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 -Drug Synthesis Database

【结构式】

【分子编号】44035

【品名】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

【CA登记号】103094-30-0

【分子式】C₂₈H₂₇ClN₂O₇

【分子量】538.98436

【元素组成】C 62.4% H 5.05% Cl 6.58% N 5.2% O 20.78%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(IV)

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：(V)

The condensation of 4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (I) with 2-chlorobenzaldehyde (II) by means of piperidine in isopropanol gives 2-(2-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (III), which is cyclized with 3-aminocrotonic acid methyl ester (IV) in hot isopropanol to yield the phthalimido amlodipine (V). Finally, this compound is deprotected by means of aqueous methylamine to afford the target amlodipine.

参考文献中间体

合成目标

【1】 Benneker, F.B.G.; Peters, T.H.A.; Slanina, P.; Bartl, J.; Process for making amlodipine, derivs. thereof, and precursors therefor. WO 0253535 .

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)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(III)	54215	ethyl (Z)-3-(2-chlorophenyl)-2-{2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]acetyl}-2-propenoate	n/a	C₂₃H₂₀ClNO₆	详情	详情
(IV)	11372	Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate		C₅H₉NO₂	详情	详情
(V)	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3

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.
【3】 Billman JH,Parker EE.Amino acids.I.Glycine.J Am Chem Soc,1943,65:761.
【4】 Soine TO,Buchdahl MR.β-Bromoethylphalimide.Org Synth,1952,32:18.
【5】 Peters THA,Benneker FBG,Slanina PBJ.Process for making amlodipine,derivatives thereof,and precursors thereof:US,Patent 2,002,143,046,2002.
【6】 Alsan T,Adiyaman M,Yurdakul A,et al.Isolation of dihydropyridine derivative and preparation salts thereof:WO,Patent 2,004,058,711,2004.
【7】 Bolugoddu V.Dahyabhai JL.Pingili RR.et al.Process for preparing amlodipine:US,Patent 2,007,260,065,2007.
【8】 Purohit AK,Desai BC,Shete BD,et al.Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate:US,Patent 2,004,044,218,2004.
【9】 Davison E,Wells JI.Salts of amlodipine:DE,Patent 3,710,457,1987.

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)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(II)	58854	2-(2-hydroxyethyl)-1H-isoindole-1,3(2H)-dione;N-Hydroxyethylphthalimide;N-(2-Hydroxyethyl)phthalimide;2-(2-hydroxyethyl)isoindoline-1,3-dione	3891-07-4	C₁₀H₉NO₃	详情	详情
(III)	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
(IV)	54215	ethyl (Z)-3-(2-chlorophenyl)-2-{2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]acetyl}-2-propenoate	n/a	C₂₃H₂₀ClNO₆	详情	详情
(V)	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
(VI)	23541	ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate	638-07-3	C₆H₉ClO₃	详情	详情
(VII)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(VIII)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(IX)	69569	Methyl 3-aminocrotonate;Methyl 3-amino-2-butenoate;(Z)-methyl 3-aminobut-2-enoate	14205-39-1	C₅H₉NO₂	详情	详情
(X)	69570	Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid;	98-11-3	C₆H₆O₃S	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.
【3】 Chava S,Ramanjaneyulu GS,Rao KB.Process for the preparation of pure amlodipine:WO,Patent 2,006,003,672,2006.

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)	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
(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】 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

Extended Information