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【结 构 式】 
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【药物名称】Semotiadil fumarate, Sesamodil fumarate, DS-4823, SD-3211 【化学名称】(+)-(R)-2-[5-Methoxy-2-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one hydrogen fumarate 【CA登记号】116476-14-3, 116476-13-2 (free base) 【 分 子 式 】C33H36N2O10S 【 分 子 量 】652.72627 |
【开发单位】Santen (Originator), Daiichi Pharmaceutical (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Calcium Channel Blockers |
合成路线1
Semotiadil fumarate has been obtained by several related ways: 1) The reaction of 2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (I) with 3-chloropropyl bromide (II) by means of NaH in DMF gives 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (III) , which is condensed with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamine (IV) by means of NaI in NaHCO3 in DMF yielding 2-[2-[3-[N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamino]propoxy]-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (V). Finally, this compound is submitted to optical resolution by salification with L-(+)-2-hydroxy-2-phenylacetic acid (VI), fractional crystallization of the resulting salts, elimination of the chiral acid with NaHCO3 and salification with fumaric acid in ethanol. 2) Compound (V) can also be obtained by condensation of benzothiazinone (I) with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine (VII) by means of NaH in DMF. 3) Compound (V) can also be obtained by condensation of 2-[5-methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (VIII) with 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate (IX) by means of triethylamine in ethanol. 4) The optical resolution of the racemic compound (V) can also be performed by chromatography over a column packed with crystalline cellulose triacetate eluted with 95% ethanol.
| 【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】 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 |
|---|---|---|---|---|---|---|
| (I) | 12558 | 2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C16H15NO3S | 详情 | 详情 | |
| (II) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (III) | 12560 | 2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C19H20BrNO3S | 详情 | 详情 | |
| (IV) | 12561 | 2-(1,3-Benzodioxol-5-yloxy)-N-methyl-1-ethanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-methylamine | C10H13NO3 | 详情 | 详情 | |
| (V) | 12562 | 2-(2-[3-[[2-(1,3-Benzodioxol-5-yloxy)ethyl](methyl)amino]propoxy]-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C29H32N2O6S | 详情 | 详情 | |
| (VI) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (VII) | 12564 | N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-3-bromo-N-methyl-1-propanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine | C13H18BrNO3 | 详情 | 详情 | |
| (VIII) | 12565 | 2-[5-Methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C20H24N2O3S | 详情 | 详情 | |
| (IX) | 12566 | 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate | C10H12O6S | 详情 | 详情 |
合成路线2
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 |