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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information