methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate -Drug Synthesis Database

【结构式】

【分子编号】44034

【品名】methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate

【CA登记号】

【分子式】C₁₂H₁₁ClO₃

【分子量】238.67024

【元素组成】C 60.39% H 4.65% Cl 14.85% O 20.11%

与该中间体有关的原料药合成路线共 8 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7 合成路线8

合成路线1

该中间体在本合成路线中的序号：(III)

Preparation of a key intermediate in the synthesis of amlodipine: The reaction of ethyl 4-(2-phthalimidoethoxy)acetoacetate (I) with ammonium acetate in refluxing toluene gives the corresponding 3-aminocrotonic acid (II), which is then cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (III) in refluxing ethanol.

参考文献中间体

合成目标

【1】 Campon Pardo, J.; Coppi, L.; Gasanz Guillen, Y. (Laboratorios del Dr. Esteve, SA); Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization. WO 0024714 .

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)	44032	Ethyl 4-(2-phthalimidoethoxy)acetoacetate;ETHYL4-[2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ETHOXYL]-3-OXOBUTANOATE;Ethyl-4(2-Phthalimido Ethoxy)Acetoacetate;ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate; Ethyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-3-oxobutanoate	88150-75-8	C₁₆H₁₇NO₆	详情	详情
(II)	44033	ethyl (E)-3-amino-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-2-butenoate		C₁₆H₁₈N₂O₅	详情	详情
(III)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(IV)	44035	Phthalimido amlodipine; Phthaloyl Amlodipine; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate	103094-30-0	C₂₈H₂₇ClN₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (II), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (IV) and ammonium acetate in refluxing ethanol to yield the azido-dihydropyridine (V). Finally, the azido group of (V) is reduced with H2 over Pd/C in ethanol to afford the target amlodipine.

参考文献中间体

合成目标

【1】 Campbell, S.F.; Cross, P.E.; Stubbs, J.K. (Pfizer Inc.); 2-(Secondary aminoalkoxymethyl)dihydropyridine derivatives as anti-ischaemic and antihypertensive agents. DD 218887; EP 0089167; JP 58167569; US 4572909 .

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)	23541	ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate	638-07-3	C₆H₉ClO₃	详情	详情
(II)	24111	2-azido-1-ethanol		C₂H₅N₃O	详情	详情
(III)	24112	ethyl 4-(2-azidoethoxy)-3-oxobutanoate		C₈H₁₃N₃O₄	详情	详情
(IV)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(V)	24115	3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₀H₂₃ClN₄O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

The reduction of 2,2-diethoxyacetic acid ethyl ester (I) with NaBH4 in dimethoxyethane gives 2,2-diethoxyethanol (II), which is condensed with ethyl 4-chloroacetoacetate (III) by means of NaH in hot THF to yield ethyl 4-(2,2-diethoxyethoxy)acetoacetate (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine in refluxing toluene affords the acrylic ester (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing toluene to provide the dihydropyridine (VIII). The reaction of (VIII) with hydroxylamine in refluxing methanol/water gives the hydroxyimino derivative (IX), which is finally reduced to the target compound by means of H2 over Pd/C in acetic acid or with NaBH4 and NiCl2 in methanol. Alternatively, intermediate dihydropyridine (VIII) can be obtained as follows: The reaction of acetoacetate (IV) with ammonium acetate in refluxing ethanol gives ethyl 3-amino-4-(2,2-diethoxyethoxy)crotonate (X), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (XI) in refluxing toluene to yield the target intermediate the dihydropyridine (VIII).

参考文献中间体

合成目标

【1】 Pedersen, S.B.; Preikschat, H.F.; Karup, G.L. (GEA A/S Farmaceutisk Fabrik); Process for the preparation of acetal derivs. of 1,4-dihydropyridines. WO 9925689 .
【2】 Karup, G.L.; Preikschat, H.F. (GEA A/S Farmaceutisk Fabrik); Process for the preparation of 1,4-dihydropyridines and cpds. used in this process. WO 9925688 .

