GW-5950X, -Drug Synthesis Database

【结构式】

【药物名称】GW-5950X

【化学名称】2(R)-Benzyl-5-[3(R),5(R)-dibenzyl-2-oxopyrrolidin-1-yl]-4(S)-hydroxy-N-[2(R)-hydroxyindan-1(S)-yl]pentanamide

【CA登记号】240127-97-3 (undefined stereoch.)

【分子式】C₃₉H₄₂N₂O₄

【分子量】602.78059

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

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2

合成路线1

Wittig reaction of N-(benzyloxycarbonyl)-L-phenylalaninal (I) with methyl (triphenylphosphoranylidene)acetate produced unsaturated ester (II). Double bond reduction in (II) with concomitant cyclization and N-deprotection upon treatment with Mg in MeOH furnished (R)-5-benzyl-2-pyrrolidinone (III), which was further protected as the N-Boc derivative (IV) (1). Alkylation of (IV) with benzyl bromide in the presence of LDA in THF at -78 C provided the trans-3,5-dimethylpyrrolidinone (V) as the predominant diastereoisomer. After Boc group cleavage using trifluoroacetic acid, pyrrolidinone (VI) was coupled with epoxide (VII) yielding adduct (VIII). The acetonide protecting group of (VIII) was finally hydrolyzed with HCl to give the title compound.

参考文献中间体

【1】 Kazmierski, W.; Andrews, W. III; Baker, C.; et al.; Heterocyclic isosteres of the P1/P2 domain of amprenavir: Discovery of novel, picomolar HIV-1 protease inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 126.
【2】 Tung, R.D.; Salituro, F.G.; Deininger, D.D.; Bhisetti, G.R.; Baker, C.T.; Spaltenstein, A.; Kazmierski, W.M.; Andrews, C.W. III (Vertex Pharmaceuticals Inc.); Aspartyl protease inhibitors. JP 2000501111; US 5945413; WO 9727180 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(I)	16586	benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate		C₁₇H₁₇NO₃	详情	详情
(II)	38970	methyl (E,4S)-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2-pentenoate		C₂₀H₂₁NO₄	详情	详情
(III)	38971	(5R)-5-benzyl-2-pyrrolidinone		C₁₁H₁₃NO	详情	详情
(IV)	38972	tert-butyl (2R)-2-benzyl-5-oxo-1-pyrrolidinecarboxylate		C₁₆H₂₁NO₃	详情	详情
(V)	38973	tert-butyl (3S,5R)-3,5-dibenzyl-2-oxo-1-pyrrolidinecarboxylate		C₂₃H₂₇NO₃	详情	详情
(VI)	38974	(3S,5R)-3,5-dibenzyl-2-pyrrolidinone		C₁₈H₁₉NO	详情	详情
(VII)	16243	(2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone		C₂₄H₂₇NO₃	详情	详情
(VIII)	38975	(3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone		C₄₂H₄₆N₂O₄	详情	详情

合成路线2

The condensation of indeno[1,2-d]oxazole derivative (I) with (S)-(+)-glycidyl tosylate (II) by means of LiHMDS gives the adduct (III), which is deprotected with HCl to yield the epoxide (IV). Finally, this compound is condensed with the dibenzylpyrrolidone (V) by means of P4 phosphazene base (commercially available) in THF to afford the target amide.

参考文献中间体

【1】 Spaltenstein, A.; Cleary, D.G.; Almond, M.R.; Kazmierski, W.M.; Wright, L.L.; Tung, R.D.; Hazen, R.J.; Furfine, E.S.; Salituro, F.G.; Bock, W.J.; Novel inhibitors of HIV protease: Design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds. Bioorg Med Chem Lett 2000, 10, 11, 1159.
【2】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.

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)	16241	1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone		C₂₁H₂₃NO₂	详情	详情
(II)	16740	(2S)-(+)-Glycidyl tosylate; (2S)oxiranylmethyl 4-methylbenzenesulfonate	70987-78-9	C₁₀H₁₂O₄S	详情	详情
(III)	16243	(2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone		C₂₄H₂₇NO₃	详情	详情
(IV)	50304	(2R)-2-benzyl-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-[(2S)oxiranyl]propanamide		C₂₁H₂₃NO₃	详情	详情
(V)	38974	(3S,5R)-3,5-dibenzyl-2-pyrrolidinone		C₁₈H₁₉NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)