【结 构 式】 |
【分子编号】38971 【品名】(5R)-5-benzyl-2-pyrrolidinone 【CA登记号】 |
【 分 子 式 】C11H13NO 【 分 子 量 】175.23036 【元素组成】C 75.4% H 7.48% N 7.99% O 9.13% |
合成路线1
该中间体在本合成路线中的序号:(III)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.
【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:(V)Alkylation of cyclopentane carboxylic acid ethyl ester (I) by treatment with dibromoethane (II) in the presence of BuLi in THF affords derivative (III), which is then converted into azide (IV) by first hydrolysis of ethyl ester with NaOH in dioxane, followed by reaction with NaN3 in DMF. Coupling of (IV) with protected cysteines (V) and (VI) by means of HBTU yields compound (VII), which is then subjected to simultaneous Trt removal and oxidation by means of iodine in CHCl3/MeOH to provide cystine derivative (VIII). Acid deprotection of (VIII), followed by coupling to protected tyrosine (IX) and final deprotection of the resulting compound, furnishes the desired cyclic cystine compound. Alternatively, (VII) can be first subjected to acid deprotection to allow next coupling with protected tyrosine (IX), furnishing derivative (X), which is finally oxidized with iodine in CHCl3/MeOH and further deprotected to afford the target cyclic cystine derivative.
【1】 Cook, C.; Kaplan, G.; Fry, D.; Tilley, J.W.; Wolitzky, B.; Hanglow, A.; Joshi, P.; Rowan, K.; Schwinge, V.; Fotouhi, N.; The design and synthesis of potent cyclic peptide VCAM-VLA-4 antagonists incorporating an achiral Asp-Pro mimetic. Bioorg Med Chem Lett 2000, 10, 11, 1171. |
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) | 46208 | ethyl cyclopentanecarboxylate | C8H14O2 | 详情 | 详情 | |
(II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
(III) | 46209 | ethyl 1-(2-bromoethyl)cyclopentanecarboxylate | C10H17BrO2 | 详情 | 详情 | |
(IV) | 46210 | 1-(2-azidoethyl)cyclopentanecarboxylic acid | C8H13N3O2 | 详情 | 详情 | |
(V) | 38971 | (5R)-5-benzyl-2-pyrrolidinone | C11H13NO | 详情 | 详情 | |
(VI) | 46211 | tert-butyl (2R)-2-amino-3-(tritylsulfanyl)propanoate | C26H29NO2S | 详情 | 详情 | |
(VII) | 46212 | tert-butyl (2R)-2-([[1-(2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoyl]amino]ethyl)cyclopentyl]carbonyl]amino)-3-(tritylsulfanyl)propanoate | C61H69N3O6S2 | 详情 | 详情 | |
(VIII) | 46213 | tert-butyl (8R,13R)-13-[(tert-butoxycarbonyl)amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylate | C23H39N3O6S2 | 详情 | 详情 | |
(IX) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
(X) | 46214 | tert-butyl (2R)-2-[[(1-[(5R,8S)-8-(4-hydroxybenzyl)-12,12-dimethyl-4,7,10-trioxo-5-[(tritylsulfanyl)methyl]-11-oxa-3,6,9-triazatridec-1-yl]cyclopentyl)carbonyl]amino]-3-(tritylsulfanyl)propanoate | C70H78N4O8S2 | 详情 | 详情 |