(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 -Drug Synthesis Database

【结构式】

【分子编号】38975

【品名】(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

【CA登记号】

【分子式】C₄₂H₄₆N₂O₄

【分子量】642.83832

【元素组成】C 78.47% H 7.21% N 4.36% O 9.96%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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

该中间体在本合成路线中的序号：(III)

The title compound has been prepared by two related ways. The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 3,4-(methylenedioxy)benzyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.

参考文献中间体

合成目标

【1】 Astles, P.C.; Brown, T.J.; Halley, F.; et al.; Selective ETA antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives. J Med Chem 2000, 43, 5, 900.
【2】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 .

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)	20094	2,4-dihydroxybenzaldehyde	95-01-2	C₇H₆O₃	详情	详情
(II)	28617	5-(chloromethyl)-1,3-benzodioxole		C₈H₇ClO₂	详情	详情
(III)	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
(IV)	38977	2-hydroxy-2-(2-methylphenyl)acetic acid		C₉H₁₀O₃	详情	详情
(V)	38978	2-[5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenoxy]-2-(2-methylphenyl)acetic acid		C₂₄H₁₉NO₆	详情	详情

Extended Information