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【结 构 式】 
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【分子编号】62488 【品名】(2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 【CA登记号】 |
【 分 子 式 】C20H24N2O3S 【 分 子 量 】372.48824 【元素组成】C 64.49% H 6.49% N 7.52% O 12.89% S 8.61% |
合成路线1
该中间体在本合成路线中的序号：(III)Alkylation of the lactam N of thiazepinone (I) with 2-(dimethylamino)ethyl chloride (II) in the presence of K2CO3 or under phase-transfer conditions gave thiazeinone (III). Subsequent esterification of (III) with acetic anhydride furnished the title compound. Alternatively, diltiazem has been prepared by acetylation of thiazeinone (I) with Ac2O to yield the lactam acetate ester (IV), which is then alkylated with chloride (II) under phase-transfer conditions
| 【1】 Coffen, D.L.; Madan, P.B.; Schwartz, A. (F. Hoffmann-La Roche AG); Process for the preparation of optically pure aminophenylthio- and aminonaphthalenylthio-propanoic acids. EP 0343474 . |
| 【2】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 . |
| 【3】 Murthy, K.; Weeratunga, G.; Burchat, A. (ACIC (Canada) Inc.); Method for the manufacture of benzothiazepine derivs.. WO 9638429 . |
| 【4】 Piselli, F.L.; Boschi, P.; Navoni, C.; A process for the preparation of diltiazem. EP 0594101 . |
| 【5】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 . |
| 【6】 Hytonen, M. (Orion Corporation); Process for the manufacture of diltiazem. EP 0728751; JP 1996253464; US 5644054 . |
| 【7】 Hulshof, L.A.; Kuilman, T.; Process for preparing 1,5-benzothiazepin derivs.. EP 0450705 . |
| 【8】 Manghisi, E.; Cascio, G. (Lusofarmaco); Process for the optical resolution of the dl-alpha-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid. US 4533748 . |
| 【9】 Simonovitch, H.; Hoffmann, T.; Sassoon, S. (Abic, Ltd.); A process for the preparation of benzothiazepin derivs.. EP 0158303 . |
| 【10】 Hytonen, M. (Orion Corporation); Method for the preparation of pharmaceutically active benzothiazepine derivs.. EP 0702009 . |
| 【11】 Manghisi, E.; Perego, B.; A process for the preparation of diltiazem. WO 9210485 . |
| 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) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (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 |
| (III) | 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 | |
| (IV) | 62452 | 2-(4-methoxyphenyl)-4-oxo-4,5-dihydro-1,5-benzothiazepin-3-yl acetate | C18H15NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem. Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem.
| 【1】 Harsanyi, K.; Gizur, T.; Demeter, A.; Aracs, Z.; Felmeri, J.; Berki, K.; Trischeler, F.; Vincze, Z. (Gedeon Richter Ltd.); Process for the preparation of benzothiazepin-4(5H)-one derivs.. ES 2001146; JP 1987108872 . |
| 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) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 62490 | (2S,3S)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate | C18H17NO4S | 详情 | 详情 | |
| (V) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (VI) | 62491 | ethyl 3-chloro-3-(3-pyridinyl)propyl(methyl)carbamate | C12H17ClN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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 |