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藥物詳細合成路線

Name Alprazolam;U-31889;Xanax XR;Panistat;Xanax
Chemical Name 8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
CAS 28981-97-7
Related CAS
Formula C17H13ClN4
Structure
Formula Weight 308.77296
Stage 上市-1983
Company Pfizer (Originator), Questcor (Not Determined), Fabre-Kramer (Licensee)
Activity/Mechanism Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Benzodiazepines, GABA(A) BZ Site Receptor Agonists
Syn. Route 3
Route 1
the reaction of 2,6-dichloro-4-phenylquinoline (i) with refluxing hydrazine hydrate gives 6-chloro-2-hydrazino-4-phenylquinoline (ii), which is cyclocondensed with triethyl orthoacetate (a) in refluxing xylene yielding 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline (iii). the oxidation of (iii) to 5-chloro-2-(3-methyl-4h-1,2,4-triazol-4-yl)benzophenone (v) can be performed with sodium periodate and ruthenium dioxide in acetone-water, or first with ozone in ch2cl2 giving 4-(2-benzoyl-4-chlorophenyl)-5-methyl-4h-1,2,4-triazol-3-carboxaldehyde (iv), which is then oxidized to (v) with silver oxide in methanol. the condensation of (v) with formaldehyde in xylene at 125 c affords 5-chloro-2-(3-(hydroxymethyl)-5-methyl-4h-1,2,4-triazol-4-yl)benzophenon (vi), which by reaction with pbr3 in chloroform is converted into 5-chloro-2-(3-bromoethyl-5-methyl-4h-1,2,4-triazol-4-yl)benzophenon (vii). finally, this product is cyclized with ammonia in thf - methanol.
List of intermediates No.
1,3-bis(trimethylsilyl)-2,4(1h,3h)-pyrimidinedione (a)
(6s)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2h-pyran-2-yloxy)-2-undecyn-1-one (i)
(1s,6s)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2h-pyran-2-yloxy)-2-undecyn-1-ol (ii)
[[(1s,6s)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2h-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1s,6s)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2h-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether (iii)
(4r,9as)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3s)-3-(tetrahydro-2h-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2h-cyclopenta[b]naphthalen-2-one (iv)
(1r,2r,3as,9as)-5-methoxy-1-[(3s)-3-(tetrahydro-2h-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[b]naphthalen-2-ol (v)
(1s,4r)-4-(1-hydroxy-1-methylethyl)-1-methyl-2-cyclohexen-1-ol (vi)
(6ar,10ar)-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6h-benzo[c]chromen-1-yl acetate (vii)
Reference 1:
    hester, j.b. jr.; process for the production of triazolobenzodiazepines and intermediates. de 2203782; fr 2124559; gb 1374822; gb 1374823; gb 1374824; gb 1374825; jp 49066679; us 3709898 .
Reference 2:
    castaner, j.; chatterjee, s.s.; alprazolam. drugs fut 1976, 1, 12, 551.

Route 2
the reaction of 7-chloro-5-phenyl-1,3-dihydro-3h-1,4-benzodiazepine-2-thione (viii) with acetylhydrazine (b) in refluxing anhydrous ethanol gives 7-chloro-5-phenyl-2-(2-acetylhydrazino)-1,3-dihydro-3h-1,4-benzodiazepine (ix), which is cyclized by heating at 250 c.
List of intermediates No.
1-nitroundecane (b)
(6ar,10ar)-3-(1,1-dimethylheptyl)-9-formyl-6,6-dimethyl-6a,7,10,10a-tetrahydro-6h-benzo[c]chromen-1-yl acetate (viii)
(2s)-2-amino-2-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol (ix)
Reference 1:
    hester, j.b. jr.; 6-phenyl-4h-s-triazolo[4,3-a][1,4]benzodiazepines. de 2012190; de 2065893; es 376689; fr 2034999; gb 1291631; us 3987052 .
Reference 2:
    castaner, j.; chatterjee, s.s.; alprazolam. drugs fut 1976, 1, 12, 551.

Route 3
the reaction of 7-chloro-5-phenyl-2-hydrazino-1,3-dihydro-3h-1,4-benzodiazepine (x) with refluxing acetaldehyde (c) gives 7-chloro-5-phenyl-2-ethylydenhydrazino-1,3-dihydro-3h-1,4-benzodiazepine (xi), which is cyclized by refluxing in chloroform (10.5 h) or by heating at 160-72 c (10 min).
List of intermediates No.
n-[(3as,5s,6r,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]-n-(2-chloroethyl)urea (c)
benzyl (1s)-1-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylcarbamate (x)
(2s)-2-[[(benzyloxy)carbonyl]amino]-2-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl methanesulfonate (xi)
Reference 1:
    hester, j.b. jr.; benzodiazepines and the manufacture thereof. ch 574425; de 2242938; fr 2154474; gb 1382605; jp 48034894 .
Reference 2:
    castaner, j.; chatterjee, s.s.; alprazolam. drugs fut 1976, 1, 12, 551.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名阿普唑侖;英文名Alprazolam;U-31889;Xanax XR;Panistat;Xanax;CAS[28981-97-7]

 
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