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【结 构 式】

【分子编号】19310

【品名】urea

【CA登记号】57-13-6

【 分 子 式 】CH4N2O

【 分 子 量 】60.05564

【元素组成】C 20% H 6.71% N 46.65% O 26.64%
与该中间体有关的原料药合成路线共 16 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation in DMF of 1,1-dimethyl-2-[(aminocarbonyl)amino]ethylamine (III) [prepared from 1,2-diamino-2-methylpropane (I) and urea (II)] and 2,3-epoxypropyl o-fluorobenzoate (VI) [prepared from o-fluorobenzoyl chloride (VI) and glycidol (V) in diethyl ether using triethylamine as a proton scavenger], followed by salt formation using 98% sulfuric acid in ethanol yields ACC-9089.

参考文献 中间体
合成目标
【1】 Mai, K.X.; Kam, S.T.; Matier, W.L.; O'Donnel, J.P.; Sum, C.Y.; Gorczynski, R.J.; Lee, R.J.; Stamfli, H.F.; Barcelon-Yang, C.; Anderson, W.G.; Borgman, R.J.; [(Arylcarbonyl)oxy]propanolamines. 1. Novel beta-blockers with ultrashort duration of action. J Med Chem 1984, 27, 8, 1007.
【2】 Day, B.W.; Pento, J.T.; ACC-9089. Drugs Fut 1985, 10, 6, 447.
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) 29645 2-amino-1,1-dimethylethylamine; 2-methyl-1,2-propanediamine 811-93-8 C4H12N2 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 29646 N-(2-amino-2-methylpropyl)urea C5H13N3O 详情 详情
(IV) 19551 2-Fluorobenzoyl chloride 393-52-2 C7H4ClFO 详情 详情
(V) 29648 2-oxiranylmethanol 556-52-5 C3H6O2 详情 详情
(VI) 29647 2-oxiranylmethyl 2-fluorobenzoate C10H9FO3 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 heating of 3,5-dimethyl-1-chloroadamantane (I) with urea (II) at 165-85 C.

参考文献 中间体
合成目标
【1】 Burkhard, J.; Landa, S.; CZ 146405 .
【2】 Peteri, D.; Scherm, A. (Merz Pharmaceuticals GmbH); Process for the preparation of 1,3,5-trisubstd. adamantan derivs.. DE 2318461 .
【3】 Castaner, J.; Thorpe, P.; Memantine. Drugs Fut 1976, 1, 9, 427.
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) 34126 1-chloro-3,5-dimethyladamantane 707-36-8 C12H19Cl 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

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4

该中间体在本合成路线中的序号：(VII)

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5

该中间体在本合成路线中的序号：(V)

The condensation of N-(2-bromoethyl)-2-nitrobenzamide (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of Na2CO3 in refluxing methyl isobutyl ketone gives N-[2-[4-(4-fluorobenzoyl)-2-piperidinyl]ethyl]-2-nitrobenzamide (III), which is reduced with H2 over Pt/C in methanol yielding the corresponding amino derivative (IV). Finally, this compound is cyclized with urea (V) in refluxing xylene.

参考文献 中间体
合成目标
【1】 Janssen, C.G.M.; Lenoir, H.A.C.; Thijssen, J.B.A.; Knaeps, A.G.; Verluyten, W.L.M.; Heykants, J.J.P.; Synthesis of 3H- and 14C-ketanserin. J Label Compd Radiopharm 1988, 25, 7, 783-92.
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) 21496 N-(2-bromoethyl)-2-nitrobenzamide C9H9BrN2O3 详情 详情
(II) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情
(III) 21498 N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-nitrobenzamide C21H22FN3O4 详情 详情
(IV) 21499 2-amino-N-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]benzamide C21H24FN3O2 详情 详情
(V) 19310 urea 57-13-6 CH4N2O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.

参考文献 中间体
合成目标
【1】 Merz, K.-H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand, G.; Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J Med Chem 1998, 41, 24, 4733.
【2】 Taylor, E.C. Jr.; Sherman, W.R.; Diaminouracil hydrochloride. Org Synth Coll 1957, 37, 15.
【3】 Schopf, C.; Reichert, R.; Zur kenntnis des leukopterins. Liebigs Ann Chem 1941, 548, 82.
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) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 19311 6-amino-2,4(1H,3H)-pyrimidinedione 873-83-6 C4H5N3O2 详情 详情
(IV) 19312 6-amino-5-nitroso-2,4(1H,3H)-pyrimidinedione C4H4N4O3 详情 详情
(V) 19313 5,6-diamino-2,4(1H,3H)-pyrimidinedione 3240-72-0 C4H6N4O2 详情 详情
(VI) 19314 2,4,6,7-pteridinetetrol C6H4N4O4 详情 详情
(VII) 19315 2,4,6,7-tetrachloropteridine C6Cl4N4 详情 详情
(VIII) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IX) 19317 2,6,7-trichloro-4-(1-pyrrolidinyl)pteridine C10H8Cl3N5 详情 详情
(X) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XI) 19319 N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine C17H16Cl2N6 详情 详情
(XII) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(X)

