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【结 构 式】

【分子编号】10295

【品名】p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride

【CA登记号】122-01-0

【 分 子 式 】C7H4Cl2O

【 分 子 量 】175.01356

【元素组成】C 48.04% H 2.3% Cl 40.51% O 9.14%
与该中间体有关的原料药合成路线共 22 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17合成路线18合成路线19合成路线20合成路线21合成路线22

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of p-chlorobenzoic acid (I) with SOCl2 gives p-chlorobenzoyl chloride (II), which is esterified with 4-fluorophenol (III) affording 4-fluorophenyl-4-chlorobenzoate (IV). The isomerization of (IV) with AlCl3 yields 4-chloro-2'-hydroxy-5'-fluorobenzophenone (V), which is condensed with 4-aminobutyric acid (VI) by means of sodium methoxide in ethanol giving 4-[[alpha-(p-chlorophenyl)-5-fluoro-2-hydroxybenzylidene]amino]butyric acid (VII). The reaction of (VII) with SOCl2 in THF affords the corresponding acyl chloride (VIII), which is then treated with NH3. An alternative way of converting the acid (VII) into its amide is by treatment with carbonyldiimidazole (A) and liquid NH3 in THF.

参考文献 中间体
合成目标
【1】 Kaplan, J.P.; et al.; Derives alpha-phenyl-benzylideniques des acides amines. FR 2358887 .
【2】 Kaplan, J.P.; et al. (Sanofi-Synthelabo); Benzylidene derivatives. ES 450300; FR 2319338; GB 1506808; JP 52019644; US 4094992 .
【3】 Kaplan, J.P.; et al. (Sanofi-Synthelabo); Preparation of benzylidene derivatives. DE 2830034; ES 471606; FR 2397397; GB 2001066; JP 54019953 .
【4】 Serradell, M.N.; Owen, R.T.; Blancafort, P.; Castaner, J.; Progabide. Drugs Fut 1980, 5, 9, 445.
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) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(I) 18359 p-chlorobenzoic acid; 4-chlorobenzoic acid 74-11-3 C7H5ClO2 详情 详情
(II) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(III) 19639 4-fluorophenol 371-41-5 C6H5FO 详情 详情
(IV) 32698 4-Fluorophenyl 4-chlorobenzoate C13H8ClFO2 详情 详情
(V) 32699 (4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methanone 62433-26-5 C13H8ClFO2 详情 详情
(VI) 13620 4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid 56-12-2 C4H9NO2 详情 详情
(VII) 32700 4-[[(Z)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylidene]amino]butyric acid C17H15ClFNO3 详情 详情
(VIII) 32701 4-[[(Z)-(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylidene]amino]butanoyl chloride C17H14Cl2FNO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of chlorobenzoyl chloride (I) with trimethyl phosphite gives dimethyl p-chlorobenzoylphosphonate (II). Addition of dimethyl phosphite to (II) in the presence of 80% molar amount of an organic base (e.g., di-n-butylamine) in diethyl ether or toluene at 0 C produces the final compound.

参考文献 中间体
合成目标
【1】 Bentzen, C.L.; Nguyen, M.L.; Niesor, E.; US 4309364 .
【2】 Nguyen, M.L.; Bentzen, C.L.; SR-202. Drugs Fut 1982, 7, 4, 271.
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) 12642 Trimethyl phosphite 121-45-9 C3H9O3P 详情 详情
(B) 32359 dimethyl phosphonate 868-85-9 C2H7O3P 详情 详情
(I) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(II) 36391 dimethyl 4-chlorobenzoylphosphonate C9H10ClO4P 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

By acylation of L-tryptophan (I) with 4-chlorobenzoyl chloride (II).

参考文献 中间体
合成目标
【1】 Rovati, L.S.; Picciola, G.; Makovec, F. (Rotta Research Laboratorium SpA); N-p-Chlorobenzoyl tryptophane salts and compsns. thereof. US 4000297 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; de Angelis, L.; Benzotript. Drugs Fut 1983, 8, 6, 487.
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) 30836 L-tryptophan 73-22-3 C11H12N2O2 详情 详情
(II) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

This compound can be prepared in several different ways: 1) By reaction of p-chlorobenzoyl chloride (I) with N-(2-aminoethyl)morpholine (II) in pyridine. 2) By reaction of p-chlorobenzoyl anhydride (III) with N-(2-aminoethyl)morpholine (II) in pyridine. 3) By reaction of methyl p-chlorobenzoate (IV) with N-(2-aminoethyl)morpholine (II) at 120 C. 4) By reaction of N-(p-chlorobenzoyl)succinimide (V) with N-(2-aminoethyl)morpholine (II) in dioxane. 5) By reaction of p-nitrophenyl p-chlorobenzoate (VI) with N-(2-aminoethyl)morpholine (II) in THF. 6) By reaction of p-chloro-N-(2-chloroethyl)benzamide (VII) with morpholine (VIII) at 100 C. 7) By reaction of p-chlorobenzoylaziridine (IX) with morpholine (VIII) in refluxing toluene. 8) By reaction of p-chlorobenzaldehyde (X) with N-(2-aminoethyl)morpholine (II) in refluxing benzene to give 4-[2-[(p-chlorobenzylidene)amino]ethyl]morpholine (XI), followed by an oxidation with H2O2 in methanol. 9) By reaction of p-chloro-N-(2-morpholinoethyl)thiobenzamide (XII) with lead tetraacetate in refluxing water. 11) By reaction of p-chlorobenzoic acid (XIV) with N-(2-aminoethyl)morpholine (II) by means of dicyclohexylcarbodiimide in pyridine, or by means of chloroformic acid ethyl ester and triethylamine in acetone. 10) By isomerization of (alpha-(p-chlorophenyl)-N-(2-morpholinoethyl)nitrone (XIII) in hot acetic acid - acetic anhydride, followed by a treatment with NaOH.

