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【结 构 式】 
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【分子编号】48687 【品名】ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C31H42N2O6 【 分 子 量 】538.68436 【元素组成】C 69.12% H 7.86% N 5.2% O 17.82% |
合成路线1
该中间体在本合成路线中的序号：(XX)Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.
| 【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939. |
| 【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 . |
| 【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 . |
| 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 | |
| (VI) | 20679 | ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (XIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XV) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XVI) | 11041 | 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone | 100-06-1 | C9H10O2 | 详情 | 详情 |
| (XVII) | 20680 | ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C21H23NO5 | 详情 | 详情 | |
| (XVIII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIX) | 33492 | N,N-dibutylamine; N-butyl-1-butanamine | 111-92-2 | C8H19N | 详情 | 详情 |
| (XX) | 48687 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate | C31H42N2O6 | 详情 | 详情 |