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Name Amprenavir;KVX-478;141W94;VX-478;Prozei;Agenerase
Chemical Name 4-Amino-N-[2(R)-hydroxy-4-phenyl-3(S)-[tetrahydrofuran-3(S)-yloxycarbonylamino]butyl]-N-isobutylbenzenesulfonamide
      (1S,2R)-3-[N-(4-Aminophenylsulfonyl)-N-ispropylamino]-1-benzyl-2-hydroxypropylcarbamic acid (3S)-tetrahydro-3-furanyl ester
CAS 161814-49-9
Related CAS
Formula C25H35N3O6S
Structure
Formula Weight 505.6382
Stage 上市-1999
Company Vertex (Originator), GlaxoSmithKline (Licensee), Kissei (Licensee)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
Syn. Route 3
Route 1
the reaction of the chiral epoxide (i) with isobutylamine (ii) in refluxing ethanol gives the secondary amine (iii), which is protected with benzyl chloroformate (iv) and tea, yielding the dicarbamate (v). selective deprotection of (v) with dry hcl in ethyl acetate affords the primary amine (vi), which is treated with 3(s)-tetrahydrofuryl n-succinimidinyl carbonate (vii) (prepared by condensation of tetrahydrofuran-3(s)-ol (viii) with phosgene and n-hydroxysuccinimide (ix)) and diea in acetonitrile to provide the corresponding carbamate (x). the deprotection of (x) by hydrogenation with h2 over pd/c in ethanol gives the secondary amine (xi), which is condensed with 4-nitrophenylsulfonyl chloride (xii) by means of nahco3 in dichloromethane/water to yield the sulfonamide (xiii). finally, the nitro group of (xiii) is reduced with h2 over pd/c in ethyl acetate to afford the target compound.
List of intermediates No.
[5-[3-benzoyl-2,4-dioxo-5-vinyl-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate (iv)
(3r,4s)-4-[(1s)-2,2-dimethylcyclopropyl]-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone (ix)
(e)-7-phenyl-2-heptenoic acid (ii)
6-chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carbaldehyde (xii)
1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-vinyl-2,4(1h,3h)-pyrimidinedione (i)
(vii)
2-(1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-ylidene)ethylamine (iii)
n-[2-(1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-ylidene)ethyl]propanamide (v)
2-(1,6,7,8-tetrahydro-2h-indeno[5,4-b]furan-8-yl)-1-ethanamine; 2-(1,6,7,8-tetrahydro-2h-indeno[5,4-b]furan-8-yl)ethylamine (vi)
n-[2-(1,6,7,8-tetrahydro-2h-indeno[5,4-b]furan-8-yl)ethyl]propanamide (viii)
(4s)-1-(4-methoxybenzyl)-4-methyl-3,4-dihydro-2(1h)-pyridinone (x)
(1s,5s,6r)-7,7-dichloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one (xi)
(1s,5s,6r,7r)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one (xiii)
Reference 1:
    tung, r.d.; murcko, m.a.; bhisetti, g.r. (vertex pharmaceuticals inc.); sulfonamide inhibitors of hiv-aspartyl protease. ep 0659181; ep 0885887; jp 1996501299; us 5585397; wo 9405639 .