参考文献 中间体
合成目标
【1】 Bukard, W.; Wyss, P.C. (F. Hoffmann-La Roche AG); Benzamides. BE 0851422; CA 1076112; DE 2706179; FR 2340940; GB 1512194; JP 52100476; NL 7701144; US 4210754; ZA 7700488 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Grau, M.; Moclobemide. Drugs Fut 1983, 8, 2, 124.
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(II) 12880 4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide 2038-03-1 C6H14N2O 详情 详情
(III) 30702 4-chloro-1-benzenecarboxylic anhydride C14H8Cl2O3 详情 详情
(IV) 30703 methyl 4-chlorobenzoate 1126-46-1 C8H7ClO2 详情 详情
(V) 30704 1-(4-chlorobenzoyl)-2,5-pyrrolidinedione C11H8ClNO3 详情 详情
(VI) 30705 4-nitrophenyl 4-chlorobenzoate C13H8ClNO4 详情 详情
(VII) 30706 4-chloro-N-(2-chloroethyl)benzamide C9H9Cl2NO 详情 详情
(VIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IX) 30707 1-aziridinyl(4-chlorophenyl)methanone C9H8ClNO 详情 详情
(X) 29029 4-chlorobenzaldehyde 104-88-1 C7H5ClO 详情 详情
(XI) 30708 N-[(E)-(4-chlorophenyl)methylidene]-2-(4-morpholinyl)-1-ethanamine; N-[(E)-(4-chlorophenyl)methylidene]-N-[2-(4-morpholinyl)ethyl]amine C13H17ClN2O 详情 详情
(XII) 30709 4-chloro-N-[2-(4-morpholinyl)ethyl]benzenecarbothioamide C13H17ClN2OS 详情 详情
(XIII) 30710 [(Z)-(4-chlorophenyl)methylidene][2-(4-morpholinyl)ethyl]ammoniumolate C13H17ClN2O2 详情 详情
(XIV) 18359 p-chlorobenzoic acid; 4-chlorobenzoic acid 74-11-3 C7H5ClO2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.

参考文献 中间体
合成目标
【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVS) 10291 (S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (2S)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3S)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether 78342-42-4 C9H16N2O2 详情 详情
(VR) 10292 (3R,6S)-3-[(2-Chloro-4-quinolinyl)methyl]-6-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; 2-Chloro-4-[[(2R,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline C19H22ClN3O2 详情 详情
(VIR) 10293 methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate C13H13ClN2O2 详情 详情
(VIIR) 10294 (2R)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid C12H12N2O3 详情 详情
(I) 10288 4-(Bromomethyl)-2(1H)-quinolinone C10H8BrNO 详情 详情
(II) 10289 4-(Bromomethyl)-2-chloroquinoline C10H7BrClN 详情 详情
(III) 10290 2-Chloro-4-(chloromethyl)quinoline C10H7Cl2N 详情 详情
(VIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VIII)

2) The same reaction sequence of (I) and (IVr) yields intermediates (Vs), (VIs) and (VIIs), and finally (S)-OPC-12759.

参考文献 中间体
合成目标
【1】 Morita, S.; Yamasaki, K.; Shimizu, T.; Uchida, M.; Otsubo, K.; Kanbe, T.; Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide). Chem Pharm Bull 1991, 39, 11, 2906.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVR) 10296 (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine 109838-85-9 C9H16N2O2 详情 详情
(VS) 10297 2-Chloro-4-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]quinoline; (3R,6S)-6-[(2-Chloro-4-quinolinyl)methyl]-3-isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether C19H22ClN3O2 详情 详情
(VIS) 10298 methyl (2S)-2-amino-3-(2-chloro-4-quinolinyl)propanoate C13H13ClN2O2 详情 详情
(VIIS) 10299 (2S)-2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid C12H12N2O3 详情 详情
(II) 10289 4-(Bromomethyl)-2-chloroquinoline C10H7BrClN 详情 详情
(III) 10290 2-Chloro-4-(chloromethyl)quinoline C10H7Cl2N 详情 详情
(VIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(V)

The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.

参考文献 中间体
合成目标
【1】 Kanbe, T.; Nakagawa, K.; Morita, S.; Uchida, M.; Komatsu, M.; Tabusa, F.; Studies on 2(1H)-quinolinone derivatives as gastri. Chem Pharm Bull 1985, 33, 9, 3775.
【2】 Uchida, M.; Komatsu, M.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs., process for their preparation. DE 3324034; US 4578381 .
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) 10288 4-(Bromomethyl)-2(1H)-quinolinone C10H8BrNO 详情 详情
(II) 16710 Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate 1068-90-2 C9H15NO5 详情 详情
(III) 23536 diethyl 2-(acetamido)-2-[(2-oxo-1,2-dihydro-4-quinolinyl)methyl]malonate C19H22N2O6 详情 详情
(IV) 10301 2-Amino-3-(2-oxo-1,2-dihydro-4-quinolinyl)propionic acid C12H12N2O3 详情 详情
(V) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线8

该中间体在本合成路线中的序号：(B)

This compound can be obtained in tvvo different ways: 1) The reaction of 3-bromophthalide (A) with 5-methoxy-2-methyl-1H-indole-3-acetic acid (I) previously salified with triethylamine in refluxing acetone gives (±)-1,3-dihydro-3-oxo-1-isobenzofuranyl-5-methoxy-2-methyl-1H-indole-3-acetate (II). Compound (II) is salified with sodium hydride and then acylated with p-chlorobenzoyl chloride (B). 2) By condensation of the organic salt of 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (III) with 3-bromophthalide (A).

