Fosamprenavir sodium, GW-433908A, 908, VX-175(free acid), -Drug Synthesis Database

【结构式】

【药物名称】Fosamprenavir sodium, GW-433908A, 908, VX-175(free acid)

【化学名称】N-[3-[N-(4-Aminophenylsulfonyl)-N-isobutylamino]-1(S)-benzyl-2(R)-(phosphonooxy)propyl]carbamic acid tetrahydrofuran-3(S)-yl ester disodium salt

【CA登记号】226700-80-7, 226700-79-4 (free acid)

【分子式】C₂₅H₃₄N₃Na₂O₉PS

【分子量】629.58183

【开发单位】GlaxoSmithKline (Originator), Vertex (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, HIV Protease Inhibitors

合成路线1 合成路线2 合成路线3

合成路线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 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) -- obtained by reaction of tetrahydrofuran-3(S)-ol (VIII) first with phosgene and then with N-hydroxysuccinimide (IX) -- and DIEA in acetonitrile to provide the corresponding carbamate (X). 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 intermediate (XIII).

参考文献中间体

【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224.
【2】 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 .
【3】 Tung, R.D. (Vertex Pharmaceuticals Inc.); THF-containing sulfonamide inhibitors of aspartyl protease. EP 0846110; WO 9633184 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	19730	tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate	98737-29-2	C₁₅H₂₁NO₃	详情	详情
(II)	13306	2-Methyl-1-propanamine; Isobutylamine	78-81-9	C₄H₁₁N	详情	详情
(III)	44417	tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate	160232-08-6	C₁₉H₃₂N₂O₃	详情	详情
(IV)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(V)	44418	benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate		C₂₇H₃₈N₂O₅	详情	详情
(VI)	44419	benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate		C₂₂H₃₀N₂O₃	详情	详情
(VII)	39664	1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione		C₉H₁₁NO₆	详情	详情
(VIII)	44420	(3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran	86087-23-2	C₄H₈O₂	详情	详情
(IX)	10264	1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione	6066-82-6	C₄H₅NO₃	详情	详情
(X)	44421	benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate		C₂₇H₃₆N₂O₆	详情	详情
(XI)	44422	(3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate		C₁₉H₃₀N₂O₄	详情	详情
(XII)	15809	4-nitrobenzenesulfonyl chloride	98-74-8	C₆H₄ClNO₄S	详情	详情
(XIII)	44423	(3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate		C₂₅H₃₃N₃O₈S	详情	详情

合成路线2

The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is condensed with 4-nitrophenylsulfonyl chloride (XII) and TEA in hot toluene, yielding sulfonamide (XIV). Deprotection of (XIV) with HCl in hot toluene/water affords the primary amine (XV), which is condensed with imidazole-1-carboxylic acid 3(S)-tetrahydrofuryl ester (XVI) -- prepared by reaction of tetrahydrofuran-3(S)-ol (VIII) with carbonyldiimidazole (CDI) in ethyl acetate -- to provide intermediate (XIII).

参考文献中间体

【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224.
【2】 Deininger, D.D.; O'Callaghan, 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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	19730	tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate	98737-29-2	C₁₅H₂₁NO₃	详情	详情
(II)	13306	2-Methyl-1-propanamine; Isobutylamine	78-81-9	C₄H₁₁N	详情	详情
(III)	44417	tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate	160232-08-6	C₁₉H₃₂N₂O₃	详情	详情
(VIII)	44420	(3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran	86087-23-2	C₄H₈O₂	详情	详情
(XII)	15809	4-nitrobenzenesulfonyl chloride	98-74-8	C₆H₄ClNO₄S	详情	详情
(XIII)	44423	(3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate		C₂₅H₃₃N₃O₈S	详情	详情
(XIV)	44938	tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate		C₂₅H₃₅N₃O₇S	详情	详情
(XV)	44939	N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide	590-90-9	C₂₀H₂₇N₃O₅S	详情	详情
(XVI)	10264	1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione	6066-82-6	C₄H₅NO₃	详情	详情

合成路线3

Esterification of the OH group of compound (XIII) with PO3H3 by means of DCC in hot pyridine gives the corresponding phosphite (XVII), which is oxidized with bis(trimethylsilyl)peroxide in bis(trimethylsilyl)azane to yield the expected phosphate (XVIII). Reduction of the nitro group of (XVIII) with H2 over Pd/C in ethyl acetate affords fosamprenavir (XIX). Finally, fosamprenavir (XIX) is treated with aqueous NaHCO3 or with calcium acetate in water to provide the corresponding salts. Alternatively, the phosphate (XIX) can be obtained directly by reaction of intermediate (XIII) with POCl3 in pyridine, followed by hydrolysis with 2N HCl.

参考文献中间体

【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224.
【3】 Armitage, I.G.; Singh, H.; Searle, A.D. (Glaxo Group Ltd.); Calcium (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. WO 0004033 .
【4】 Kaldor, I.; Hale, M.R.; Furfine, E.S.; Baker, C.T.; Tung, R.D.; Kazmierski, W.M.; Spaltenstein, A. (Vertex Pharmaceuticals Inc.); Prodrugs of aspartyl protease inhibitors. WO 9933792 .
【5】 Kazmierski, W.W.; Hale, M.R.; Tung, R.D.; Furfine, E.S.; Kaldor, I.; Baker, C.T.; Spaltenstein, A. (Vertex Pharmaceuticals Inc.); Sulphonamide derivs. as prodrugs of aspartyl protease inhibitors. CA 2231700; EP 0933372; JP 1999209337; WO 9933815 .
【6】 Spaltenstein, A.; Kazmierski, W.M.; Kaldor, I.; Baker, C.T.; Hale, M.R.; Tung, R.D.; Furfine, E.S. (Vertex Pharmaceuticals Inc.); Prodrugs of aspartyl protease inhibitors. WO 9933793 .
【7】 Crawley, K.; Searle, A.D. (Glaxo Group Ltd.); Derivs. of (3S) tetrahydro-3-furanyl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate. WO 0100635 .
【2】 Furfine, E.S.; Bridson, G.; Hale, M.R.; Baker, C.; Heiser, A.; Chaturvedi, P.R.; Tung, R.D.; Spaltenstein, A.; Discovery of VX-175/GW433908, a novel, water-soluble prodrug of amprenavir. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F916.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	44423	(3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate	C₂₅H₃₃N₃O₈S	详情	详情
(XVII)	45767	(1R,2S)-1-([isobutyl[(4-nitrophenyl)sulfonyl]amino]methyl)-3-phenyl-2-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)propyl hydrogen phosphonate	C₂₅H₃₄N₃O₁₀PS	详情	详情
(XVIII)	45768	(3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]-2-(phosphonooxy)propylcarbamate	C₂₅H₃₄N₃O₁₁PS	详情	详情
(XIX)	45769	(3S)tetrahydro-3-furanyl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy)propylcarbamate	C₂₅H₃₆N₃O₉PS	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)