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【结 构 式】 
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【分子编号】20818 【品名】ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate 【CA登记号】 |
【 分 子 式 】C13H15F3O5S 【 分 子 量 】340.3203096 【元素组成】C 45.88% H 4.44% F 16.75% O 23.51% S 9.42% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.
| 【1】 Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.); Process for the preparation of benazepril. WO 0276375 . |
| 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) | 58105 | (R)-2-Hydroxy-4-phenylbutyric acid ethyl ester; Ethyl (R)-2-hydroxy-4-phenylbutyrate | 90315-82-5 | C12H16O3 | 详情 | 详情 |
| (II) | 20818 | ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate | C13H15F3O5S | 详情 | 详情 | |
| (III) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The condensation of acyl chloride (I) with hexahydropyridazine (II) gives the corresponding amide (III), which is debenzylated with H2 over Pd/C and cyclized by means of SOCl2 to yield the pyridazinodiazepinedione (IV). Selective reduction of (IV) with borane in THF affords the pyridazinodiazepinone (V), which is treated with hydrazine to provide (1S,9S)-9-amino-10-oxoperhydropyridazino[1,2-a]azepine-1-carboxylic acid tert-butyl ester (VI). Finally, this compound is condensed with 4-phenyl-2(R)-(trifluoromethanesulfonyloxy)butyric acid ethyl ester (VII) and selectively hydrolyzed to afford the target carboxylic acid.
| 【1】 Natoff, I.L.; Redshaw, S.; Angiotensin-converting enzyme inhibitors - Cilazapril and other bicyclic hexahydropyridazines. Drugs Fut 1987, 12, 5, 475. |
| 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) | 44036 | phenyl (6S)-7-chloro-6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-7-oxoheptanoate | C21H18ClNO5 | 详情 | 详情 | |
| (II) | 44037 | di(tert-butyl) (3S)tetrahydro-1,3(2H)-pyridazinedicarboxylate | C14H26N2O4 | 详情 | 详情 | |
| (III) | 44038 | di(tert-butyl) (3S)-2-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-6-phenoxyhexanoyl]tetrahydro-1,3(2H)-pyridazinedicarboxylate | C34H41N3O9 | 详情 | 详情 | |
| (IV) | 44039 | tert-butyl (1S,9S)-9-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6,10-dioxooctahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate | C22H25N3O6 | 详情 | 详情 | |
| (V) | 44040 | tert-butyl (1S,9S)-9-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-10-oxooctahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate | C22H27N3O5 | 详情 | 详情 | |
| (VI) | 44041 | tert-butyl (1S,9S)-9-amino-10-oxooctahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate | C14H25N3O3 | 详情 | 详情 | |
| (VII) | 20818 | ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate | C13H15F3O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XX)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 |