成路线126

该中间体在本合成路线中的序号：(VI)

　

参考文献 中间体
合成目标
【1】 Lu XZ, Zhang SW, Zhao YL. 200l. Preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino]ethoxybenzyl]thiazolidine-2,4-dione and its salts. 发明专利申请公开说明书，CN 1301700(本专利属于China Medicine Research and Development Centre, Peop Rep China)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17505 2-[methyl(2-pyridinyl)amino]-1-ethanol C8H12N2O 详情 详情
(II) 13909 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene 100-00-5 C6H4ClNO2 详情 详情
(III) 66659 N-methyl-N-(2-(4-nitrophenoxy)ethyl)pyridin-2-amine 329249-47-0 C14H15N3O3 详情 详情
(IV) 66660 N-(2-(4-aminophenoxy)ethyl)-N-methylpyridin-2-amine 　 C14H17N3O 详情 详情
(V) 66661 methyl 2-chloro-3-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)propanoate 　 C18H21ClN2O3 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线127

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Feng MS, Cao YP, Han AX, et al.2009. Synthesis of 2-[3-cyano-4-(isobutoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid. Zhongguo Xinyao Zazhi, 18(11): 1066～1069.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25109 4-hydroxybenzonitrile 767-00-0 C7H5NO 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 43801 4-hydroxybenzenecarbothioamide 25984-63-8 C7H7NOS 详情 详情
(IV) 21337 ethyl 2-chloro-3-oxobutanoate 609-15-4 C6H9ClO3 详情 详情
(V) 43803 ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C13H13NO3S 详情 详情
(VII) 67130 ethyl 2-(4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 144060-97-9 C17H21NO3S 详情 详情
(VIII) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情
(IX) 43805 ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C18H21NO4S 详情 详情
(X) 43797 ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C18H20N2O3S 详情 详情

合成路线128

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Zhang ZX,Xue MX, Zhao Y, et al. 2010.Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. Shengyan Yaoke Daxue Xuebao, 27(5): 365～368.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 43804 ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C14H13NO4S 详情 详情
(I) 25109 4-hydroxybenzonitrile 767-00-0 C7H5NO 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 21337 ethyl 2-chloro-3-oxobutanoate 609-15-4 C6H9ClO3 详情 详情
(IV) 43803 ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C13H13NO3S 详情 详情
(VI) 43806 ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C14H12N2O3S 详情 详情
(VII) 24599 1-bromo-2-methylpropane 78-77-3 C4H9Br 详情 详情
(VIII) 43797 ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate C18H20N2O3S 详情 详情

合成路线129

该中间体在本合成路线中的序号：(XXIV)

Reaction of 2-acetyl-4-methylpyridine (XVI) with (trimethylsilyl)trifluoromethane (XVII) in the presence of NaOAc in DMSO produces the silylated tertiary alcohol (XVIII), which is further desilylated to alcohol (XIX) by treatment with k2CO3 in MeOH. Treatment of alcohol (XIX) with MsCl and NaH in THF, followed by substitution of the resultant mesylate (XX) with Me3Al in cyclohexane/hexane provides 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (XXI). Metalation of pyridine (XXI) with LDA (prepared from n-hexyllithium and didiisopropylamine in hexane) in THF, followed by condensation with Weinreb amide (XXII) at –15 °C, and subsequent quenching with H2SO4 in toluene leads to ketone (XXIII). Cyclization of crude ketone (XXIII) with thiourea (XXIV) in the presence of NBS in toluene/EtOH gives the hydrobromide salt 2-aminothiazole (XXV), which is finally converted to the free base intermediate (X) using pyridine in THF . Alternatively, intermediate (XXI) can be obtained by lithiation of 2,4-lutidine (XXVI) with BuLi in methyltetrahydrofuran at –30 °C, followed by condensation with diethyl carbonate (XXVII) in the same solvent, and subsequent dialkylation with MeI to produce the 2-pyridylisobutyrate (XXVIII). Finally, ethyl ester (XXVIII) is hydrolyzed with NaOH in EtOH at 78 °C, and the obtained sodium carboxylate (XXIX) subsequently fluorinated by using SF4 and HF .

