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【结 构 式】 
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【分子编号】62439 【品名】methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate 【CA登记号】 |
【 分 子 式 】C17H19NO4S 【 分 子 量 】333.4082 【元素组成】C 61.24% H 5.74% N 4.2% O 19.19% S 9.62% |
合成路线1
该中间体在本合成路线中的序号：(XV)In a further process, the racemic trans glycidic ester (XII), prepared by Darzen's condensation between anisaldehyde (X) and methyl chloroacetate (XI), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2S,3R) acid (XIII), while leaving intact the required (2R,3S)-glycidic ester (XIV) (4-7). Opening of the chiral epoxide (XIV) with 2-aminobenzenethiol (VII) proceeded with retention of the configuration, producing methyl (2S,3S)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (XV) (8). Alternatively, the (S,S)-amino ester (XV) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (XII) and 2-aminobenzenethiol (VII) (9). Cyclization of amino ester (XV) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (VIII) (9). The cyclization of (XV) to lactam (VIII) was also accomplished by means of trichloroacetic acid or under basic conditions
| 【1】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (X) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XI) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (XII) | 11905 | methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C11H12O4 | 详情 | 详情 | |
| (XIII) | 62438 | (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylic acid | C10H10O4 | 详情 | 详情 | |
| (XIV) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (XV) | 62439 | methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate | C17H19NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. The racemic trans-glycidic ester (IX) was prepared by Darzen's condensation between anisaldehyde (VII) and methyl chloroacetate (VIII). Opening of the epoxide group of (IX) with 2-aminothiophenol (X) in hot chlorobenzene in the presence of FeCl3 gave rise to the racemic threo adduct (XI) which, without isolation, was cyclized to the cis-lactam (XII) by addition of methanesulfonic acid and then heating to reflux. Alkylation of the lactam N of (XII) with 2-(dimethylamino)ethyl chloride (II) led to the racemic precursor (XIII). Resolution of (XIII) to provide the (S,S)-isomer (VII) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (XIII) upon seeding with the desired enantiomer. Racemic diltiazem (XIV), obtained by acetylation of (XIII), has been resolved via formation of the corresponding diastereoisomeric salts with (S)-naproxen
| 【1】 Gizur, T.; Harsanyi, K.; Fogassy, E.; Studies of the resolution of racemates in the synthesis of diltiazem. J Prakt Chem Chem-Ztg 1994, 336, 7, 628. |
| 【2】 Yamada, S.; Yoshioka, R.; Shibatani, T.; Optical resolution of a 1,5-benzothiazepine derivative,a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation. Chem Pharm Bull 1997, 45, 12, 1922. |
| 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 |
| (VII) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (VII) | 62488 | (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C20H24N2O3S | 详情 | 详情 | |
| (VIII) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (IX) | 11905 | methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C11H12O4 | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (XI) | 62439 | methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate | C17H19NO4S | 详情 | 详情 | |
| (XII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (XIII) | 62487 | 5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C20H24N2O3S | 详情 | 详情 | |
| (XIV) | 62489 | 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate | C22H26N2O4S | 详情 | 详情 |