ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】35061

【品名】ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₃₅H₄₂N₂O₆

【分子量】586.72836

【元素组成】C 71.65% H 7.22% N 4.77% O 16.36%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(Xb),(XI)

Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).

参考文献中间体

合成目标

【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668.
【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 .
【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
	17470	diethyl carbonate; diethylcarbonate	105-58-8	C₅H₁₀O₃	详情	详情
	39563	nitromethane	75-52-5	CH₃NO₂	详情	详情
(VIIa)	35056	ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₂₃H₂₇NO₅	详情	详情
(VIIb)	35057	ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₂₃H₂₇NO₅	详情	详情
(Xa)	35060	ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₃₅H₄₂N₂O₆	详情	详情
(Xb),(XI)	35061	ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₃₅H₄₂N₂O₆	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)	35052	1-(4-propoxyphenyl)-1-ethanone		C₁₁H₁₄O₂	详情	详情
(IV)	35053	ethyl 3-oxo-3-(4-propoxyphenyl)propanoate		C₁₄H₁₈O₄	详情	详情
(V)	35054	ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate		C₂₃H₂₅NO₈	详情	详情
(VI)	35055	ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate		C₂₃H₂₅NO₅	详情	详情
(VIII)	35058	2,6-diethylphenylamine; 2,6-diethylaniline	579-66-8	C₁₀H₁₅N	详情	详情
(IX)	35059	2-bromo-N-(2,6-diethylphenyl)acetamide		C₁₂H₁₆BrNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(Xb),(XI)

Then, hydrolysis of the ester group of (Xa, Xb) with NaOH gave rise to the title trans,trans pyrrolidine-3-carboxylic acid. The undesired cis,trans isomeric ester (XI) was not hydrolyzed under these conditions, allowing its removal from the product by means of differential extraction

参考文献中间体

合成目标

【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668.
【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 .
【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Xa)	35060	ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₃₅H₄₂N₂O₆	详情	详情
(Xb),(XI)	35061	ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate		C₃₅H₄₂N₂O₆	详情	详情

Extended Information