参考文献 中间体
合成目标
【1】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 67537 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine 　 C13H14F3N3S 详情 详情
(XVI) 67540 2-acetyl-4-methylpyridine；1-(4-Methylpyridin-2-yl)ethanone 59576-26-0 C8H9NO 详情 详情
(XVII) 67541 trimethyl(trifluoromethyl)silane 　 C4H9F3Si 详情 详情
(XVIII) 67542 4-methyl-2-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)pyridine 　 C12H18F3NOSi 详情 详情
(XIX) 67543 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol 　 C9H10F3NO 详情 详情
(XX) 67544 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-yl methanesulfonate 　 C10H12F3NO3S 详情 详情
(XXI) 67545 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine 　 C10H12F3N 详情 详情
(XXII) 17426 N-methoxy-N-methylacetamide 78191-00-1 C4H9NO2 详情 详情
(XXIII) 67546 1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)propan-2-one 　 C12H14F3NO 详情 详情
(XXIV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXV) 67547 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine hydrobromide 　 C13H14F3N3S.HBr 详情 详情
(XXVI) 67548 2,4-lutidine 108-47-4 C7H9N 详情 详情
(XXVII) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(XXVIII) 67549 ethyl 2-methyl-2-(4-methylpyridin-2-yl)propanoate 　 C12H17NO2 详情 详情
(XXIX) 67550 sodium 2-methyl-2-(4-methylpyridin-2-yl)propanoate 　 C10H12NaNO2 详情 详情

合成路线130

该中间体在本合成路线中的序号：(III)

Bromination of 1-(4-chloro-2-thienyl)ethanone (I) with Br2 in Et2O gives 2-bromo-1-(4-chloro-2-thienyl)ethanone (II), which by cyclocondensation with thiourea (III) in EtOH at 80 °C provides 2-amino-4-(4-chloro-2-thienyl)thiazole (IV). Treatment of thiazole (IV) with NBS in DMF and subsequent condensation with 1-cyclohexylpiperazine (V) by means of Et3N at 70 °C affords the 5-piperazinyl-thiazole derivative (VI). Coupling of the 2-aminothiazole (VI) with 5,6-dichloronicotinic acid (VII) in the presence of POCl3 in pyridine yields amide (VIII), which is then condensed with ethyl isonipecotate (IX) in THF at 50 °C to obtain the ethyl 1-(pyridyl)piperidine-4-carboxylate derivative (X). Finally, ethyl ester (X) is hydrolyzed by means of NaOH in MeOH .

参考文献 中间体
合成目标
【1】 Watanuki, S., Nagata, H., Wakayama, R. et al. 2-Acylaminothiazole derivative or salt thereof. EP 1466912, EP 2314586, JP 2009111001, US 2005153977, US 7638536, US 2010222329, US 2010222361, WO 2003062233.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 68277 1-(4-chloro-2-thienyl)ethanone;4-Chloro-2-acetylthiophene 34730-20-6 C6H5ClOS 详情 详情
(II) 68278 2-bromo-1-(4-chloro-2-thienyl)ethanone 　 C6H4BrClOS 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 68279 2-amino-4-(4-chloro-2-thienyl)thiazole 　 C7H5ClN2S2 详情 详情
(V) 23174 1-cyclohexylpiperazine 17766-28-8 C10H20N2 详情 详情
(VI) 68280 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine 　 C17H23ClN4S2 详情 详情
(VII) 68282 5,6-dichloronicotinic acid 41667-95-2 C6H3Cl2NO2 详情 详情
(VIII) 68281 5,6-dichloro-N-(4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)nicotinamide 　 C23H24Cl3N5OS2 详情 详情
(IX) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(X) 68283 ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate 　 C31H38Cl2N6O3S2 详情 详情

合成路线131

该中间体在本合成路线中的序号：(VIII)

　

参考文献 中间体
合成目标
【1】 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982.
【2】 胡艾希，徐娟娟，伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229
【3】 程清蓉，刘志雄，李翔，等.去甲氨噻肟酸乙酯的合成研究.化学世界，2007,48:480
【4】 郑庚修，李贺，赵叶青.制备去甲氨噻肟酸乙酯的方法：CN,Patent 101,007,793,2007.
【5】 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743.
【6】 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738.
【7】 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995.
【8】 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001.
【9】 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989.
【10】 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997.
【11】 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(II) 39961 ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate C6H8ClNO4 详情 详情
(III) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情
(IV) 48461 (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate；ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate C26H23N3O3S 详情 详情
(V) 48462 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid 128438-01-7 C24H19N3O3S 详情 详情
(VI) 69620 1-(2,5-dimethoxyphenyl)propan-2-amine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate C24H19N3O3S.C11H17NO2 详情 详情
(VII) 69619 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate C31H22N4O2S3 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线132

