【结 构 式】 |
【分子编号】20682 【品名】(2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic 1,1-dimethylpropionic anhydride 【CA登记号】 |
【 分 子 式 】C29H35NO8 【 分 子 量 】525.59884 【元素组成】C 66.27% H 6.71% N 2.66% O 24.35% |
合成路线1
该中间体在本合成路线中的序号:(VIII)The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.
【1】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039. |
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) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
(II) | 20676 | ethyl 3-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
(III) | 20677 | ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate | C21H21NO8 | 详情 | 详情 | |
(IV) | 20678 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C21H21NO5 | 详情 | 详情 | |
(V) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
(VI) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
(VII) | 20681 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid | C24H27NO7 | 详情 | 详情 | |
(VIII) | 20682 | (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic 1,1-dimethylpropionic anhydride | C29H35NO8 | 详情 | 详情 | |
(IX) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
(X) | 20684 | tert-butyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate | C34H36N2O8 | 详情 | 详情 | |
(XI) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
(XII) | 20686 | 2-[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidinyl]-N,N-dibutylacetamide | C39H47N3O7 | 详情 | 详情 |