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【结 构 式】 
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【药物名称】 【化学名称】Benzyloxycarbonyl-L-aspartyl-L-valyl-L-3-(2-methylphenyl) alanyl-L-(3-methyl)valyl-L-leucine N-(1-boronopropyl)amide 【CA登记号】208520-63-2 【 分 子 式 】C42H63BN6O11 【 分 子 量 】838.81501 |
【开发单位】Roche (Originator) 【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, HCV NS3 Protease Inhibitors |
合成路线1
The title compound was prepared by solid phase peptide synthesis. The dioxoborolane-linked resin (XI) was obtained as shown in Scheme 1. 3,7-Dimethyl-6-octenoic acid (I) was protected as the tert-butyl ester (II) by treatment with isobutylene and sulfuric acid, and subsequently oxidized with KMnO4 to afford the hydroxy ketone (III). Addition of methylmagnesium bromide to the keto group of (III) provided diol (IV), which upon reaction with dichloromethyl diisopropoxyborane furnished dioxaborolane (V). Displacement of one chlorine group of (V) with ethylmagnesium bromide at -78 C gave rise to the chloropropyl dioxaborolane (VI). The remaining chlorine atom of (VI) was displaced with lithium bis(trimethylsilyl)amide to yield, after acid desilylation, amine (VII). This was coupled with N-Fmoc-L-leucine (VIII) via the mixed anhydride with isobutyl chloroformate to give amide (IX). After cleavage of the tert-butyl ester of (IX) with trifluoroacetic acid, the resulting carboxylic acid (X) was coupled to the 4-methylbenzhydrylamine resin by means of 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), yielding resin (XI).
| 【1】 Dunsdon, R.M.; et al.; Solid phase synthesis of aminoboronic acids: Potent inhibitors of the hepatitis C virus NS3 proteinase. Bioorg Med Chem Lett 2000, 10, 14, 1577. |
| 【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
| 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) | 43339 | 3,7-dimethyl-6-octenoic acid | 502-47-6 | C10H18O2 | 详情 | 详情 |
| (II) | 43340 | tert-butyl 3,7-dimethyl-6-octenoate | C14H26O2 | 详情 | 详情 | |
| (III) | 43341 | tert-butyl 7-hydroxy-3,7-dimethyl-6-oxooctanoate | C14H26O4 | 详情 | 详情 | |
| (IV) | 43342 | tert-butyl 6,7-dihydroxy-3,6,7-trimethyloctanoate | C15H30O4 | 详情 | 详情 | |
| (V) | 43343 | tert-butyl 5-[2-(dichloromethyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3-methylpentanoate | C16H29BCl2O4 | 详情 | 详情 | |
| (VI) | 43344 | tert-butyl 5-[2-(1-chloropropyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3-methylpentanoate | C18H34BClO4 | 详情 | 详情 | |
| (VII) | 43345 | tert-butyl 5-[2-(1-aminopropyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3-methylpentanoate | C18H36BNO4 | 详情 | 详情 | |
| (VIII) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (IX) | 43346 | tert-butyl 5-(2-[1-[((2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoyl)amino]propyl]-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl)-3-methylpentanoate | C39H57BN2O7 | 详情 | 详情 | |
| (X) | 43347 | 5-(2-[1-[((2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoyl)amino]propyl]-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl)-3-methylpentanoic acid | C35H49BN2O7 | 详情 | 详情 | |
| (XI) | 43348 | 9H-fluoren-9-ylmethyl (1S)-1-[([1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]amino)carbonyl]-3-methylbutylcarbamate | C35H50BN3O6 | 详情 | 详情 |
合成路线2
The Fmoc protecting group of resin (XI) was removed by treatment with piperidine in DMF to give (XII). This was subsequently coupled with N-Fmoc-3-methyl-L-valine (XIII) to provide, after Fmoc deprotection with piperidine, the dipeptide resin (XIV). Further coupling and deprotection cycles with N-Fmoc-3-(2-methylphenyl)-L-alanine (XV) and N-Fmoc-D-valine (XVII) yielded resins (XVI) and (XVIII), respectively. Resin (XVIII) was then coupled with N-(benzyloxycarbonyl)-L-aspartic acid beta-tert-butyl ester (XIX), and the title compound was finally deprotected and liberated from the resin by means of trifluoroacetic acid in CH2Cl2.
| 【1】 Dunsdon, R.M.; et al.; Solid phase synthesis of aminoboronic acids: Potent inhibitors of the hepatitis C virus NS3 proteinase. Bioorg Med Chem Lett 2000, 10, 14, 1577. |
| 【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 43348 | 9H-fluoren-9-ylmethyl (1S)-1-[([1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]amino)carbonyl]-3-methylbutylcarbamate | C35H50BN3O6 | 详情 | 详情 | |
| (XII) | 43349 | (2S)-2-amino-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C20H40BN3O4 | 详情 | 详情 | |
| (XIII) | 43350 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3,3-dimethylbutyric acid | 132684-60-7 | C21H23NO4 | 详情 | 详情 |
| (XIV) | 43351 | (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C26H51BN4O5 | 详情 | 详情 | |
| (XV) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (XVI) | 43352 | (2S)-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanamide | C36H62BN5O6 | 详情 | 详情 | |
| (XVII) | 43354 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
| (XVIII) | 43353 | (2S)-2-[((2S)-2-[[(2S)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-N-[1-[4-(5-amino-3-methyl-5-oxopentyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-2-yl]propyl]-4-methylpentanamide | C41H71BN6O7 | 详情 | 详情 | |
| (XIX) | 36564 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 |