Route 2
reaction of the chiral epoxide (i) with isobutylamine (ii) in refluxing ethanol gives the secondary amine (iii), which is condensed with 4-nitrophenylsulfonyl chloride (iv) and tea in hot toluene to yield the sulfonamide (v). deprotection of (v) with hcl hot toluene/water affords the primary amine (vi), which is condensed with imidazole-1-carboxylic acid 3(s)-tetrahydrofuryl ester (vii) [prepared by reaction of tetrahydrofuran-3(s)-ol (viii) with carbonyldiimidazole (cdi) in ethyl acetate] to provide the corresponding carbamate (ix). finally, the nitro group of (ix) is reduced with h2 over pd/c in ethyl acetate to afford the target compound.
List of intermediates No.
(e)-7-phenyl-2-heptenoic acid (ii)
6-chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carbaldehyde (iv)
1-[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-vinyl-2,4(1h,3h)-pyrimidinedione (i)
2-(1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8h-indeno[5,4-b]furan-8-ylidene)ethylamine (iii)
n-[2-(1,6,7,8-tetrahydro-2h-indeno[5,4-b]furan-8-yl)ethyl]propanamide (viii)
(1s,5s,6r,7r)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one (ix)
methyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-hexenoate (v)
methyl (2s)-2-[(tert-butoxycarbonyl)amino]-6-(diethoxyboryl)hexanoate (vi)
methyl (2s)-2-[(tert-butoxycarbonyl)amino]-6-[(1s,2s,6r,8s)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]hexanoate (vii)
Reference 1:
    deininger, d.d.; ocallaghan, j.; mcguie, s.; singh, h.; robertson, m.s.; rodgers, k.; tung, r.d.; al-farhan, e.; rout, s.j. (glaxo group ltd.); process for the synthesis of hiv protease inhibitors. wo 9948885 .

Route 3
the reaction of n,n-dibenzyl-l-alaninal (i) with nitromethane, catalyzed by the chiral ammonium salt (ii) and kf in thf gives the chiral nitroalcohol (iii), which is reduced with nicl2 and nabh4 to yield the aminoalcohol (iv). the condensation of (iv) with isobutyraldehyde (v) affords the schiff base (vi), which is reduced with nabh4 to provide the secondary amine (vii). the reaction of (vii) with 4-nitrobenzenesulfonyl chloride (viii) and tea in dichloromethane furnishes the sulfonamide (ix), which is deprotected by hydrogenation with h2 over pd/c in methanol, giving the diamino compound (x). finally, this compound is condensed with 3(s)-tetrahydrofuryl (n-oxysuccinimidyl) carbonate (xi) by means of tea in dichloromethane to afford the target carbamate.
List of intermediates No.
tert-butyl [(3r,4s)-1-benzyl-4-(trifluoromethyl)pyrrolidinyl]methylcarbamate (v)
6-chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carbaldehyde (viii)
ethyl (2s)-2-amino-4-((2r)-2-[[(2s)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1h-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate (i)
2-nitroethyl acetate (vii)
(xi)
benzyl (2s)-5-[(benzoyloxy)(methyl)amino]-2-[((2s)-2,6-bis{[2,3-bis(acetyloxy)benzoyl]amino}hexanoyl)amino]-5-oxopentanoate (ii)
(2s)-5-[(benzoyloxy)(methyl)amino]-2-[((2s)-2,6-bis{[2,3-bis(acetyloxy)benzoyl]amino}hexanoyl)amino]-5-oxopentanoic acid (iii)
(7s,11s,12r,13s,14r,15r,16r,17s,18s)-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,27,29-tetraoxo-8,30-dioxa-24-azatetracyclo[23.3.1.1~4,7~.0~5,28~]triaconta-1(28),2,4,9,19,21,25-heptaen-13-yl acetate (iv)
(7s,11s,12r,13s,14r,15r,16r,17s,18s)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[23.11.1.1~4,7~.0~5,36~.0~26,35~.0~28,33~]octatriaconta-1(36),2,4,9,19,21,25,28,30,32,34-undecaen-13-yl acetate (vi)
n-isobutyl piperazine (ix)
(7s,11s,12r,13s,14r,15r,16r,17s,18s)-32-{[tert-butyl(dimethyl)silyl]oxy}-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[23.11.1.1~4,7~.0~5,36~.0~26,35~.0~28,33~]octatriaconta-1(36),2,4,9,19,21,25,28,30,32,34-undecaen-13-yl acetate (x)
Reference 1:
    corey, e.j.; zhang, f.-y.; re- and si-face-selective nitroaldol reactions catalyzed by a rigid chiral quaternary ammonium salt: a highly stereoselective synthesis of the hiv protease inhibitor amprenavir (vertex 478). angew chem. int ed engl 1999, 38, 13-14, 1931.

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安普那韦;英文名Amprenavir;KVX-478;141W94;VX-478;Prozei;Agenerase;CAS[161814-49-9]

 
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