参考文献 中间体
合成目标
【1】 AR 282717 .
【2】 Torriani, H.; Talmetacin. Drugs Fut 1982, 7, 11, 825.
【3】 Los, M.A.; BE 0858897 .
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(A) 24560 3-Bromophthalide; 3-Bromo-2-benzofuran-1(3H)-one 6940-49-4 C8H5BrO2 详情 详情
(I) 37079 5-Methoxy-2-methyl-1H-indole-3-acetic acid; 2-(5-Methoxy-2-methyl-1H-indol-3-yl)acetic acid 2882-15-7 C12H13NO3 详情 详情
(II) 37080 3-oxo-1,3-dihydro-2-benzofuran-1-yl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate C20H17NO5 详情 详情
(III) 22930 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid C19H16ClNO4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(B)

3) The reaction of p-methoxyphenylhydrazine (V) with benzyl levulinate (IV) in acetic acid gives the corresponding hydrazone (VI), which, without isolation, is cyclized to benzyl 5-methoxy-2-methylindole-3-acetoxyacetate (VII) at 80 C in acetic acid. Then this compound is benzoylated with p-chlorobenzoyl chloride (B) by means of NaH in DMF. 4) The hydrazone (VI) can also be benzoylated first giving the corresponding hydrazone (VIII), which is then cyclized at 80 C in acetic acid.

参考文献 中间体
合成目标
【1】 Boltze, K.; Brendler, O.; Dell, H.-D.; Jacobi, H.; Novel substituted indole compound, process for the preparation and therapeutic compositions containing it.. DE 2234651; ES 416877; FR 2192828; JP 49043970; US 3910952 .
【2】 Leeson, P.A.; Castaner, J.; Acemetacin. Drugs Fut 1977, 2, 7, 423.
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(I) 33962 2-(benzyloxy)-2-oxoethyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate C28H24ClNO6 详情 详情
(IV) 33963 2-(benzyloxy)-2-oxoethyl 4-oxopentanoate C14H16O5 详情 详情
(V) 12688 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine 3471-32-7 C7H10N2O 详情 详情
(VI) 33964 2-(benzyloxy)-2-oxoethyl 4-[(Z)-2-(4-methoxyphenyl)hydrazono]pentanoate C21H24N2O5 详情 详情
(VII) 33966 2-(benzyloxy)-2-oxoethyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate C21H21NO5 详情 详情
(VIII) 33965 2-(benzyloxy)-2-oxoethyl 4-[(Z)-2-(4-chlorobenzoyl)-2-(4-methoxyphenyl)hydrazono]pentanoate C28H27ClN2O6 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VIII)

The synthesis of [14C]- and deuterium-labeled bisaramil hydrochloride has been reported: 1) The reduction of (14)CO2 with LiAlH4 in THF gives labeled formaldehyde (II), which by a Mannich reaction is condensed with ethylamine (IV) and N-methylpiperidin-4-one (III) by means of acetic acid in refluxing methanol to yield labeled 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one (V). The reduction of (V) with NaBH4 in methanol/NaOH affords a mixture of the alpha- and beta-isomers of the labeled 9-hydroxy derivative (VI + VII). After separation by its different solubility in isopropanol, the alpha-isomer is condensed with 4-chlorobenzoyl chloride (VIII) in hot pyridine to give [2,4-14C]-labeled bisaramil.

参考文献 中间体
合成目标
【1】 Mlinko, S.; Simon Trompler, E.; Szammer, J.; Synthesis of bisaramil labelled with carbon-14 and deuterium. J Label Compd Radiopharm 1994, 34, 4, 313.
【2】 Lapis, E.; YUTAC. Drugs Fut 1985, 10, 10, 837.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(V) 10920 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(V) 44684 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(VI) 10921 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(VI) 44685 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(VII) 10922 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(VII) 44686 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(VIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

2) Hexadeuteroethyl alcohol (IX) is treated with red phosphorus and I2 at reflux temperature to give pentadeuteroethyl iodide (X), which is condensed with potassium phthalimide (XI) in DMF, yielding N-(pentadeuteroethyl)phthalimide (XII). The hydrolysis of (XII) with hydrazine and HCl affords pentadeuteroethylamine (XIII), which is condensed with 1-methylpiperidin-4-one (III) and formaldehyde (XIV) in a Mannich reaction to give 3-methyl-7-(pentadeuteroethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (XV). The reduction of (XV) with NaBH4 as before yields the diastereomeric mixture (XVI + XVII). Finally, the alpha-isomer (XVI) is condensed with 4-chlorobenzoyl chloride (VIII) as before to give the pentadeuterium-labeled bisaramil.