The reaction of 4-hydroxypyridine-3-sulfonic acid (VI) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (VII), which is treated with ammonia at room temperature yielding the sulfonamide (VIII). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IX), which is cyclized with urea (X) to provide the pyridothiadiazinone (XI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (XII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (XIII). Finally, this compound (XIII) is condensed with the chiral intermediate (R)(-)-1,2-dimethylpropylamine (R)(-)-(I) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (XIII) with the chiral intermediate (S)(+)-1,2-dimethylpropylamine (S)(+)-(I) to afford the chiral (S)(+)-target compound.

参考文献 中间体
合成目标
【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13.
【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(R)(-)-(I) 38922 (1R)-1,2-dimethylpropylamine; (2R)-3-methyl-2-butanamine C5H13N 详情 详情
(S)(+)-(I) 38923 (1S)-1,2-dimethylpropylamine; (2S)-3-methyl-2-butanamine C5H13N 详情 详情
(VI) 28520 4-hydroxy-3-pyridinesulfonic acid C5H5NO4S 详情 详情
(VII) 28521 4-chloro-3-pyridinesulfonyl chloride C5H3Cl2NO2S 详情 详情
(VIII) 22151 4-chloro-3-pyridinesulfonamide C5H5ClN2O2S 详情 详情
(IX) 38924 4-amino-3-pyridinesulfonamide C5H7N3O2S 详情 详情
(X) 19310 urea 57-13-6 CH4N2O 详情 详情
(XI) 38925 1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C6H5N3O3S 详情 详情
(XII) 38926 3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione C6H5N3O2S2 详情 详情
(XIII) 38927 3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione C7H7N3O2S2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(V)

Esterification of (4'-biphenyl)acetic acid (I) with ethanol and p-toluenesulfonic acid provides the corresponding ethyl ester (II). Subsequent carbethoxylation of (II) with diethyl carbonate (III) under Claisen's condensation conditions furnishes the biphenylmalonate (IV). Cyclization of malonate (IV) with urea (V) in the presence of NaOEt leads to 5-(4'-biphenyl)barbituric acid (VI), which is further brominated to (VII) employing Br2 in aqueous HBr. The title compound is finally obtained by displacement of the 5-bromo barbituric acid (VII) with N-(4-nitrophenyl)piperazine (VIII) in refluxing MeOH.

参考文献 中间体
合成目标
【1】 Bosies, E.; Esswein, A.; Grams, F.; Krell, H.-W.; Menta, E. (Roche Diagnostics GmbH); New barbituric acid derivs., processes for their production and pharmaceutical agents containing these cpds.. DE 19548624; EP 0869947; JP 2000505069; US 6110924; US 6472396; WO 9723465 .
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) 58170 2-[1,1'-biphenyl]-4-ylacetic acid C14H12O2 详情 详情
(II) 58171 ethyl 2-[1,1'-biphenyl]-4-ylacetate C16H16O2 详情 详情
(III) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(IV) 58172 diethyl 2-[1,1'-biphenyl]-4-ylmalonate C19H20O4 详情 详情
(V) 19310 urea 57-13-6 CH4N2O 详情 详情
(VI) 58173 5-[1,1'-biphenyl]-4-yl-2,4,6(1H,3H,5H)-pyrimidinetrione C16H12N2O3 详情 详情
(VII) 58174 5-[1,1'-biphenyl]-4-yl-5-bromo-2,4,6(1H,3H,5H)-pyrimidinetrione C16H11BrN2O3 详情 详情
(VIII) 20299 1-(4-nitrophenyl)piperazine 6269-89-2 C10H13N3O2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

