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【结 构 式】 
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【药物名称】Ro-32-6168 【化学名称】1-[N-(4-Hydroxysuccinyl)-L-aspartyl-L-glutamyl-L-(2-methyl)phenyl-alanyl-L-(3-methyl)valyl-L-leucylamino]propylboronic acid 【CA登记号】208520-10-9 【 分 子 式 】C38H59BN6O14 【 分 子 量 】834.73673 |
【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
Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).
| 【1】 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) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (III) | 22253 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 22254 | benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate | C19H30N2O3 | 详情 | 详情 | |
| (V) | 22255 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid | C25H23NO4 | 详情 | 详情 | |
| (VI) | 22256 | benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate | C44H51N3O6 | 详情 | 详情 | |
| (VII) | 22257 | benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate | C29H41N3O4 | 详情 | 详情 | |
| (VIII) | 22258 | (2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid | 104091-08-9 | C24H27NO6 | 详情 | 详情 |
| (IX) | 22259 | benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate | C38H56N4O7 | 详情 | 详情 | |
| (X) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XI) | 22261 | 1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate | C46H69N5O10 | 详情 | 详情 | |
| (XII) | 22262 | 4-(tert-butoxy)-4-oxobutyric acid | C8H14O4 | 详情 | 详情 | |
| (XIII) | 22263 | 1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate | C54H81N5O13 | 详情 | 详情 |
合成路线2
Hydrogenolysis of the benzyl ester of (XIII) over Pd/C gave peptide acid (XIV), which was converted to the mixed anhydride (XV) using isobutyl chloroformate and N-methylmorpholine. (Aminopropyl)- dioxaborolane (XIX) was obtained by treatment of the (dichloromethyl)dioxaborolane (XVI) with ethylmagnesium bromide (XVII), and subsequent displacement of the remaining chlorine atom with lithium bis(trimethylsilyl)amide. Condensation of anhydride (XV) with racemic aminoborolane (XIX) produced (XX) as a diastereomeric mixture. Finally, removal of the tert-butyl esters and hydrolysis of the dioxaborolane to the target boronic acid was effected with trifluoroacetic acid in CH2Cl2.
| 【1】 Attwood, M.R.; Campbell, A.D.; Bennett, J.M.; et al.; The design and synthersis of potent inhibitors of hepatitis C virus NS3-4A proteinase. Antivir Chem Chemother 1999, 10, 5, 259. |
| 【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 |
|---|---|---|---|---|---|---|
| (XIV) | 22264 | (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-21,21-dimethyl-8-(2-methylbenzyl)-4,7,10,13,16,19-hexaoxo-20-oxa-3,6,9,12,15-pentaazadocosan-1-oic acid | C47H75N5O13 | 详情 | 详情 | |
| (XV) | 22265 | 4-Tert-butoxysuccinyl-(4-O-tert-butyl)-L-aspartyl-(5-O-tert-butyl)-L-glutamyl-(2-methyl)-L-phenylalanyl-L-tert-leucyl-L-leucine isobutoxycarbonyl anhydride; 4-Tert-butoxysuccinyl-(4-O-tert-butyl)-L-aspartyl-(5-O-tert-butyl)-L-glutamyl-(2-methyl)-L-phenylalanyl-L-tert-leucyl-L-leucine isobutoxycarbonyl anhydride | C52H83N5O15 | 详情 | 详情 | |
| (XVI) | 22266 | 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | C7H13BCl2O2 | 详情 | 详情 | |
| (XVII) | 22267 | (bromomethyl)(ethyl)magnesium | C3H7BrMg | 详情 | 详情 | |
| (XVIII) | 22268 | 2-(1-chloropropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane | C9H18BClO2 | 详情 | 详情 | |
| (XIX) | 22269 | 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-propanamine; 1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propylamine | C9H20BNO2 | 详情 | 详情 | |
| (XX) | 22270 | tert-butyl (6S,9S,12S,15S,18S)-18-[2-(tert-butoxy)-2-oxoethyl]-15-[3-(tert-butoxy)-3-oxopropyl]-9-(tert-butyl)-6-isobutyl-12-(2-methylbenzyl)-5,8,11,14,17,20-hexaoxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,7,10,13,16,19-hexaazatricosan-23-oate | C56H93BN6O14 | 详情 | 详情 |