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【结 构 式】

【分子编号】35043

【品名】methyl 3-(1,3-benzodioxol-5-yl)-5-pentyl-3,4-dihydro-2H-pyrrole-4-carboxylate

【CA登记号】

【 分 子 式 】C18H23NO4

【 分 子 量 】317.38496

【元素组成】C 68.12% H 7.3% N 4.41% O 20.16%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

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
Extended Information