|
【结 构 式】 
|
【分子编号】62473 【品名】methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate 【CA登记号】 |
【 分 子 式 】C20H21NO8S 【 分 子 量 】435.45468 【元素组成】C 55.17% H 4.86% N 3.22% O 29.39% S 7.36% |
合成路线1
该中间体在本合成路线中的序号：(XXV). 4-Hydroxycinnamic acid (XV) was acetylated with Ac2O in pyridine, and the resultant 4-acetoxycinnamic acid (XVI) was converted to the cinnamyl alcohol (XVIII) via conversion to the mixed anhydride (XVII) and subsequent reduction with NaBH4. Sharpless asymmetric epoxidation of (XVIII) furnished the chiral epoxide alcohol (XIX). After oxidation of alcohol (XIX) to the glycidic acid (XX) by means of RuO2/NaIO4, treatment with dimethyl sulfate and Et3N gave rise to the corresponding methyl ester (XXI). Epoxide opening in (XXI) with HCl and pyridine hydrochloride produced chlorohydrin (XXII) as a mixture of the desired (2S,3R)-isomer and minor amounts of the corresponding 3-chloro epimer. Condensation of (XXII) with 2-nitrothiophenol (XXIII) provided, after recrystallization from EtOH, the pure (S,S)-thioether adduct (XXIV). The hydroxyl group of (XXIV) was then protected as the methoxymethyl ether (XXV) by means of methylal in the presence of P2O5
| 【1】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 . |
| 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) | 37809 | (E)-3-(4-Hydroxyphenyl)-2-propenoic acid; 4-Hydroxy cinnamic acid | 501-98-4 | C9H8O3 | 详情 | 详情 |
| (XVI) | 62479 | (E)-3-[4-(acetyloxy)phenyl]-2-propenoic acid | C11H10O4 | 详情 | 详情 | |
| (XVII) | 62480 | C14H14O6 | 详情 | 详情 | ||
| (XVIII) | 62481 | 4-[(E)-3-hydroxy-1-propenyl]phenyl acetate | C11H12O3 | 详情 | 详情 | |
| (XIX) | 62482 | 4-[(2S,3S)-3-(hydroxymethyl)oxiranyl]phenyl acetate | C11H12O4 | 详情 | 详情 | |
| (XX) | 62483 | (2R,3S)-3-[4-(acetyloxy)phenyl]-2-oxiranecarboxylic acid | C11H10O5 | 详情 | 详情 | |
| (XXI) | 62484 | methyl (2R,3S)-3-[4-(acetyloxy)phenyl]-2-oxiranecarboxylate | C12H12O5 | 详情 | 详情 | |
| (XXII) | 62485 | methyl (2S)-3-[4-(acetyloxy)phenyl]-3-chloro-2-hydroxypropanoate | C12H13ClO5 | 详情 | 详情 | |
| (XXIII) | 62460 | 2-nitrobenzenethiol; 2-nitrophenylhydrosulfide | C6H5NO2S | 详情 | 详情 | |
| (XXIV) | 62486 | methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-hydroxy-3-[(2-nitrophenyl)sulfanyl]propanoate | C18H17NO7S | 详情 | 详情 | |
| (XXV) | 62473 | methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate | C20H21NO8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXV)Selective hydrolysis of the acetate ester of (XXV) using benzylamine in THF led to phenol (XXVI), which was further methylated by means of diazomethane, yielding methyl ether (XXVII). Reduction of the nitro group (XXVII) to the corresponding aniline (XXVIII) was then performed employing ferrous sulfate and ammonium hydroxide. Subsequent saponification of the methyl ester group of (XXVIII) gave amino acid (XXIX). Cyclization of (XXIX) with ethyl chloroformate and triethylamine furnished lactam (XXX). The lactam N of (XXX) was then alkylated by 2-(dimethylamino)ethyl chloride (II) to produce (XXXI). Finally, deprotection of the methoxymethyl group of (XXXI) and concomitant O-acetylation was accomplished by treatment with acetyl chloride and TiCl4
| 【1】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 . |
| 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) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (XXV) | 62473 | methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate | C20H21NO8S | 详情 | 详情 | |
| (XXVI) | 62474 | methyl (2S,3S)-3-(4-hydroxyphenyl)-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate | C18H19NO7S | 详情 | 详情 | |
| (XXVII) | 62475 | methyl (2S,3S)-2-(methoxymethoxy)-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate | C19H21NO7S | 详情 | 详情 | |
| (XXVIII) | 62476 | methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoate | C19H23NO5S | 详情 | 详情 | |
| (XXIX) | 62477 | (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoic acid | C18H21NO5S | 详情 | 详情 | |
| (XXX) | 62470 | (2S,3S)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C18H19NO4S | 详情 | 详情 | |
| (XXXI) | 62478 | (2S,3S)-5-[2-(dimethylamino)ethyl]-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C22H28N2O4S | 详情 | 详情 |