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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information