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药物详细合成路线

Name Bifonazole;Bay-h-4502;Azolmen;Amycor;Mycospor
Chemical Name (±)-1-(p,alpha-Diphenylbenzyl)imidazole;(±)-1-[alpha-(4-Biphenylyl)benzyl]imidazole;(±)-1-[(1,1-Biphenyl)-4-ylphenylmethyl]-1H-imidazole
CAS 60628-96-8
Related CAS 60629-09-6 (monoHCl), 60629-08-5 (sulfate)
Formula C22H18N2
Structure
Formula Weight 310.40216
Stage 上市-1983
Company Bayer (Originator), Lipha (Not Determined), Menarini (Licensee)
Activity/Mechanism Antifungal Agents, ANTIINFECTIVE THERAPY
Syn. Route 2
Route 1
the reduction of 4-phenylbenzophenone (i) with nabh4 in ethanol gives 4-phenylbenzhydrol (ii), which is then condensed with imidazole (iii) by means of socl2 in acetonitrile.
List of intermediates No.
(3r,4s)-1-(4-methoxyphenyl)-4-[(e)-1-propenyl]-3-[(triisopropylsilyl)oxy]-2-azetidinone (iii)
(4s)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one (i)
2,4,6-triisopropylbenzenesulfonyl azide (ii)
Reference 1:
    regel, e.; draber, w.; buechel, k.h.; plempel, m. (bayer ag); alpha-(4-biphenylyl)-benzylazolium salts and their use for combating microorganisms. be 0859041; de 2643563; fr 2365559; gb 1535148; jp 53044568; nl 7710489; us 4243670 .
Reference 2:
    regel, e.; draber, w.; buechel, k.h.; plempel, m. (bayer ag); substituted azol-1-ylmethanes. be 0836924; ca 1059134; ch 619454; dd 124729; de 2461406; fr 2295747; gb 1469617; jp 51091260; nl 7514940; us 4118487 .
Reference 3:
    regel, e.; draber, w.; buechel, k.h.; plempel, m. (bayer ag); combating crop damaging fungi with alpha-(4-biphenylyl)-benzyl-azolium salts. de 2714290; jp 53121941; us 4251540 .
Reference 4:
    serradell, m.n.; blancafort, p.; castaner, j.; bifonazole. drugs fut 1982, 7, 2, 87.

Route 2
the condensation of (s)-1-(4-bromophenyl)-1-phenylmethylamine (s)-(i) with phenylboronic acid (ii) by means of pd(oac)2, pph3 and na2co3 in propanol/water gives the corresponding biphenyl derivative (s)-(iii), which is condensed with 3-bromopropanal dimethylacetal (iv) by means of k2co3 in dmf yielding the secondary amine (s)-(v). the reaction of (s)-(v) with refluxing butyl formate (vi) affords the formamide (s)-(vii), which is cyclized with ammonium acetate in acetic acid to furnish the (s)-enantiomer of the target compound.the corresponding (r)-enantiomer has been obtained by the same reaction sequence but starting from (r)-1-(4-bromophenyl)-1-phenylmethylamine (r)-(i).
List of intermediates No.
(4ar,6r,7r,7as)-6-(6-amino-9h-purin-9-yl)-2,7-dihydroxytetrahydro-4h-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-2-one (ii)
4-[(2s,3r)-3-[(3s)-3-(acetoxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]phenyl acetate (iv)
benzyl (2s)-1-((2s)-2-[[(2s,4s)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate (s-i)
benzyl (2s)-1-[(2s,5s,7s,11s,12r,15s,16r,19s)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-15-[[(2r)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1s)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl]-2-pyrrolidinecarboxylate (s-iii)
(2r)-n-[(3s,6r,7s,10r,11s,15s,17s,20s,25as)-11-[[tert-butyl(dimethyl)silyl]oxy]-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1s)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15h-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide (s-v)
(2r)-n-[(3s,6r,7s,10r,11s,15s,17s,20s,25as)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1s)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15h-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide (vi)
(2s)-2-(benzyloxy)propionic acid (s-vii)
(2s)-1-[(2s)-2-(benzyloxy)propanoyl]-2-pyrrolidinecarboxylic acid (r-i)
(2s,4s)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoic acid (r-iii)
2-(trimethylsilyl)ethyl (2s)-2-amino-4-methylpentanoate (r-v)
2-(trimethylsilyl)ethyl (2s)-2-[[(2s,4s)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoate (r-vii)
Reference 1:
    botta, m.; et al.; chiral azole derivatives.4.enantiomers of bifonazole and related antifungal agents. synthesis, configuration assignment, and biological evaluation. j org chem 2000, 65, 15, 4736.

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联苯苄唑;英文名Bifonazole;Bay-h-4502;Azolmen;Amycor;Mycospor;CAS[60628-96-8]

 
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