Acid-catalyzed condensation of ethanolamine (I) with urea (II) produced oxazolidinone (III). Subsequent reaction of (III) with triethyloxonium fluoborate yielded ethoxyoxazoline (IV). This was finally condensed with 2-(3,4-dimethoxyphenyl)- ethylamine to afford the title compound, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Xu, J.Y.; et al.; Synthesis of imidazoline, oxazoline derivatives and antihypertensive activity. J Chin Pharm Univ 1998, 29, 5, 336.
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) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 21456 1,3-oxazolidin-2-one 497-25-6 C3H5NO2 详情 详情
(IV) 25692 4,5-dihydro-1,3-oxazol-2-yl ethyl ether; 2-ethoxy-4,5-dihydro-1,3-oxazole C5H9NO2 详情 详情
(V) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

The acylation of 3-aminobenzoic acid with acetic anhydride in ethyl acetate gives the corresponding acetamide (II), which is treated with SOCl2 in refluxing ethyl acetate yielding 3-(trifluoroacetamido)benzoyl chloride (III). The reaction of (III) with urea (IV) in toluene at 100 C gives the acylated urea (V), which is deprotected with butylamine in refluxing methanol to afford N-(3-aminobenzoyl)urea (VI). The acylation of (VI) with chloroacetyl chloride (VII) in dimethylacetamide provides the corresponding amide (VIII), which is finally treated with NaI in dimethylacetamide.

参考文献 中间体
合成目标
【1】 Bekesi, J.G.; Holland, J.F.; Jiang, J.-D.; Ma, L.; Roboz, J.; Deng, L.; Weisz, I.; Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas. Anti-Cancer Drug Des 1998, 13, 7, 735.
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) 26638 3-Aminobenzoic acid 99-05-8 C7H7NO2 详情 详情
(II) 26639 3-[(2,2,2-trifluoroacetyl)amino]benzoic acid C9H6F3NO3 详情 详情
(III) 26640 3-[(2,2,2-trifluoroacetyl)amino]benzoyl chloride C9H5ClF3NO2 详情 详情
(IV) 19310 urea 57-13-6 CH4N2O 详情 详情
(V) 26641 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2,2,2-trifluoroacetamide C10H8F3N3O3 详情 详情
(VI) 26642 N-(3-aminobenzoyl)urea C8H9N3O2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 26643 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2-chloroacetamide C10H10ClN3O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：

3-Aminobenzoic acid (I) was protected as the trifluoroacetamide (II) using trifluoroacetic anhydride and then converted to acid chloride (III) by means of SOCl2. Subsequent condensation of (III) with urea provided 3-(trifluoroacetamido)benzoylurea (IV). After cleavage of the trifluoroacetamido group of (IV) by treatment with methanolic n-butylamine, the deprotected aniline (V) was coupled with bromoacetyl bromide in DMA to furnish the title bromoacetamide.

参考文献 中间体
合成目标
【1】 Bekesi, J.G.; Holland, J.F.; Jiang, J.-D.; Ma, L.; Roboz, J.; Deng, L.; Weisz, I.; Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas. Anti-Cancer Drug Des 1998, 13, 7, 735.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
19310 urea 57-13-6 CH4N2O 详情 详情
(I) 26638 3-Aminobenzoic acid 99-05-8 C7H7NO2 详情 详情
(II) 26639 3-[(2,2,2-trifluoroacetyl)amino]benzoic acid C9H6F3NO3 详情 详情
(III) 26640 3-[(2,2,2-trifluoroacetyl)amino]benzoyl chloride C9H5ClF3NO2 详情 详情
(IV) 26641 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2,2,2-trifluoroacetamide C10H8F3N3O3 详情 详情
(V) 26642 N-(3-aminobenzoyl)urea C8H9N3O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(V)

The reaction of 4-hydroxypyridine-3-sulfonic acid (I) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (II), which is treated with ammonia at room temperature yielding the sulfonamide (III). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IV), which is cyclized with urea (V) to provide the pyridothiadiazinone (VI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (VII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (VII) (2). Finally, this compound (VIII) is condensed with the chiral intermediate (R)(-)-1-methylpropylamine (R)(-)-(IX) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (VIII) with the chiral intermediate (S)(+)-1-methylpropylamine (S)(+)-(IX) to afford the chiral (S)(+)-target compound.