参考文献 中间体
合成目标
【1】 Mlinko, S.; Simon Trompler, E.; Szammer, J.; Synthesis of bisaramil labelled with carbon-14 and deuterium. J Label Compd Radiopharm 1994, 34, 4, 313.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(VIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(IX) 10924 Ethyl alcohol; Ethanol 1516-08-1 C2H6O 详情 详情
(IX) 44687 Ethanol-d6 C2H6O 详情 详情
(X) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(X) 44688 1-iodoethane-d5 C2H5I 详情 详情
(XI) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(XII) 10927 2-Ethyl-1H-isoindole-1,3(2H)-dione 5022-29-7 C10H9NO2 详情 详情
(XII) 44689 2-ethyl-1H-isoindole-1,3(2H)-dione C10H9NO2 详情 详情
(XIII) 10928 Ethanamine 75-04-7 C2H7N 详情 详情
(XIII) 44690 ethylamine; 1-ethanamine C2H7N 详情 详情
(XV) 10929 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(XV) 44691 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one C10H18N2O 详情 详情
(XVI) 10921 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVI) 44692 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVII) 10922 3-Ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情
(XVII) 44693 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-ol C10H20N2O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IV)

Reduction of 3,5-dichlorobenzoyl chloride (I) with NaBH4 in THF in the presence of N-methyl pyrrolidone (NMP) provides benzyl alcohol derivative (II), which is then treated with tert-butyl dimethylsilyl chloride (TBDMSCl) in DMF in the presence of imidazole and DMAP to furnish protected compound (III). Lithiation of (III) with BuLi (occasionally in the presence of tetramethylethylenediamine) in THF followed by reaction with p-chlorobenzoyl chloride (IV) in THF affords benzophenone derivative (V), which is then deprotected by means of concentrated HCl to yield benzyl alcohol derivative (VI). Conversion of alcohol (VI) into chloride (VII) is then performed by reaction with SOCl2. Next, reaction of (VII) with NaN3 and NaI in refluxing ethanol gives benzylazide derivative (VIII), which is finally converted into the desired product by reaction with cyanoacetamide (IX) and K2CO3 in DMSO.

参考文献 中间体
合成目标
【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 .
【2】 Hube, D. (Merck & Co., Inc.); 5-Amino or substd. amino-1,2,3-triazoles useful as anti-metastasis agents. JP 1991056417; US 5045543 .
【3】 Hupe, D.; Azzolina, B.A.; Argenbright, L.; Behrens, N. (Merck & Co., Inc.); 5-Amino or substd. amino 1,2,3-triazoles useful as antiproliferative agents. EP 0304221; JP 1989068321; US 4847257 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
49483 N,N,N',N'-Tetramehylenediamine; 1,2-Bis(dimethylamino)ethane C6H16N2 详情 详情
(I) 27769 3,5-dichlorobenzoyl chloride 2905-62-6 C7H3Cl3O 详情 详情
(II) 24168 (3,5-dichlorophenyl)methanol 60211-57-6 C7H6Cl2O 详情 详情
(III) 49482 tert-butyl(dimethyl)silyl 3,5-dichlorobenzyl ether; tert-butyl[(3,5-dichlorobenzyl)oxy]dimethylsilane C13H20Cl2OSi 详情 详情
(IV) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(V) 49484 [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone C20H23Cl3O2Si 详情 详情
(VI) 49485 (4-chlorophenyl)[2,6-dichloro-4-(hydroxymethyl)phenyl]methanone C14H9Cl3O2 详情 详情
(VII) 49486 (4-chlorophenyl)[2,6-dichloro-4-(chloromethyl)phenyl]methanone C14H8Cl4O 详情 详情
(VIII) 49487 [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone C14H8Cl3N3O 详情 详情
(IX) 12122 Cyanoacetamide; 2-Cyanoacetamide 107-91-5 C3H4N2O 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

Alternatively, the target compound can be obtained as follows: Condensation between 2,6-dichloro-4-methylbenzonitrile (X) and 4-chloroiodobenzene (XI) by means of Mg in refluxing ether gives methyleneimine derivative (XII), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (XIII) by refluxing in dioxane-aqueous phosphate buffer. (Alternatively, compound (XIII) can also be obtained either by condensation of 3,5-dichlorotoluene (XIV) with p-chlorobenzoyl chloride (IV) by means of BuLi in THF or by treatment of 2,6-dichloro-4-methylbenzoic acid (XV) with thionyl chloride (SOCl2) in refluxing DMF to give (XVI), which then reacts with chlorobenzene (XVII) by means of AlCl3 in refluxing CCl4). Bromination of (XIII) is then performed by reaction with N-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (XVIII). (Alternatively, (XVIII) can also be synthesized by treatment of the already reported benzophenone derivative (V) with HOAc in THF/H2O followed by reaction with phosphorus tribromide in diethyl ether.) Finally, (XVIII) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (XIX) by means of NaH in refluxing EtOH or by first reaction of (XVIII) with KN3 in refluxing EtOH to furnish benzyl azide (VIII), followed by reaction with cyanoacetamide (IX) and NaOMe in refluxing EtOH.

