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【结 构 式】 
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【药物名称】Temocapril hydrochloride, CS-622, RS-5142, Acecol 【化学名称】2-[(2S,6R)-6-[1(S)-(Ethoxycarbonyl)-3-phenylpropylamino]-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid hydrochloride 【CA登记号】110221-44-8, 111902-57-9 (free base), 102090-90-4 (monoHCl;undefined isomer) 【 分 子 式 】C23H29ClN2O5S2 【 分 子 量 】513.07898 |
【开发单位】Sankyo (Originator), Nippon Boehringer Ingelheim (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II), which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III). The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV), which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI). The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII), which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII). The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X), which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI). The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII), which is finally deprotected with trifluoroacetic acid in anisole.
| 【1】 Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 . |
| 【2】 Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336. |
| 【3】 Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984. |
| 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) | 20799 | 2-hydroxy-2-(2-thienyl)acetonitrile | C6H5NOS | 详情 | 详情 | |
| (II) | 20800 | 2-amino-1-(2-thienyl)-1-ethanol | C6H9NOS | 详情 | 详情 | |
| (III) | 20801 | tert-butyl 2-hydroxy-2-(2-thienyl)ethylcarbamate | C11H17NO3S | 详情 | 详情 | |
| (IV) | 20802 | tert-butyl 2-chloro-2-(2-thienyl)ethylcarbamate | C11H16ClNO2S | 详情 | 详情 | |
| (V) | 20803 | benzhydryl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-sulfanylpropanoate | C24H19NO4S | 详情 | 详情 | |
| (VI) | 20804 | benzhydryl 3-[[2-[(tert-butoxycarbonyl)amino]-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C35H34N2O6S2 | 详情 | 详情 | |
| (VII) | 20805 | 3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propionic acid | C17H16N2O4S2 | 详情 | 详情 | |
| (VIII) | 20806 | 2-[5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]-1H-isoindole-1,3(2H)-dione | C17H14N2O3S2 | 详情 | 详情 | |
| (IX) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (X) | 20808 | tert-butyl 2-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate | C23H24N2O5S2 | 详情 | 详情 | |
| (XI) | 20809 | tert-butyl 2-[6-amino-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate | 112968-38-4 | C15H22N2O3S2 | 详情 | 详情 |
| (XII) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (XIII) | 20811 | ethyl 2-[[4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate | C27H36N2O5S2 | 详情 | 详情 |
合成路线2
2) The addition of tert-butoxycarbonyl)-L-cysteine (XIV) to 2-(2-nitroethenyl)thiophene (XV) by means of N-methylmorpholine in toluene gives S-[2-nitro-1-(2-thienyl)ethyl-N-(tert-butoxycarbonyl-L-cysteine (XVI), which is reduced with H2 over Pd/C in acetic acid yielding the corresponding amine (XVII). The cyclization of (XVII) by means of diphenyl phosphorazidate (DPN) and N-methylmorpholine in DMF affords (2RS,6R)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (XVIII), which by hydrolysis and fractional crystallization gives (2S,6R)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (XIX). The condensation of (XIX) with ethyl 2(R)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (XX) by means of triethylamine in dichloromethane yields (2S,2R)-6-[1(S)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (XXI), which is condensed with tert-butyl bromoacetate (XXII) by means of NaH in DMF to give the precursor (XXIII). Finally, this compound is hydrolyzed with 4N-HCl-dioxane at room temperature.
| 【1】 Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 . |
| 【2】 Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984. |
| 【3】 Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 20812 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-sulfanylpropionic acid | 20887-95-0 | C8H15NO4S | 详情 | 详情 |
| (XV) | 20813 | 2-[(Z)-2-nitroethenyl]thiophene | C6H5NO2S | 详情 | 详情 | |
| (XVI) | 20814 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-nitro-1-(2-thienyl)ethyl]sulfanyl]propionic acid | C14H20N2O6S2 | 详情 | 详情 | |
| (XVII) | 20815 | (2R)-3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H22N2O4S2 | 详情 | 详情 | |
| (XVIII) | 20816 | tert-butyl (6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-ylcarbamate | C14H20N2O3S2 | 详情 | 详情 | |
| (XIX) | 20817 | (2S,6R)-6-amino-2-(2-thienyl)-1,4-thiazepan-5-one | 110221-26-6 | C9H12N2OS2 | 详情 | 详情 |
| (XX) | 20818 | ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate | C13H15F3O5S | 详情 | 详情 | |
| (XXI) | 20819 | ethyl (2S)-2-[[(2S,6R)-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate | C21H26N2O3S2 | 详情 | 详情 | |
| (XXII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XXIII) | 20821 | ethyl (2S)-2-[[(2S,6R)-4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate | C27H36N2O5S2 | 详情 | 详情 |