参考文献 中间体
合成目标
【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13.
【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(R)(-)-(IX) 38928 (1R)-1-methylpropylamine; (2R)-2-butanamine C4H11N 详情 详情
(S)(+)-(IX) 38929 (1S)-1-methylpropylamine; (2S)-2-butanamine C4H11N 详情 详情
(I) 28520 4-hydroxy-3-pyridinesulfonic acid C5H5NO4S 详情 详情
(II) 28521 4-chloro-3-pyridinesulfonyl chloride C5H3Cl2NO2S 详情 详情
(III) 22151 4-chloro-3-pyridinesulfonamide C5H5ClN2O2S 详情 详情
(IV) 38924 4-amino-3-pyridinesulfonamide C5H7N3O2S 详情 详情
(V) 19310 urea 57-13-6 CH4N2O 详情 详情
(VI) 38925 1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C6H5N3O3S 详情 详情
(VII) 38926 3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione C6H5N3O2S2 详情 详情
(VIII) 38927 3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione C7H7N3O2S2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(A)

This compound can be prepared in several ways: 1) By cyclization of 2-isopropylamino-4-methyl-4'-fluorobenzophenone (I) with potassium cyanate in hot acetic acid. 2) By cyclization of 2-isopropylamino-4-methyl-4'-fluorobenzophenone (I) with urea (A) or alkyl carbamates in the presence of an acid. 3) By condensation of 2-isopropylamino-4-methyl-4'-fluorobenzophenone (I) with ethyl chloroformate (B) at 100 C to give 2-(N ethoxycarbonyl-N-isopropylamino)-4-methyl-4'-fluorobenzophenone (II), followed by cyclization with ammonium acetate at 130 C.

参考文献 中间体
合成目标
【1】 Serradell, M.N.; Blancafort, P.; Castañer, J.; Hilier, K.; Fluproquazone. Drugs Fut 1980, 5, 3, 130.
【2】 Hardtmann, G.E.; FR 2174828 .
【3】 Hardtmann, G.E.; DE 2230393 .
【4】 Gamboni, G.; DE 2753970 .
【5】 Hardtmann, G.E.; US 3937705 .
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) 12229 (2R,3S)-5,5-Dimethoxy-3-(phenylselanyl)-1,2-pentanediol C13H20O4Se 详情 详情
(A) 19310 urea 57-13-6 CH4N2O 详情 详情
(I) 39078 (4-fluorophenyl)[2-(isopropylamino)-4-methylphenyl]methanone C17H18FNO 详情 详情
(II) 39079 ethyl 2-(4-fluorobenzoyl)-5-methylphenyl(isopropyl)carbamate C20H22FNO3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(X)

The cyclization between 3,4-difluorobenzaldehyde (VIII), methyl 4-methoxyacetoacetate (IX) and urea (X) in the presence of cuprous oxide and boron trifluoride etherate gave rise to racemic pyrimidinone (XI). Optical resolution of (XI) by means of chiral HPLC furnished the desired (-)-enantiomer (XII), which was then hydrolyzed to carboxylic acid (XIII). Alternatively, kinetic resolution of (XI) by enzymatic hydrolysis using subtilistin furnished the desired (-)-carboxylic acid (XIII), which was then separated from the unreacted (+)-ester. Finally, coupling of carboxylic acid (XIII) with amine (V) using EDC and HOBt yielded the title amide.

参考文献 中间体
合成目标
【1】 Rittle, K.; et al.; Dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 90.
【2】 Selnick, H.G.; Barrow, J.C.; Nanterment, P.G.; et al.; In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha1A receptor antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 2000, 43, 14, 2703.
【3】 Selnick, H.G.; Nantermet, P.G.; Barrow, J.C. (Merck & Co., Inc.); alpha1a Adrenergic receptor antagonists. WO 0006565 .
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) 39302 3-[4-(4-fluorophenyl)-1-piperidinyl]propylamine; 3-[4-(4-fluorophenyl)-1-piperidinyl]-1-propanamine C14H21FN2 详情 详情
(VIII) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(IX) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(X) 19310 urea 57-13-6 CH4N2O 详情 详情
(XI) 39303 methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XII) 39304 methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XIII) 39305 (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid C13H12F2N2O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XXIX)

In a related synthetic method, condensation between 4-methoxyacetoacetate (XIV), 3,4-difluorobenzaldehyde (XVII) and urea (XXIX) in the presence of copper acetate and boron trifluoride etherate furnished the racemic pyrimidinone (XXX). Enzymatic resolution of (XXX) by incubation with subtilisin yielded a separable mixture of the (R)-acid (XXXII) and the unreacted (S)-ester (XXXI). Alternatively, the (S)-enantiomer (XXXI) was isolated by chiral preparative HPLC. Pyrimidinone (XXXI) was activated by conversion to either aryl carbamate (XXXIII) using 4-nitrophenyl chloroformate or to imidazolide (XXXIV) with carbonyl diimidazole. Finally, coupling of the intermediate amine (X) with either the carbamate (XXXIII) or the imidazolide (XXXIV) furnished the title compound.

