2-cyanoethyl (E)-3-amino-2-butenoate -Drug Synthesis Database

【结构式】

【分子编号】13987

【品名】2-cyanoethyl (E)-3-amino-2-butenoate

【CA登记号】

【分子式】C₇H₁₀N₂O₂

【分子量】154.16868

【元素组成】C 54.54% H 6.54% N 18.17% O 20.76%

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：(VII)

CD-832.HCl can be obtained by several different ways: 1) The cyclization of benzaldehyde (IX) with acetoacetate (V) and crotonate (VII) in refluxing isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) 5-[2-(3-pyridylcarboxamido)ethyl] diester (X), which by reaction with tetrabutylammonium fluoride in THF/DMF, or with Na2S in dichloromethane/methanol, eliminates vinyl cyanide yielding the dihydropyridine monoester (XI). Finally, this compound is esterified with (XII) by means of acetyl chloride and acetic anhydride in dichloromethan). 2) The cyclization of benzaldehyde (IX) with crotonate (VI) and acetoacetate (VIII) as before also gives dihydropyridine (X). 3) The reaction of benzaldehyde (IX) with acetoacetate (V) by means of piperidinium acetate in refluxing benzene gives the corresponding 3-nitrobenzylidene derivative (XIII), which is then cyclized with crotonate (VII) to afford the previously obtained dihydropyridine (X). 4) The reaction of benzaldehyde (IX) with acetoacetate (V) by means of piperidinium acetate in refluxing benzene gives the 3-nitrobenzylidene derivative (XIII), which is then cyclized with 3-aminocrotonic acid ester (XIV) in refluxing isopropanol.

参考文献中间体

合成目标

【1】 Mealy, N.; Martel, A.M.; Castaner, J.; CD-832.HCl. Drugs Fut 1996, 21, 12, 1221.
【2】 Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y.; Mild and facile cleavage of 2-cyanoethyl ester using sodium sulfide or tetrabutylammonium fluoride. Synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetrical 1,4-dihydropyridine dicarboxylates. Chem Pharm Bull 1994, 42, 8, 1579-89.
【3】 Ogawa, T.; Ota, T.; Sato, S.; Sunaga, T.; Watanabe, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivs. EP 0370821; JP 1990223580; US 5047543 .
【4】 Kelly, R.C.; Martin, D.G.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs. AU 8812290; EP 0340243; WO 8804659 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	13984	2-[(3-pyridinylcarbonyl)amino]ethyl 3-oxobutanoate		C₁₂H₁₄N₂O₄	详情	详情
(VI)	13985	2-[(3-pyridinylcarbonyl)amino]ethyl (E)-3-amino-2-butenoate		C₁₂H₁₅N₃O₃	详情	详情
(VII)	13987	2-cyanoethyl (E)-3-amino-2-butenoate		C₇H₁₀N₂O₂	详情	详情
(VIII)	13993	2-cyanoethyl 3-oxobutanoate		C₇H₉NO₃	详情	详情
(IX)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(X)	13989	3-(2-cyanoethyl) 5-[2-[(3-pyridinylcarbonyl)amino]ethyl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₆H₂₅N₅O₇	详情	详情
(XI)	13990	2,6-Dimethyl-4-(3-nitrophenyl)-5-([2-[(3-pyridinylcarbonyl)amino]ethoxy]carbonyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₂₃H₂₂N₄O₇	详情	详情
(XII)	13991	3-(Nitrooxy)-1-propanol		C₃H₇NO₄	详情	详情
(XIII)	13998	2-[(3-pyridinylcarbonyl)amino]ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate		C₁₉H₁₇N₃O₆	详情	详情
(XIV)	13999	3-(nitrooxy)propyl (E)-3-amino-2-butenoate		C₇H₁₂N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Condensation of 4-nitrobenzaldehyde (I) with N-methyl acetoacetamide (II) in the presence of piperidine acetate gave benzylideneacetoacetamide (III). This was further condensed with 2-cyanoethyl 3-amino-2-butenoate (IV) to provide dihydropyridine (V), which was resolved into the enantiomers using chiral HPLC. Then, basic hydrolysis of the cyanoethyl ester from the appropriate enantiomer of (V) yielded carboxylic acid (VI). The aminopropyl piperidine (X) was obtained by esterification of 4-phenyl-4-piperidinecarboxylic acid (VII) with MeOH and H2SO4, followed by alkylation of piperidine (VIII) with 3-bromopropylamine (IX). Finally, amine (X) was coupled to acid (VI) by means of EDC and DMAP to furnish the target compound.

参考文献中间体

合成目标

【1】 Nagarathnam, D.; Wetzel, J.M.; Miao, S.W.; Marzabadi, M.R.; Chiu, G.; Wong, W.C.; Hong, X.; Fang, J.; Forray, C.; Branchek, T.A.; Heydorn, W.E.; Chang, R.S.; Broten, T.; Schorn, T.W.; Gluchowski, C.; Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J Med Chem 1998, 41, 26, 5320.

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)	18184	4-Nitrobenzaldehyde	555-16-8	C₇H₅NO₃	详情	详情
(II)	25443	N-methyl-3-oxobutanamide	20306-75-6	C₅H₉NO₂	详情	详情
(III)	25444	(Z)-2-acetyl-N-methyl-3-(4-nitrophenyl)-2-propenamide		C₁₂H₁₂N₂O₄	详情	详情
(IV)	13987	2-cyanoethyl (E)-3-amino-2-butenoate		C₇H₁₀N₂O₂	详情	详情
(V)	25445	2-cyanoethyl 2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate		C₁₉H₂₀N₄O₅	详情	详情
(VI)	25446	2,6-dimethyl-5-[(methylamino)carbonyl]-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid		C₁₆H₁₇N₃O₅	详情	详情
(VII)	25447	4-phenyl-4-piperidinecarboxylic acid	3627-45-0	C₁₂H₁₅NO₂	详情	详情
(VIII)	25448	methyl 4-phenyl-4-piperidinecarboxylate		C₁₃H₁₇NO₂	详情	详情
(IX)	25449	3-bromo-1-propanamine; 3-bromopropylamine	18370-81-5	C₃H₈BrN	详情	详情
(X)	25450	methyl 1-(3-aminopropyl)-4-phenyl-4-piperidinecarboxylate		C₁₆H₂₄N₂O₂	详情	详情

Extended Information