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Name Nivadipine;Nilvadipine;CL-287389;SK&F-102362;FK-235;FR-34235;Escor;Nivadil
Chemical Name 2-Cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl 3-methyl ester
CAS 75530-68-6
Related CAS
Formula C19H19N3O6
Structure
Formula Weight 385.37978
Stage 上市-1989
Company Fujisawa (Originator), Fujisawa Deutschland (Originator)
Activity/Mechanism CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Calcium Channel Blockers
Syn. Route 3
Route 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.
List of intermediates No.
ethyl (2e,4e)-5-[4-[(ethoxycarbonyl)oxy]-3-methoxyphenyl]-2,4-pentadienoate (i)
(2e,4e)-5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoic acid (ii)
ethyl (e)-4-(diethoxyphosphoryl)-2-butenoate (iii)
Reference 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.

Route 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.
List of intermediates No.
5-[4-(ethoxycarbonyl)-3-methoxyphenyl]-2(e),4(e)-pentadienoic acid ethoxycarbonyl anhydride (i)
2-[4-(benzhydryloxy)-1-piperidinyl]ethylamine; 2-[4-(benzhydryloxy)-1-piperidinyl]-1-ethanamine (ii)
ethyl 4-hydroxy-1-piperidinecarboxylate (iv)
2-[2-[4-(benzhydryloxy)-1-piperidinyl]ethyl]-1h-isoindole-1,3(2h)-dione (va)
benzhydryl 4-bromo-3-oxobutanoate (vb)
Reference 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.

Route 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.
List of intermediates No.
ethyl 2-cyano-2-(1-methyl-4-piperidinylidene)acetate (iii)
n-(2-aminoethyl)-n-methylcarbamic acid tert-butyl ester; tert-butyl 2-aminoethyl(methyl)carbamate (ii)
(2,3,5-trichlorophenyl)methanol (i)
benzyl (2s,3s,4r,5s)-3-azido-5-methoxy-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-2-furancarboxylate (iv)
benzyl (2s,3s,4r,5r)-3-azido-5-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-2-furancarboxylate (v)
benzyl (2s,3s,4r,5s)-3-azido-5-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-2-furancarboxylate (vi)
Reference 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 .
Reference 2:
    blancafort, p.; castaner, j.; serradell, m.n.; fr-34,235. drugs fut 1983, 8, 9, 776.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名尼伐地平;英文名Nivadipine;Nilvadipine;CL-287389;SK&F-102362;FK-235;FR-34235;Escor;Nivadil;CAS[75530-68-6]

 
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