Nivadipine, Nilvadipine, CL-287389, SK&F-102362, FK-235, FR-34235, Escor, Nivadil, -Drug Synthesis Database

【结构式】

【药物名称】Nivadipine, Nilvadipine, CL-287389, SK&F-102362, FK-235, FR-34235, Escor, Nivadil

【化学名称】2-Cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl 3-methyl ester

【CA登记号】75530-68-6

【分子式】C₁₉H₁₉N₃O₆

【分子量】385.37978

【开发单位】Fujisawa (Originator), Fujisawa Deutschland (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Calcium Channel Blockers

合成路线1 合成路线2 合成路线3

合成路线1

1) The synthesis of deuterated nilvadipine has been reported: The selective hydrolysis of nilvadipine (I) with lithium iodide and pyridine gives the monolithium salt (II), which is then treated with perdeuterated methanol and 2-bromo-1-methylpyridinium bromide and dimethylaniline in DMF.

参考文献中间体

【1】 Okumura, K.; Satoh, Y.; Shiokawa, Y.; Studies on nilvadipine. IV. Synthesis of deuterated and optically active isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxylate (nilvadipine). Chem Pharm Bull 1994, 42, 4, 950.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	10998	5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate	C₁₉H₁₉N₃O₆	详情	详情
(II)	10999	2-Cyano-5-(isopropoxycarbonyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid lithium salt	C₁₈H₁₆LiN₃O₆	详情	详情
(III)	11000	5-isopropyl 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate	C₁₉H₁₉N₃O₆	详情	详情

合成路线2

2) The optical isomers of nilvidapine have also been synthesized: The selective hydrolysis of nilvadipine (I) with formic acid gives the monocarboxylic acid (II), which is treated with (-)-cinconidine, yielding the corresponding salt (IV) as a diastereomeric mixture, which is separated by fractional crystallization to give, after hydrolysis with HCl, 2-cyano-3-(methoxycarbonyl)-6-methyl-4(R)-(3-nitrophenyl)-1,4-dihydropy ridine-5-carboxylic acid (Va) and 2-cyano-3-(methoxycarbonyl)-6-methyl-4(S)-(3-nitrophenyl)-1,4-dihydropy ridine-5-carboxylic acid (Vb) as pure optical isomers. Both compounds are esterified by conversion to the corresponding acyl chlorides with PCl5 and esterification with isopropyl alcohol.

参考文献中间体

【1】 Okumura, K.; Satoh, Y.; Shiokawa, Y.; Studies on nilvadipine. IV. Synthesis of deuterated and optically active isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxylate (nilvadipine). Chem Pharm Bull 1994, 42, 4, 950.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(Va)	11004	(4R)-6-Cyano-5-(methoxycarbonyl)-2-methyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid	C₁₆H₁₃N₃O₆	详情	详情
(Vb)	11005	(4S)-6-Cyano-5-(methoxycarbonyl)-2-methyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid	C₁₆H₁₃N₃O₆	详情	详情
(I)	11001	5-(tert-butyl) 3-methyl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate	C₂₀H₂₁N₃O₆	详情	详情
(II)	11002	6-Cyano-5-(methoxycarbonyl)-2-methyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid	C₁₆H₁₃N₃O₆	详情	详情
(IV)	11003	6-Cyano-5-(methoxycarbonyl)-2-methyl-4-phenyl-1,4-dihydro-3-pyridinecarboxylic acid	C₁₆H₁₄N₂O₄	详情	详情

合成路线3

The condensation of isopropyl acetoacetate (I) with 3-nitrobenzaldehyde (II) gives isopropyl 2-(3-nitrobenzylidene)acetoacetate (III), which is cyclized with methyl 3-amino-4,4-dimethoxycrotonate (IV) at 100 C yielding 5-isopropyl-3-methyl-2-(dimethoxymethyl)-6-methyl-4-(3-nitropheny)-1,4-dihydropyridine-3,5-dicarboxylate (V). The hydrolysis of the acetal group of (V) with HCl in acetone affords the corresponding 2-formyl derivative (VI), which is finally treated with hydroxylamine and acetic anhydride in acetic acid at 100 C.

参考文献中间体

【1】 Satu, Y. (Fujisawa Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivatives and pharmaceutical method of the same. BE 0879263; DE 2940833; FR 2438654; GB 2036722; US 4284634; US 4338322 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; FR-34,235. Drugs Fut 1983, 8, 9, 776.

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)	13332	isopropyl 3-oxobutanoate; Isopropyl acetoacetate	542-08-5	C₇H₁₂O₃	详情	详情
(II)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(III)	12595	isopropyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate		C₁₄H₁₅NO₅	详情	详情
(IV)	31096	methyl (E)-3-amino-4,4-dimethoxy-2-butenoate		C₇H₁₃NO₄	详情	详情
(V)	31097	5-isopropyl 3-methyl 2-(dimethoxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate		C₂₁H₂₆N₂O₈	详情	详情
(VI)	31098	5-isopropyl 3-methyl 2-formyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate		C₁₉H₂₀N₂O₇	详情	详情

Extended Information