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)	25674	ethyl 2,2-diethoxyacetate	6065-82-3	C₈H₁₆O₄	详情	详情
(II)	48253	2,2-diethoxy-1-ethanol	621-63-6	C₆H₁₄O₃	详情	详情
(III)	23541	ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate	638-07-3	C₆H₉ClO₃	详情	详情
(IV)	48254	ethyl 4-(2,2-diethoxyethoxy)-3-oxobutanoate		C₁₂H₂₂O₆	详情	详情
(V)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(VI)	48255	ethyl (Z)-3-(2-chlorophenyl)-2-[2-(2,2-dimethoxyethoxy)acetyl]-2-propenoate		C₁₇H₂₁ClO₆	详情	详情
(VII)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(VIII)	48256	3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2,2-dimethoxyethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₂H₂₈ClNO₇	详情	详情
(IX)	48258	3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(hydroxyimino)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₀H₂₃ClN₂O₆	详情	详情
(X)	48257	ethyl (E)-3-amino-4-(2,2-diethoxyethoxy)-2-butenoate		C₁₂H₂₃NO₅	详情	详情
(XI)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Arrowsmith JE,Campbell SF,Cross PE,et al.Long-acting dihydropyridine calcium antagonists.1.2-Alkoxymethyl derivatives incorporating basic substituents.J Med Chem,1986,29:1696.
【2】 Campbell SF,Cross PE,Stubbs JK.Dihydropyridine anti-ischemic and antihypertensive agents and pharmaceutical compositions containing them:EP,Patent 89,167,1983.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	24112	ethyl 4-(2-azidoethoxy)-3-oxobutanoate		C₈H₁₃N₃O₄	详情	详情
(V)	24115	3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₀H₂₃ClN₄O₅	详情	详情
(I)	23541	ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate	638-07-3	C₆H₉ClO₃	详情	详情
(II)	24111	2-azido-1-ethanol		C₂H₅N₃O	详情	详情
(IV)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(VI)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】张上嘉，刘万煌，叶财龙.制备酮酯化合物的方法：TW,Patent 234,560,2005.

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)	24112	ethyl 4-(2-azidoethoxy)-3-oxobutanoate		C₈H₁₃N₃O₄	详情	详情
(II)	69571	(E)-ethyl 3-amino-4-(2-azidoethoxy)but-2-enoate		C₈H₁₄N₄O₃	详情	详情
(III)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(IV)	24115	3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₀H₂₃ClN₄O₅	详情	详情
(V)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	详情	详情

合成路线6

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】 Coppi L,Gasanz GY,Campon PJ.Intermediate for the synthesis of amlodipine,preparation process and corresponding utilization:WO,Patent 2,000,024,714,2000.
【2】 Berenguer Maimo R,Merodio Cabanillas JF,Medriano Reperez J.Acetone solvate of phthaloylamlodipine:EP,Patent 1,975,167,2008.
【3】石卫兵，赖宜生，张奕华.苯磺酸氨氯地平的合成研究.中国药物化学杂志，2006,16:161.

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)	44032	Ethyl 4-(2-phthalimidoethoxy)acetoacetate;ETHYL4-[2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ETHOXYL]-3-OXOBUTANOATE;Ethyl-4(2-Phthalimido Ethoxy)Acetoacetate;ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate; Ethyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-3-oxobutanoate	88150-75-8	C₁₆H₁₇NO₆	详情	详情
(II)	44033	ethyl (E)-3-amino-4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-2-butenoate		C₁₆H₁₈N₂O₅	详情	详情
(III)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(IV)	44035	Phthalimido amlodipine; Phthaloyl Amlodipine; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate	103094-30-0	C₂₈H₂₇ClN₂O₇	详情	详情
(V)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	详情	详情

合成路线7

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】潘仙华，毛海舫.氨氯地平苯磺酸盐的制备方法：CN,Patent 1,927,837,2007.

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)	48261	ethyl 3-oxo-4-[2-(tritylamino)ethoxy]butanoate		C₂₇H₂₉NO₄	详情	详情
(II)	69572	(E)-ethyl 3-amino-4-(2-(tritylamino)ethoxy)but-2-enoate		C₂₇H₃₀N₂O₃	详情	详情
(III)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(IV)	48262	5-ethyl 3-methyl 4-(2-chlorophenyl)-2-methyl-6-[[2-(tritylamino)ethoxy]methyl]-1,4-dihydro-3,5-pyridinedicarboxylate		C₃₉H₃₉ClN₂O₅	详情	详情
(V)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	详情	详情

合成路线8

该中间体在本合成路线中的序号：(VII)

参考文献中间体

合成目标

【1】 Artus Surroca JJ,Janet Bonet M,Rafecas Jane L.Intermediate compounds for obtaining main active anti-hypertensive agents together with corresponding procedures:ES,Patent 2,211,317,2004.
【2】 Yiu SH,Knaus EE.Synthesis,calcium channel antagonist activity,and anticonvulsant activity of 3-ehtyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy)methyl]-6-methyl-4-(2,3-dichloro-phenyl)-3,5-pyridinedicarboxylate coupled to a 1-methyl-1,4-dihydropyridyl-3-carbonyl chemical delivery system. Arch Pharma,1999,332:363.

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)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(II)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(III)	69576	2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol		C₇H₁₄O₃	详情	详情
(IV)	23541	ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate	638-07-3	C₆H₉ClO₃	详情	详情
(V)	69577	ethyl 3-oxo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)butanoate		C₁₃H₂₂O₆	详情	详情
(VI)	69578	ethyl 4-(2-hydroxyethoxy)-3-oxobutanoate		C₈H₁₄O₅	详情	详情
(VII)	44034	methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate		C₁₂H₁₁ClO₃	详情	详情
(VIII)	69579	3-ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-hydroxyethoxy)methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate		C₂₀H₂₄ClNO₆	详情	详情
(IX)	69580	3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-((2-((methylsulfonyl)oxy)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate		C₂₁H₂₆ClNO₈S	详情	详情
(X)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	详情	详情

Extended Information