|
【结 构 式】 
|
【药物名称】CI-1029, PD-178390 【化学名称】6(S)-[2-(4-Aminophenyl)ethyl]-3-[2-tert-butyl-4-(hydroxymethyl)-5-methylphenylsulfanyl]-4-hydroxy-6-isopropyl-5,6-dihydro-2H-pyran-2-one 【CA登记号】207736-05-8 【 分 子 式 】C28H37NO4S 【 分 子 量 】483.67539 |
【开发单位】Pfizer (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors |
合成路线1
The condensation of 5-[4-(tert-butoxycarbonylamino)phenyl]-2-methyl-3-pentanone (I) with tert-butylacetate (II) by means of LDA in THF, followed by hydrolysis of the ether with LiOH gives the racemic 3-hydroxypentanoic acid (III), which is submitted to optical resolution with (S)-alpha-methylbenzylamine affording the (S)-enantiomer (IV). The condensation of (IV) with the magnesium salt of monoethyl malonate (V) affords the beta-keto ester (VI), which is cyclized by means of NaOH to provide the dihydropyrone (VII). The condensation of (VII) with thiosulfonate (VIII) by means of K2CO3 in DMF yields the expected thioether (IX), which is finally treated with NaOH in DMSO/water to eliminate the tert-butoxycarbonyl protecting group.
| 【1】 Domagala, J.M.; Boyer, F.E.; Vara Prasad, J.V.N.; et al.; Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor. Bioorg Med Chem 1999, 7, 12, 2775. |
| 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) | 38701 | tert-butyl 4-(4-methyl-3-oxopentyl)phenylcarbamate | C17H25NO3 | 详情 | 详情 | |
| (II) | 38702 | tert-butyl propionate | 20487-40-5 | C7H14O2 | 详情 | 详情 |
| (III) | 38703 | 3-[4-[(tert-butoxycarbonyl)amino]phenethyl]-3-hydroxy-4-methylpentanoic acid | C19H29NO5 | 详情 | 详情 | |
| (IV) | 38704 | (3S)-3-[4-[(tert-butoxycarbonyl)amino]phenethyl]-3-hydroxy-4-methylpentanoic acid | C19H29NO5 | 详情 | 详情 | |
| (V) | 38705 | Mg | 详情 | 详情 | ||
| (VI) | 38706 | ethyl (5S)-5-[4-[(tert-butoxycarbonyl)amino]phenethyl]-5-hydroxy-6-methyl-3-oxoheptanoate | C23H35NO6 | 详情 | 详情 | |
| (VII) | 38707 | tert-butyl 4-[2-[(2S)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]phenylcarbamate | C21H29NO5 | 详情 | 详情 | |
| (VIII) | 38708 | S-[2-(tert-butyl)-4-(hydroxymethyl)-5-methylphenyl] 4-methylbenzenesulfonothioate | C19H24O3S2 | 详情 | 详情 | |
| (IX) | 38709 | tert-butyl 4-[2-((2S)-5-[[2-(tert-butyl)-4-(hydroxymethyl)-5-methylphenyl]sulfanyl]-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]phenylcarbamate | C33H45NO6S | 详情 | 详情 |
合成路线2
The hydrolysis of the ketoester (I) with NaOH gives the corresponding ketoacid (II), which is condensed with 4-nitrobenzaldehyde (III) by means of pyridine to yield the hydroxyketone (IV). The reaction of (IV) with acetic anhydride and pyridine affords the acetoxy compound (V), which is dehydrated by means of hot pyridine to provide the enone (VI). The condensation of (VI) with benzyl acetate (VII) by means of LDA gives 3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester (VIII), which is fully hydrogenated with H2 over Pd(OH)2 to yield the amino acid (IX). Finally, (IX) is treated with acetic anhydride to afford the target 5-(4-acetamidophenyl)-3-hydroxy-3-isopropylpentanoic acid intermediate (X).
| 【1】 Deering, C.F.; et al.; Application of the Schöpf method to optimization of the synthesis of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid: Simultaneous reduction of three functional groups to maximine yield and throughput. Org Process Res Dev 2000, 4, 6, 596. |
| 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) | 43331 | methyl 4-methyl-3-oxopentanoate | 42558-54-3 | C7H12O3 | 详情 | 详情 |
| (II) | 50030 | 4-methyl-3-oxopentanoic acid | C6H10O3 | 详情 | 详情 | |
| (III) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (IV) | 50031 | 1-hydroxy-4-methyl-1-(4-nitrophenyl)-3-pentanone | C12H15NO4 | 详情 | 详情 | |
| (V) | 50032 | 4-methyl-1-(4-nitrophenyl)-3-oxopentyl acetate | C14H17NO5 | 详情 | 详情 | |
| (VI) | 50033 | (E)-4-methyl-1-(4-nitrophenyl)-1-penten-3-one | C12H13NO3 | 详情 | 详情 | |
| (VII) | 35457 | benzyl acetate | 140-11-4 | C9H10O2 | 详情 | 详情 |
| (VIII) | 50034 | benzyl (E)-3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoate | C21H23NO5 | 详情 | 详情 | |
| (IX) | 50035 | 3-(4-aminophenethyl)-3-hydroxy-4-methylpentanoic acid | C14H21NO3 | 详情 | 详情 | |
| (X) | 50036 | 3-[4-(acetamido)phenethyl]-3-hydroxy-4-methylpentanoic acid | C16H23NO4 | 详情 | 详情 |