参考文献 中间体
合成目标
【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 .
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(V) 49484 [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone C20H23Cl3O2Si 详情 详情
(VIII) 49487 [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone C14H8Cl3N3O 详情 详情
(IX) 12122 Cyanoacetamide; 2-Cyanoacetamide 107-91-5 C3H4N2O 详情 详情
(X) 49488 2,6-dichloro-4-methylbenzonitrile C8H5Cl2N 详情 详情
(XI) 19395 1-chloro-4-iodobenzene 637-87-6 C6H4ClI 详情 详情
(XII) 49489 (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanimine C14H10Cl3N 详情 详情
(XIII) 49490 (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone C14H9Cl3O 详情 详情
(XIV) 49491 1,3-dichloro-5-methylbenzene C7H6Cl2 详情 详情
(XV) 49492 2,6-dichloro-4-methylbenzoic acid C8H6Cl2O2 详情 详情
(XVI) 49493 2,6-dichloro-4-methylbenzoyl chloride C8H5Cl3O 详情 详情
(XVII) 10190 1-Chlorobenzene 108-90-7 C6H5Cl 详情 详情
(XVIII) 49494 [4-(bromomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone C14H8BrCl3O 详情 详情
(XIX) 49495 5-amino-1H-1,2,3-triazole-4-carboxamide C3H5N5O 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Alovudine can be obtained by several related ways: 1) The acylation of thymidine (I) with 4-chlorobenzoylchloride (II) in pyridine gives 5'-O-(4-chlorobenzoyl)thymidine (IX), which is then treated with diethylamino sulfur trifluoride in methylene chloride at -79 C, and finally with NaHCO3 in refluxing methanol. 2) By reaction of 2,3'-anhydro-1-(2'-deoxy-beta-D-xylofuranosyl)thymine (III) with AlF3 and 1% HF in anhydrous dioxan at 150-7 C. 3) By reaction of (III) with KHF2 or NH4F in diethylene glycol at 190C, or in ethanol at 150 C. 4) The reaction of 2,3'-anhydro-5'-O-(methylsufonyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (IV) with AlF3 and HF as before gives 3'-deoxy-3'-fluoro-5'-O-(methylsulfonyl)thymidine (V), which is then treated with NaOH in refluxing ethanol. 5) By reaction of 5'-O-(triphenylmethyl)thymidine (VI) with diethylamino sulfur trifluoride in THF, and then with aqueous, NaHCO3. 6) By reaction of 3'-O-(methylsulfonyl)thymidine (VII) with KHF2 or NH4F in diethylene glycol at 190 C. 7) By reaction of 2,3'-anhydro-5'-O-(triphenylmethyl)-1-(2'-deoxy-beta-D-xylofuranosyl) thymine (VIII) with 4-6% HF in anhydrous dioxan at 90 C.

参考文献 中间体
合成目标
【1】 Selway, J.W.T.; Beacham III, L.M.; Daluge, S.M.; Tuttle, J.V.; Krenitsky, T.A. (Glaxo Wellcome plc); 2,3-Dideoxy-3'-fluorothymidine and related cpds. for the treatment of adenovirus infections. AU 8821429; EP 0305117; EP 0479336; JP 1989068325; US 5070078 .
【2】 Etzold, G.; Hintsche, R.; Langen, P. (Akademie der Wissenschaften der DDR); Cytostatically-active 2',3'-didesoxy-3'-fluoropyrimidine nucleosides. GB 1189973 .
【3】 Castaner, J.; Hoshi, A.; Alovudine. Drugs Fut 1994, 19, 3, 221.
【4】 Baba, M.; De Clercq, E.; Pauwels, R.; Herdewijn, P.; Balzarini, J.; Vanderhaeghe, H.; Broder, S.; 3'-Substituted 2',3'-dideoxynucleoside analogues as potential anti-HIV (HTLV-III/LAV) agents. J Med Chem 1987, 30, 8, 1270-8.
【5】 Kowollik, G.; Etzold, G.; Hintsche, R.; Langen, P.; Synthesis and reactivity of 3'-fluoro and 3'-chloro-3'-desoxy-thymidine. Tetrahedron 1971, 27, 2463-72.
【6】 Langen, P.; Von Janta-Lipinski, M.; Gaertner, K.; Etzold, G.; Von Kowollik, G.; A novel access to 1-(2,3-didesoxy-3-fluoro-beta-D-ribofuranosyl)-pyrimidines. J Prakt Chem 1973, 315, 5, 895-900.
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) 12161 Thymidine; 1-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 50-89-5 C10H14N2O5 详情 详情
(II) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(III) 12163 (1R,9R,10R)-10-(Hydroxymethyl)-4-methyl-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one C10H12N2O4 详情 详情
(IV) 12164 [(1R,9R,10R)-4-methyl-5-oxo-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-10-yl]methyl methanesulfonate C11H14N2O6S 详情 详情
(V) 12165 [(2R,3S,5R)-3-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl methanesulfonate C11H15FN2O6S 详情 详情
(VI) 12166 1-[(2R,4S,5R)-4-Hydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C29H28N2O5 详情 详情
(VII) 12167 (2R,3S,5R)-2-(hydroxymethyl)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl methanesulfonate C11H16N2O7S 详情 详情
(VIII) 12168 (1R,9R,10R)-4-Methyl-10-[(trityloxy)methyl]-8,11-dioxa-2,6-diazatricyclo[7.2.1.0(2,7)]dodeca-3,6-dien-5-one C29H26N2O4 详情 详情
(IX) 63321 methyl 4-[2-(tert-butylamino)acetyl]-7-hydroxy-1H-indole-2-carboxylate C16H20N2O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The reaction of 1,2-O-isopropylidene-D-xylofuranose (I) with 4-chlorobenzoyl chloride (II) and TEA gives the 5-O-(4-chlorobenzoate) (III), which is oxidized with TEMPO and NaClO to yield the 3-oxo derivative (IV). The ethynylation of (IV) by means of trimethylsilylethynyl magnesium bromide (V) affords the 3-C-trimethylsilylethynyl derivative (VI), which is hydrolyzed by means of refluxing aqueous HCOOH to provide the 3-C-ethynylated sugar (VII). The acylation of (VII) by means of 4-chlorobenzoyl chloride (II), TEA and DMAP gives the tetrabenzoate sugar (VIII), which is used for the glycosylation of bis trimethylsilyl cytosine (IX) by means of SnCl4 to yield the protected precursor (X). Finally, this compound is desilylated and debenzoylated by means of DBU in hot methanol to afford the target nucleoside.

