【结 构 式】 ![]() |
【分子编号】34785 【品名】3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-methylphenyl acetate 【CA登记号】 |
【 分 子 式 】C35H41N3O5S 【 分 子 量 】615.79376 【元素组成】C 68.27% H 6.71% N 6.82% O 12.99% S 5.21% |
合成路线1
该中间体在本合成路线中的序号:(VI)The reaction of the unsaturated acetonide (I) with ammonia gives a diastereomeric, not separable mixture, of amino derivatives (II) + (III), which is reduced with BF3/Et2O and NaI to yield a mixture of sulfanyl derivatives (IV)+ (V). The condensation of this mixture with 3-acetoxy-2-methylbenzoic acid (VI) by means of EDC and HOBT affords a separable mixture of amides, from which the desired diastereomer (VII) is isolated. The hydrolysis of the acetonide group of (VII) by means of HCl in methanol provide the dihydroxyamide (VIII), which is finally condensed with the perhydroisoquinoline (IX) by means of Tes-Cl and TEA to furnish the target Nelfinavir.
【1】 Ma, D.; et al.; A short synthesis of the HIV-protease inhibitor nelfinavir via a diastereoselective addition of ammonia to the alpha,beta-unsaturated sulfoxide derived from (R)-glyceraldehyde acetonide. Tetrahedron Lett 2002, 43, 47, 8511. |
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) | 60477 | (4S)-2,2-dimethyl-4-[(E)-2-(phenylsulfinyl)ethenyl]-1,3-dioxolane; (E)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethenyl phenyl sulfoxide | C13H16O3S | 详情 | 详情 | |
(II) | 60478 | (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)-1-ethanamine; (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)ethylamine | C13H19NO3S | 详情 | 详情 | |
(III) | 60479 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)-1-ethanamine; (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfinyl)ethylamine | C13H19NO3S | 详情 | 详情 | |
(IV) | 60480 | (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)-1-ethanamine; (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylamine | C13H19NO2S | 详情 | 详情 | |
(V) | 60481 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)-1-ethanamine; (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylamine | C13H19NO2S | 详情 | 详情 | |
(VI) | 34785 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-methylphenyl acetate | C35H41N3O5S | 详情 | 详情 | |
(VII) | 60482 | 3-({[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethyl]amino}carbonyl)-2-methylphenyl acetate | C23H27NO5S | 详情 | 详情 | |
(VIII) | 60483 | 3-[({(1R,2S)-2,3-dihydroxy-1-[(phenylsulfanyl)methyl]propyl}amino)carbonyl]-2-methylphenyl acetate | C20H23NO5S | 详情 | 详情 | |
(IX) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XII)Treatment of penicillamine (I) with formaldehyde produced thiazolidine (II), which was then protected with Boc2O to give carbamate (III). Coupling of (III) with 2-methylbenzylamine (IV) by means of either diphenylphosphoryl chloride (DPPCl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) or dicyclohexylcarbodiimide (DCC) afforded the corresponding amide (V). After acid cleavage of the Boc group of (V), the deprotected thiazolidine (VI) was coupled with N-Boc-(S,S)-3-amino-2-hydroxy-4-phenylbutyric acid (VII) using EDC to give diamide (VIII). Further acid deprotection of the Boc group of (VIII) yielded (IX). This was finally coupled with 3-hydroxy-2-methylbenzoic acid (X) to furnish the title compound. Alternatively, amine (IX) was coupled with 3-acetoxy-2-methylbenzoic acid (XI) to afford (XII), which was then deacetylated using NaOH in MeOH.
【1】 Mimoto, T.; Takaku, H.; Kato, R.; et al.; Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine. J Med Chem 1999, 42, 10, 1789. |
【2】 Kiso, Y.; Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors. Yuki Gosei Kagaku Kyokaishi 1998, 56, 11, 896. |
【3】 Kato, R.; Mimoto, T.; Fukazawa, T.; Morohashi, N.; Kiso, Y. (Japan Energy Corp.); HIV-protease inhibitors. CA 2179935; EP 0751145; JP 1998025242 . |
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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
(II) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
(III) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
(IV) | 34778 | (2-methylphenyl)methanamine; 2-methylbenzylamine | 89-93-0 | C8H11N | 详情 | 详情 |
(V) | 34779 | tert-butyl (4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidine-3-carboxylate | C19H28N2O3S | 详情 | 详情 | |
(VI) | 34780 | (4R)-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C14H20N2OS | 详情 | 详情 | |
(VII) | 34781 | (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-phenylbutyric acid | C16H23NO4 | 详情 | 详情 | |
(VIII) | 34782 | tert-butyl (1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropylcarbamate | C30H41N3O4S | 详情 | 详情 | |
(IX) | 34783 | (4R)-3-[(2S,3S)-3-amino-2-methyl-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C25H33N3O2S | 详情 | 详情 | |
(X) | 16759 | 3-hydroxy-2-methylbenzoic acid | 603-80-5 | C8H8O3 | 详情 | 详情 |
(XI) | 34784 | 3-(acetoxy)-2-methylbenzoic acid | 168899-58-9 | C10H10O4 | 详情 | 详情 |
(XII) | 34785 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-methylphenyl acetate | C35H41N3O5S | 详情 | 详情 |