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 程清蓉，刘志雄，李翔，等.去甲氨噻肟酸乙酯的合成研究.化学世界，2007,48:480
【2】 郑庚修，李贺，赵叶青.制备去甲氨噻肟酸乙酯的方法：CN,Patent 101,007,793,2007.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线133

该中间体在本合成路线中的序号：(IV)

　

参考文献 中间体
合成目标
【1】 Gonzalez M,Rodriguez Z,Tolon B,et al.An alternative procedure for preparation of cedinir.Farmaco,2003,58:409.
【2】 朱阳，刘国庆，陆建中，等.（Z）-2-(2-氨基噻唑-4-基)-2-三苯甲氧基亚氨基乙酸合成的改进.中国医药工业杂志，1997,28:27.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(III) 39961 ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate C6H8ClNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线134

该中间体在本合成路线中的序号：(III)

　

参考文献 中间体
合成目标
【1】 任红阳，厉昆，陈亮.制备（Z)-2-(2-氨基-4-噻唑)-2-羟基亚胺乙酸酯及其衍生物的方法：CN,Patent 1,709,879,2005.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69621 (Z)-ethyl 2-(hydroxymethylene)-3-oxobutanoate C7H10O4 详情 详情
(II) 69622 (Z)-ethyl 4-chloro-2-(hydroxymethylene)-3-oxobutanoate C7H9ClO4 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线135

该中间体在本合成路线中的序号：(III)

　

参考文献 中间体
合成目标
【1】 宫平，宫凤仙，王钝.2-(2-氨基-噻唑)-(Z)-羟基亚胺基乙酸乙酯的合成.沈阳药科大学学报，1998,15:235.
【2】 Arita H,Ikeda K,Akamatsu H.Production of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid ester:JP,Patent 09,194,470 1997.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 36651 Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate 13176-46-0 C6H9BrO3 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线136

该中间体在本合成路线中的序号：(VI)

　

参考文献 中间体
合成目标
【1】 Datta D,Dantu M,Mishra B,et al.Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates:WO,Patent 2,004,058,695,2004.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 58114 4-bromo-2-(methoxyimino)-3-oxobutanoic acid;(Z)-4-bromo-2-(methoxyimino)-3-oxobutanoic acid C5H6BrNO4 详情 详情
(II) 69629 　 C3H7Cl2NO3S 详情 详情
(III) 69630 　 C8H12BrClN2O6S 详情 详情
(IV) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(V) 69631 (6R,7R)-7-((Z)-4-bromo-2-(methoxyimino)-3-oxobutanamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H14BrN3O6S 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线137

该中间体在本合成路线中的序号：(IX)

　

参考文献 中间体
合成目标
【1】 Lopez M,Rodriguez Z,Gonzalez M,et al.Synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino)acetic acids.Farmaco,2000,55:40.
【2】 Parthasaradhi Reddy B,Rathnakar Reddy K,Raji Reddy R,et al.An improved process for the preparation of ceficime:WO,Patent 2,006,103,686,2006.
【3】 程先波，胡立蓬，叶树祥，等.头孢克肟的制备方法：CN,Patent 101,319,246,2008.
【4】 潘行远.一种头孢克肟的合成方法：CN,Patent 101,016,305,2007.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27907 Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate 1694-31-1 C8H14O3 详情 详情
(II) 69635 (Z)-tert-butyl 2-(hydroxyimino)-3-oxobutanoate C8H13NO4 详情 详情
(III) 69636 (Z)-tert-butyl 2-((2-methoxy-2-oxoethoxy)imino)-3-oxobutanoate C11H17NO6 详情 详情
(IV) 69637 4-Chloro-2-[(2-methoxy-2-oxoethoxy)imino]-3-oxobutanoic acid；4-Chloro-2-(Z)-methoxycarbonylmethoxyimino-3-oxobutyric acid;(Z)-4-chloro-2-((2-methoxy-2-oxoethoxy)imino)-3-oxobutanoic acid 95759-10-7 C7H8ClNO6 详情 详情
(V) 69638 (Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetic acid 80544-17-8 C8H9N3O5S 详情 详情
(VI) 69639 (Z)-methyl 2-(((1-(2-aminothiazol-4-yl)-2-(benzo[d]thiazol-2-ylthio)-2-oxoethylidene)amino)oxy)acetate 246035-38-1 C15H12N4O4S3 详情 详情
(VII) 69640 (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-((2-methoxy-2-oxoethoxy)imino)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C17H17N5O7S2 详情 详情
(VIII) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(IX) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(X) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
Extended Information