参考文献 中间体
合成目标
【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301.
【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 .
【3】 Evans, B.; Dunn, M.; Lagu, B.; Kari, H.P.; Nagarathnam, D.; Vyas, K.P.; Cui, D.; Davis, M.R.; Zhang, K. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 0037026 .
【4】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 .
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) 48387 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine C13H21N3 详情 详情
(XIV) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(XVII) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(XXIX) 19310 urea 57-13-6 CH4N2O 详情 详情
(XXX) 39303 methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXI) 48402 methyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXII) 39304 methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXIII) 48400 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C21H17F2N3O8 详情 详情
(XXXIV) 48401 methyl (4S)-4-(3,4-difluorophenyl)-3-(1H-imidazol-1-ylcarbonyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C18H16F2N4O5 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Cyclocondensation of ethyl 3-amino-4-methyl-2-thiophenecarboxylate (I) with urea (II) at 190 °C gives 7-methylthieno[3,2-d]pyrimidine-2,4-dione (III), which is chlorinated with POCl3 at reflux to yield 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (IV). Condensation of compound (IV) with morpholine (V) in MeoH affords 2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine (VI) , which, after metalation with BuLi in THF, is formylated with DMF, providing the thieno[3,2-d]pyrimidine-6-carbaldehyde derivative (VII) . Reductive amination of aldehyde (VII) with N-Boc-piperazine (VIII) in the presence of HC(oMe)3, AcoH and naBH(oAc)3 in dichloroethane gives the piperazinylmethyl derivative (IX) , which by cleavage of the Boc moiety by means of HCl in CH2Cl2 produces the N-deprotected piperazine derivative (X). N-Acylation of compound (X) with (S)-lactic acid (XI) in the presence of HATU and DIEA in DMF generates the corresponding amide (XII), which is finally submitted to Suzuki coupling with the boronate ester (XIII) in the presence of PdCl2(PPh3)4 and Na2CO3 or K2CO3 in acetonitrile .
Alternatively, Suzuki coupling of chloro intermediate (IX) with boronate ester (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in acetonitrile under microwave irradiation produces the 2-aminopyrimidine derivative (XIV), which is then N-deprotected by means of HCl in CH2Cl2 to yield the free piperazine derivative (XV). Finally, piperazine derivative (XV) is condensed with (S)-lactic acid (XI) in the presence of DIEA and HATU in DMF .

参考文献 中间体
合成目标
【1】 Belvin, M., Friedman, L., Hoeflich, K. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use. Cn 101939006, EP 2205242, JP 2010539177, KR 2010085912, US 2011223619, US 8247397, Wo 2009036082.
【2】 Ebens, A.J. Jr., Friedman, L. (Genentech, Inc.). Combination of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic a gents for the treatment of hematopoietic malignancies. Cn 102369011, EP 2405916, JP 2012520313, KR 2011132442, US 2010233164, US 8536161, Wo 2010105008.
【3】 Sutherlin, D.P., Bao, L., Berry, M. et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) kinase inhibitor. J Med Chem 2011, 54(21): 7579-87.
【4】 Bayliss, T., Chuckowree, I., Folkes, A. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Phosphoinositide 3-kinase inhibitor compounds and methods of use. CA 2671782, EP 2114949, EP 2518074, JP 2010512338, US 2008242665, US 7888352, US 8383620, US 2013129820, WO 2008070740.
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) 68092 ethyl 3-amino-4-methyl-2-thiophenecarboxylate 　 C8H11NO2S 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 68093 7-methylthieno[3,2-d]pyrimidine-2,4-dione 35265-81-7 C7H6N2O2S 详情 详情
(IV) 68094 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine 35265-83-9 C7H4Cl2N2S 详情 详情
(V) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VI) 68095 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine;2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine 　 C11H12ClN3OS 详情 详情
(VII) 68096 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 　 C12H12ClN3O2S 详情 详情
(VIII) 68097 tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18NO2 详情 详情
(IX) 68098 tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate 　 C21H30ClN5O3S 详情 详情
(X) 68099 4-(2-chloro-7-methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine hydrochloride 　 C16H22ClN5OS.HCl 详情 详情
(XI) 68100 (S)-lactic acid;(S)-2-hydroxypropanoic acid 　 C3H6O3 详情 详情
(XII) 68101 (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one 　 C19H26ClN5O3S 详情 详情
(XIII) 68102 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine 402960-38-7 C10H16BN3O2 详情 详情
(XIV) 68103 tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate 　 C25H34N8O3S 详情 详情
(XV) 68104 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine 　 C20H26N8OS 详情 详情
Extended Information