3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate -Drug Synthesis Database

【结构式】

【分子编号】24115

【品名】3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate

【CA登记号】

【分子式】C₂₀H₂₃ClN₄O₅

【分子量】434.87928

【元素组成】C 55.24% H 5.33% Cl 8.15% N 12.88% O 18.4%

与该中间体有关的原料药合成路线共 6 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1

该中间体在本合成路线中的序号：(VI)

The condensation of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (III), which is submitted to a Hantzsch cyclocondensation with methyl 3-aminocrotonate (IV) and 2-chlorobenzaldehyde (V) in refluxing methanol affording 3-ethyl 5-methyl 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (VI), Finally, this compound is reduced with Zn and 3N HCl in methanol, or with H2 over Pd/CaCO3 in ethanol.

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 .
【2】 Castaner, J.; Prous, J.; Amlodipine. Drugs Fut 1986, 11, 2, 89.

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)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(V)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(VI)	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2

该中间体在本合成路线中的序号：(V)

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：(XIII)

The two enantiomers of amlodipine have been obtained as follows: The reaction of 2-azidoethanol (I) with chloroacetic acid (II) by means of NaH in THF gives 2-(2-azidoethoxy)acetic acid (III), which is condensed with Meldrum's acid (IV) and 3-hydroxypropionitrile (V) in dichloromethane to yield the 2-cyanoethyl acetoacetate (VI). The cyclization of (VI) with 2-chlorobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing ethanol affords the dihydropyridine (IX), which is selectively hydrolyzed at the 2-cyanoethylester with NaOH to give the dihydropyridine monocarboxylic acid (X). The esterification of (X) with (S)-2-methoxy-2-phenylethanol (XI) by means of CDI in dichloromethane provides the ester (XII) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (XXI A) and (XII B). The selective ethanolysis of (XII A) and (XII B) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(XIII) and (-)-(XIII), which are finally reduced with H2 over Pd/CaCO3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.

参考文献中间体

合成目标

【1】 Arrowsmith, J.E.; et al.; Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem 1986, 29, 9, 1696.

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)	24111	2-azido-1-ethanol		C₂H₅N₃O	详情	详情
(II)	11847	2-Chloroacetic acid; Chloroacetic Acid	79-11-8	C₂H₃ClO₂	详情	详情
(III)	48263	2-(2-azidoethoxy)acetic acid		C₄H₇N₃O₃	详情	详情
(IV)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(V)	14029	Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile	109-78-4	C₃H₅NO	详情	详情
(VI)	48264	2-cyanoethyl 4-(2-azidoethoxy)-3-oxobutanoate		C₉H₁₂N₄O₄	详情	详情
(VII)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(VIII)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(IX)	48265	3-(2-cyanoethyl) 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₁H₂₂ClN₅O₅	详情	详情
(X)	48266	2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-3-pyridinecarboxylic acid		C₁₈H₁₉ClN₄O₅	详情	详情
(XI)	48267	(2S)-2-methoxy-2-phenyl-1-ethanol	66051-01-2	C₉H₁₂O₂	详情	详情
(XII)	48268	3-[(2S)-2-methoxy-2-phenylethyl] 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₇H₂₉ClN₄O₆	详情	详情
(XIII)	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4

该中间体在本合成路线中的序号： (V)

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：(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
(I)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(II)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(III)	24112	ethyl 4-(2-azidoethoxy)-3-oxobutanoate		C₈H₁₃N₃O₄	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：(IV)

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

Extended Information