参考文献 中间体
合成目标
【1】 Nomura, M.; Sato, T.; Masato, W.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A.; Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbruggen glycosylation . Tetrahedron 2002, 58, 7, 1279.
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) 41907 (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol 20031-21-4 C8H14O5 详情 详情
(II) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(III) 61573 [(3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl 4-chlorobenzoate C15H17ClO6 详情 详情
(IV) 61574 [(3aR,5R,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl 4-chlorobenzoate C15H15ClO6 详情 详情
(V) 34561 methyl 3-methyl-1-(2-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[3,2-c]quinolin-6-yl ether; 6-methoxy-3-methyl-1-(2-methylphenyl)-2-(trimethylsilyl)-1H-pyrrolo[3,2-c]quinoline C23H26N2OSi 详情 详情
(VI) 61575 {(3aR,5R,6R,6aR)-6-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-5-yl}methyl 4-chlorobenzoate C20H25ClO6Si 详情 详情
(VII) 61576 {(2R,3S,4R)-3,4,5-trihydroxy-3-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}methyl 4-chlorobenzoate C17H21ClO6Si 详情 详情
(VIII) 61577 (3R,4R,5R)-3,4-bis[(4-chlorobenzoyl)oxy]-5-{[(4-chlorobenzoyl)oxy]methyl}-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl 4-chlorobenzoate C38H30Cl4O9Si 详情 详情
(IX) 61578 N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-(trimethylsilyl)-N-{2-[(trimethylsilyl)oxy]-4-pyrimidinyl}amine C10H21N3OSi2 详情 详情
(X) 61579 (2R,3R,4R,5R)-4-[(4-chlorobenzoyl)oxy]-5-{[(4-chlorobenzoyl)oxy]methyl}-2-[2-oxo-4-[(trimethylsilyl)amino]-1(2H)-pyrimidinyl]-4-[2-(trimethylsilyl)ethynyl]tetrahydro-3-furanyl 4-chlorobenzoate C38H38Cl3N3O8Si2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The title hydrazide was prepared from 4-chlorobenzoic acid (I) via conversion to the corresponding acid chloride (II), followed by condensation with 4-methylphenylhydrazine (III).

参考文献 中间体
合成目标
【1】 Sui, Z.; et al.; 1,3-Diarylcycloalkano-[1,2-d]-pyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 202.
【2】 Ferro, M.P.; Sui, Z.; Guan, J.; et al.; 1,3-Diarylcycloalkanopyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2. Bioorg Med Chem Lett 2000, 10, 6, 601.
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) 18359 p-chlorobenzoic acid; 4-chlorobenzoic acid 74-11-3 C7H5ClO2 详情 详情
(II) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(III) 20387 1-(4-methylphenyl)hydrazine C7H10N2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

The Sandmeyer reaction of 4-aminophenyl-alpha-methylacetonitrile (I) with NaNO2, HCl and H2SO4 gives 4-hydroxyphenyl-alpha-methylacetonitrile (II), which is nitrated with nitric acid in acetic acid yielding 4-hydroxy-3-nitrophenyl-alpha-methylacetonitrile (III). The reduction of (III) with SnCl2.2H2O and HCl in ethanol, or with H2 over Pd/C in the same solvent affords 4-hydroxy-3-aminophenyl-alpha-methylacetonitrile (IV), which is hydrolyzed with refluxing concentrated HCl to 4-hydroxy-3-aminophenyl-alpha-methylacetic acid (V). The esterification of (V) with ethanol and HCl affords the corresponding ethyl ester (VI), which is cyclized with p-chlorobenzoyl chloride (VII) in pyridine at 100 C yielding ethyl 2-(4-chlorophenyl)-alpha-methyl-5-benzoxazoleacetate (VIII). Finally, this compound is hydrolyzed with NaOH in ethanol.

