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【结 构 式】 
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【分子编号】12572 【品名】(2R)-2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one 【CA登记号】 |
【 分 子 式 】C16H15NO3S 【 分 子 量 】301.36604 【元素组成】C 63.77% H 5.02% N 4.65% O 15.93% S 10.64% |
合成路线1
该中间体在本合成路线中的序号：(XV)5) The cyclization of D-penicillamine (X) with 2-methoxybenzaldehyde (XI) in ethanol gives (4S)-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XII), which by acetylation with hot acetic anhydride and fractional crystallization yields the chiral (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XIII). The esterification of (XIII) with the hydroxyl group of benzothiazinone (I) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in DMF affords a diastereomeric mixture of esters, which is separated by fractional crystallization giving ester (XIV). Elimination of the chiral auxiliar by treatment with calcium borohydride in THF or sodium borohydride in ethanol (2) gives (R)-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XV), which is condensed with 3-bromopropanol (XVI) by means of triphenylphosphine and diethyl azodicarboxylate in DMF or THF yielding (R)-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XVII). Finally, this compound is condensed with the secondary amine (IV) by means of NaI and NaHCO3 as already described, and treated with fumaric acid as before.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229. |
| 【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 . |
| 【3】 Iwao, J.; Iso, T.; Kawashima, Y. (Santen Pharmaceutical Co., Ltd.); Sulfur-containing polycyclic cpds. JP 1988104969 . |
| 【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (XI) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XII) | 12569 | (4S)-2-(2-Methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C13H17NO3S | 详情 | 详情 | |
| (XIII) | 12570 | (2S,4S)-3-Acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C15H19NO4S | 详情 | 详情 | |
| (XIV) | 12571 | 4-methoxy-2-[(2R)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]phenyl (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate | C31H32N2O6S2 | 详情 | 详情 | |
| (XV) | 12572 | (2R)-2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C16H15NO3S | 详情 | 详情 | |
| (XVI) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (XVII) | 12574 | (2R)-2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C19H20BrNO3S | 详情 | 详情 |