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药物详细合成路线

Name Voriconazole;UK-109496;Vfend
Chemical Name (2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol
CAS 137234-62-9
Related CAS
Formula C16H14F3N5O
Structure
Formula Weight 349.31808
Stage 上市-2002
Company Pfizer (Originator)
Activity/Mechanism Antifungal Agents, ANTIINFECTIVE THERAPY
Syn. Route 3
Route 1
the cyclization of 2-fluoro-3-oxopentanoic acid ethyl ester (i) with formamidine (ii) by means of sodium methoxide in refluxing methanol gives 6-ethyl-5-fluoropyrimidin-4(3h)-one (iii), which by reaction with refluxing pocl3 is converted into 4-chloro-6-ethyl-5-fluoropyrimidine (iv). the condensation of (iv) with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (v) by means of lithium diisopropylamide in thf yields two pairs of diastereomers (r*,s*)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)-2-butanol (vi) (racemic pair a) and the (r*,r*)-racemic pair b (vii). the reductive dechlorination of (vi) with h2 over pd/c in ethanol affords the racemic pair (viii), which is submitted to optical resolution with 1(s)-(+)-10-camphorsulfonic acid.
List of intermediates No.
1-(4-chlorophenyl)-2-pyrrolidinone (i)
ethyl 1-(4-chlorophenyl)-2-oxo-3-pyrrolidinecarboxylate (ii)
1-(4-chlorophenyl)-3-(hydroxymethyl)-2-pyrrolidinone (iii)
[1-(4-chlorophenyl)-2-oxo-3-pyrrolidinyl]methyl methanesulfonate (iv)
4-(2-methoxyethyl)-1-piperazinecarbaldehyde (v)
1-(2-methoxyethyl)piperazine (vi)
1-(4-chlorophenyl)-3-[[4-(2-methoxyethyl)-1-piperazinyl]methyl]-2-pyrrolidinone (vii)
2-bromoaniline (viii)
Reference 1:
    fromtling, r.a.; castaner, j.; voriconazole. drugs fut 1996, 21, 3, 266.
Reference 2:
    ray, s.j.; richardson, k. (pfizer inc.); triazole antifungal agents. ep 0440372; jp 1992211078; jp 1997208583; us 5278175; us 5773443 .

Route 2
the fluorination of 3-oxopentanoic acid methyl ester with f2 gas gives 2-fluoro-3-oxopentanoic acid methyl ester (ii), which is cyclized with formamidine (iii) by means of naome yielding 6-ethyl-5-fluoropyrimidin-4-ol (iv). reaction of (iv) with pocl3 and tea in dichloromethane affords 4-chloro-6-ethyl-5-fluoropyrimidine (v), which is brominated with nbs and aibn in dichloromethane to provide 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (vi). compound (vi) is condensed with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (vii) by means of i2 and zn in thf furnishing a mixture of the diastereomeric racemates (2r*,3r*)- and (2r*,3s*)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1h-1,2,4-triazol-1-yl)-2-butanol (viii) in a 1:10.3 molar ratio. the reductive dechlorination of (2r*,3s*)-(viii) with h2 over pd/c gives the (2r*,3s*)-racemate (ix), which is submitted to optical resolution by means of crystallization with (1r)-10-camphorsulfonic acid.
List of intermediates No.
ethyl 1-(4-chlorophenyl)-2-oxo-3-pyrrolidinecarboxylate (iii)
[1-(4-chlorophenyl)-2-oxo-3-pyrrolidinyl]methyl methanesulfonate (v)
4-(2-methoxyethyl)-1-piperazinecarbaldehyde (vii)
1-(2-methoxyethyl)piperazine (viii)
2-bromoaniline (ix)
2-bromoacetyl chloride (i)
4-methyl-1,2,3-thiadiazole-5-carboxylic acid (ii)
(2s)-4-(benzyloxy)-2-({(2s)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoyl}amino)-4-oxobutanoic acid (iv)
(2s)-2-{[(2s)-2-amino-5-(benzyloxy)-5-oxopentanoyl]amino}-4-(benzyloxy)-4-oxobutanoic acid (vi)
Reference 1:
    butters, m.; et al.; process development of voriconazole: a novel broad-spectrum triazole antifungal agent. org process res dev 2001, 5, 1, 28.

Route 3
alternatively, 6-ethyl-5-fluoropyrimidin-4-ol (iv) can be obtained by reaction of 2,4-dichloro-5-fluoropyrimidine (x) with ethylmagnesium bromide in thf to give the dihydropyrimidine derivative (xi), which is aromatized by reaction with i2 and tea in thf yielding 2,4-dichloro-6-ethyl-5-fluoropyrimidine (xii). the reaction of (xii) with naoh and nh4cl affords the aminooxy derivative (xiii) which is finally submitted to a reductive dechlorination and deamination with h2 over pd/c in ethanol/water.
List of intermediates No.
(2s)-4-(benzyloxy)-2-({(2s)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoyl}amino)-4-oxobutanoic acid (iv)
(5s,8s,11s)-11-[2-(benzyloxy)-2-oxoethyl]-8-[3-(benzyloxy)-3-oxopropyl]-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid (x)
benzyl (5s,8s,11s)-11-[2-(benzyloxy)-2-oxoethyl]-8-[3-(benzyloxy)-3-oxopropyl]-5-methyl-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oate (xi)
1-({[bis(tert-butoxycarbonyl)amino]oxy}methyl)benzene (xii)
2-({[(tert-butoxycarbonyl)(hydroxy)amino]carbonyl}oxy)-2-methylpropane (xiii)
Reference 1:
    butters, m.; et al.; process development of voriconazole: a novel broad-spectrum triazole antifungal agent. org process res dev 2001, 5, 1, 28.

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伏立康唑;英文名Voriconazole;UK-109496;Vfend;CAS[137234-62-9]

 
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