参考文献 中间体
合成目标
【1】 Castañer, J.; Blancafort, P.; Benoxaprofen. Drugs Fut 1977, 2, 9, 565.
【2】 Dunwell, D.W.; et al.; 2-Aryl-5-benzoxazolealkanoic acid derivatives with notable antiinflammatory activity. J Med Chem 1975, 18, 1, 53.
【3】 Dunwell, D.W.; et al. (Lilly Industries Ltd.); Benzoxazole derivatives. DE 2324443; ES 414863; FR 2184966; FR 2284592; GB 1435721; JP 49054363; JP 56167645; US 3912748 .
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) 40156 2-(3-aminophenyl)propanenitrile C9H10N2 详情 详情
(II) 40157 2-(3-hydroxyphenyl)propanenitrile C9H9NO 详情 详情
(III) 40158 2-(3-hydroxy-4-nitrophenyl)propanenitrile C9H8N2O3 详情 详情
(IV) 40159 2-(4-amino-3-hydroxyphenyl)propanenitrile C9H10N2O 详情 详情
(V) 40160 2-(4-amino-3-hydroxyphenyl)propionic acid C9H11NO3 详情 详情
(V) 40161 ethyl 2-(4-amino-3-hydroxyphenyl)propanoate C11H15NO3 详情 详情
(VII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(VIII) 40162 ethyl 2-[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]propanoate C18H16ClNO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(B)

The starting product ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate (I) can be obtained by condensation of diethyl acetonedicarboxylate (X) with chloroacetone (IX) by means of methylamine in water, the compound (XI) being formed as an intermediate which is not isolated. The Friedel-Crafts aroylation of (I) with p-chlorobenzoyl chloride (B) and AlCl3 in refluxing dichloroethane gives ethyl 5-(p-chlorobenzoyl)-1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate (VI), which by hydrolysis with aqueous 1N NaOH yields 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetic acid (VII). The partial esterification of (VII) with ethanol and HCl produces ethyl 5-(p-chlorobenzoyl)-1,4-dimethyl-3-carboxypyrrole-2-acetate (VIII), which by decarboxylation at 210-30 C is converted into the ester (V) already obtained.

参考文献 中间体
合成目标
【1】 Carson, J.R.; Aroyl-substituted pyrroles. DE 2102746; FR 2081455; GB 1327308; JP 55033401; JP 55033402; US 3752826; US 3865840; US 4070368 .
【2】 Hillier, K.; Castañer, J.; Zomepirac. Drugs Fut 1977, 2, 10, 698.
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(I) 40135 ethyl 2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate C13H19NO4 详情 详情
(V) 40140 ethyl 2-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetate C17H18ClNO3 详情 详情
(VI) 40143 ethyl 5-(4-chlorobenzoyl)-2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate C20H22ClNO5 详情 详情
(VII) 40144 2-(carboxymethyl)-5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid C16H14ClNO5 详情 详情
(VIII) 40145 5-(4-chlorobenzoyl)-2-(2-ethoxy-2-oxoethyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid C18H18ClNO5 详情 详情
(IX) 15288 1-Chloroacetone; Chloroacetone 78-95-5 C3H5ClO 详情 详情
(X) 40141 diethyl 3-oxopentanedioate 105-50-0 C9H14O5 详情 详情
(XI) 40142 methanaminium 1-chloro-6-ethoxy-3-(ethoxycarbonyl)-2-methyl-4,6-dioxo-2-hexanolate C13H24ClNO6 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

The benzoylation of tyramine (2-(p-hydroxyphenyl)ethylamine) (I) with 4-chlorobenzoyl chloride (II) in pyridine gives 4-(4-chlorobenzoylaminoethyl)phenol (III), which by condensation with ethyl alpha-bromoisobutyrate (IV) by means of K2CO3 in refluxing butanone affords ethyl alpha-[4-(4-chlorobenzoylaminoethyl)phenoxy]isobutyrate (V). Finally, this compound is hydrolyzed with KOH in dioxane - water.

参考文献 中间体
合成目标
【1】 Castañer, J.; Thorpe. P.; Bezafibrate. Drugs Fut 1978, 3, 4, 258.
【2】 Witte, E.C.; et al. (Boehringer Ingelheim GmbH); Phenoxyalkylcarbosaurederivate und Verfahren zur Herstellung derselben. DE 2149070; ZA 7206638 .
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) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(II) 19988 4-(2-Aminoethyl)phenol; Tyramine 51-67-2 C8H11NO 详情 详情
(III) 39798 4-chloro-N-(4-hydroxyphenethyl)benzamide 41859-57-8 C15H14ClNO2 详情 详情
(IV) 39799 ethyl 2-bromo-2-methylpropanoate 600-00-0 C6H11BrO2 详情 详情
(V) 39800 ethyl 2-(4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy)-2-methylpropanoate C21H24ClNO4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VI)

Reduction of ethyl ester (I) with LiAlH4 provides primary carbinol (II), which is then converted into amine (III) by Mitsunobu reaction with phthalimide (A) in the presence of PPh3 and DEAD in THF, followed by an hydrazine mediated deprotection in EtOH. Reaction of amine (III) with 2-nitrophenyl isocyanate (IV) in CHCl3/THF or CH2Cl2, followed by reduction of the nitro group by hydrogenation over Pd/C in EtOH, affords aniline (V). Finally, aniline (V) is condensed with acid chloride (VI) in CHCl3 in the presence of pyridine to furnish the target compound.

