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【结 构 式】 
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【药物名称】 【化学名称】(2S*,3R*,4S*)-4-(1,3-Benzodioxol-5-yl)-1-(N,N-dibutylcarbamoylmethyl)-2-pentylpyrrolidine-3-carboxylic acid 【CA登记号】178608-00-9 【 分 子 式 】C27H42N2O5 【 分 子 量 】474.64619 |
【开发单位】Abbott (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin ETA Receptor Antagonists |
合成路线1
Condensation of piperonal (I) with nitromethane in the presence of NaOH provided nitrostyrene (II). Subsequent conjugate addition of (II) to ketoester (III) using DBU provided adduct (IV). Reduction of the nitro group of (IV), with concomitant ring closure and olefinic double bond hydrogenation formed the cyclic imine (V), which was reduced with NaBH3CN to yield the pyrrolidine (VI) as a diastereomeric mixture. The crude mixture was isomerized to a mixture of only cis,trans and trans,trans pyrrolidines (VII) by base-catalyzed equilibration with NaOEt. N-Alkylation of the pyrrolidines (VII) with N,N-dibutyl bromoacetamide (VIII) furnished (IX). Basic hydrolysis of the ester group of (IX) with either NaOH or LiOH gave rise to the target trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (X) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction.
| 【1】 Boyd, S.A.; Mantei, R.A.; Tasker, A.S.; et al.; Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity. Bioorg Med Chem 1999, 7, 6, 991. |
| 【2】 Dive, V.; Toma, F.; Yiotakis, A. (Commissariat a l'Energie Atomique); Derivs. of peptides usable as inhibitors of bacterial collagenases. US 5500414 . |
| 【3】 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 . |
| 【4】 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 |
|---|---|---|---|---|---|---|
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35045 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (VIIb) | 35046 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (IXa) | 35047 | methyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate | C28H44N2O5 | 详情 | 详情 | |
| (IXb),(X) | 35048 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-pentyl-3-pyrrolidinecarboxylate | C28H44N2O5 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35041 | methyl (E)-3-oxo-6-octenoate | C9H14O3 | 详情 | 详情 | |
| (IV) | 35042 | methyl (E)-2-[1-(1,3-benzodioxol-5-yl)-2-nitroethyl]-3-oxo-6-octenoate | C18H21NO7 | 详情 | 详情 | |
| (V) | 35043 | methyl 3-(1,3-benzodioxol-5-yl)-5-pentyl-3,4-dihydro-2H-pyrrole-4-carboxylate | C18H23NO4 | 详情 | 详情 | |
| (VI) | 35044 | methyl 4-(1,3-benzodioxol-5-yl)-2-pentyl-3-pyrrolidinecarboxylate | C18H25NO4 | 详情 | 详情 | |
| (VIII) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 |