参考文献 中间体
合成目标
【1】 Tinsley, J.M.; Franciskoich, J.B.; Masters, J.J.; et al.; Non-amidine-containing 1,2-dibezamidobenzene inhibitors of human factor Xa with potent anticoagulant and antithrombotic activity. J Med Chem 2000, 43, 11, 2087.
【2】 Antithrombotic agents. WO 9900121 .
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) 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
(I) 44838 ethyl 1-(4-pyridinyl)-4-piperidinecarboxylate C13H18N2O2 详情 详情
(II) 44839 1-(4-pyridinyl)-4-piperidinyl hydroperoxide C10H14N2O2 详情 详情
(III) 44840 O-[1-(4-pyridinyl)-4-piperidinyl]hydroxylamine; 4-(aminooxy)-1-(4-pyridinyl)piperidine C10H15N3O 详情 详情
(IV) 32771 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate 3320-86-3 C7H4N2O3 详情 详情
(V) 44841 N-(2-aminophenyl)-N'-[[1-(4-pyridinyl)-4-piperidinyl]oxy]urea C17H21N5O2 详情 详情
(VI) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(III)

(4-Methoxyphenyl)-2-pyrrolidone (I) is reacted with methanol / acid to the compound (II), which can be acetylated with 4-chlorobenzoyl chloride (III) in pyridine to yield (IV) and finally hydrolyzed to clanobutin

参考文献 中间体
合成目标
【1】 Unterhalt, B.; Clanobutin. Drugs Fut 1979, 4, 6, 411.
【2】 Klemm, K.; et al.; Synthese und physikalish-chemische Eigenschaften von Clanobutin. Arzneim-Forsch/Drug Res 1979, 29, 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
(I) 60952 1-(4-methoxyphenyl)-2-pyrrolidinone C11H13NO2 详情 详情
(II) 60953 methyl 4-(4-methoxyanilino)butanoate C12H17NO3 详情 详情
(III) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(IV) 60954 methyl 4-[(4-chlorobenzoyl)-4-methoxyanilino]butanoate C19H20ClNO4 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XIII)

The condensation of 3-ethylphenol (I) with 4-piperidone (II) by means of gaseous HCl in acetic acid gives 5-ethyl-2-(1,2,3,6-tetrahydropyridin-4-yl)phenol (III), which is treated with acetic anhydride in pyridine to yield the diacetyl derivative (IV). The selective hydrolysis of the O-acetyl group of (IV) by means of K2CO3 in methanol affords the phenol derivative (V), which is hydrogenated with H2 over Pd/C in methanol to provide the acetyl piperidine (VI). The alkylation of the phenolic group of (VI) with ethyl iodide and Cs2CO3 in refluxing acetone gives 1-acetyl-4-(2-ethoxy-4-ethylphenyl)piperidine (VII), which is deacetylated by means of NaOH in refluxing methanol to yield 4-(2-ethoxy-4-ethylphenyl)piperidine (VIII). The alkylation of the piperidine (VIII) with N-(4-bromobutyl)phthalimide (IX) by means of Cs2CO3 in refluxing acetone affords the adduct (X), which is cleaved with hydrazine in hot methanol to provide 1-(4-aminobutyl)-4-(2-ethoxy-4-ethylphenyl)piperidine (XI). Finally, this amine is condensed with 4-(4-chlorobenzamido)benzoic acid (XII) by means of EDC, HOBT and TEA in DMF to give the target diamide. The intermediate 4-(4-chlorobenzamido)benzoic acid (XII) is obtained as follows: The condensation of 4-aminobenzoic acid ethyl ester (XIV) with 4-chlorobenzoyl chloride (XIII) by means of TEA and DMAP gives 4-(4-chlorobenzamido)benzoic acid ethyl ester (XV), which is finally hydrolyzed with NaOH to afford the target benzoic acid intermediate (XII).

参考文献 中间体
合成目标
【1】 Grand-Perret, T.A.R.; Issandou, M. (GlaxoSmithKline plc); Binding competition of SREBP-cleavage activating protein (SCAP) antagonists. WO 0106261 .
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) 53495 3-Ethyl phenol; m-Ethyl phenol 620-17-7 C8H10O 详情 详情
(II) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(III) 53496 5-ethyl-2-(1,2,3,6-tetrahydro-4-pyridinyl)phenol n/a C13H17NO 详情 详情
(IV) 53497 2-(1-acetyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-ethylphenyl acetate n/a C17H21NO3 详情 详情
(V) 53498 1-[4-(4-ethyl-2-hydroxyphenyl)-3,6-dihydro-1(2H)-pyridinyl]-1-ethanone n/a C15H19NO2 详情 详情
(VI) 53499 1-[4-(4-ethyl-2-hydroxyphenyl)-1-piperidinyl]-1-ethanone n/a C15H21NO2 详情 详情
(VII) 53500 1-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-ethanone n/a C17H25NO2 详情 详情
(VIII) 53501 4-(2-ethoxy-4-ethylphenyl)piperidine; ethyl 5-ethyl-2-(4-piperidinyl)phenyl ether n/a C15H23NO 详情 详情
(IX) 17163 N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione 5394-18-3 C12H12BrNO2 详情 详情
(X) 53502 2-{4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butyl}-1H-isoindole-1,3(2H)-dione n/a C27H34N2O3 详情 详情
(XI) 53503 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-butanamine; 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butylamine n/a C19H32N2O 详情 详情
(XII) 53504 4-[(4-chlorobenzoyl)amino]benzoic acid n/a C14H10ClNO3 详情 详情
(XIII) 10295 p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride 122-01-0 C7H4Cl2O 详情 详情
(XIV) 16498 Benzocaine; ethyl 4-aminobenzoate 94-09-7 C9H11NO2 详情 详情
(XV) 53505 Ethyl 4-(4-chlorobenzamido)benzoate n/a C16H14ClNO3 详情 详情
Extended Information