【结 构 式】 |
【分子编号】46605 【品名】(3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide 【CA登记号】 |
【 分 子 式 】C26H39N3O4 【 分 子 量 】457.61348 【元素组成】C 68.24% H 8.59% N 9.18% O 13.99% |
合成路线1
该中间体在本合成路线中的序号:(X)A new concise synthesis of nelfinavir has been reported: The asymmetric desymmetrization of the meso-epoxide (I) by means of azidotrimethylsilane and a chiral (R,R)-(salen)chromium(III) complex as catalyst gives the chiral 3-(trimethylsilyloxy)-4-azidotetrahydrofuran (II), which is deprotected with TFA in methanol yielding the chiral 4-azidotetrahydrofuran-3-ol (III). Hydrogenation of (III) with H2 over PtO2 affords the chiral 4-aminotetrahydrofuran-3-ol (IV), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (V) by means of NaHCO3 in dichloromethane to provide amide (VI). The mesylation of the OH group of (VI) with Ms-Cl gives mesylate (VII), which is isomerized with Ac2O and H2SO4 to yield oxazoline (VIII). Condensation of compound (VIII) with the perhydroisoquinoline-3-carboxamide derivative (IX) by means of K2CO3 in methanol affords the oxazoline-adduct (X). Finally, the oxazoline-ring opening of compound (X) is performed with thiophenol (XI) and KHCO3.
【1】 Inaba, T.; Cho, H.; Yamada, Y.; Sagawa, S.; Abe, H.; (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate, a versatile building block for chiral 2-aminoalkanols: Concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor. J Org Chem 2000, 65, 6, 1623. |
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) | 46598 | 3,6-dioxabicyclo[3.1.0]hexane | C4H6O2 | 详情 | 详情 | |
(II) | 46599 | [[(3R,4S)-4-azidotetrahydro-3-furanyl]oxy](trimethyl)silane; (3R,4S)-4-azidotetrahydro-3-furanyl trimethylsilyl ether | C7H15N3O2Si | 详情 | 详情 | |
(III) | 46600 | (3R,4S)-4-azidotetrahydro-3-furanol | C4H7N3O2 | 详情 | 详情 | |
(IV) | 46601 | (3R,4S)-4-aminotetrahydro-3-furanol | C4H9NO2 | 详情 | 详情 | |
(V) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
(VI) | 46602 | 3-([[(3S,4R)-4-hydroxytetrahydro-3-furanyl]amino]carbonyl)-2-methylphenyl acetate | C14H17NO5 | 详情 | 详情 | |
(VII) | 46603 | 2-methyl-3-[([(3S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-3-furanyl]amino)carbonyl]phenyl acetate | C15H19NO7S | 详情 | 详情 | |
(VIII) | 46604 | (2R)-2-[(4S)-2-[3-(acetoxy)-2-methylphenyl]-4,5-dihydro-1,3-oxazol-4-yl]-2-[(methylsulfonyl)oxy]ethyl acetate | C17H21NO8S | 详情 | 详情 | |
(IX) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
(X) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
(XI) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XVI)The reaction of D-tartaric acid (I) with 2,2-dimethoxypropane (II) and Ts-OH gives the acetonide (III), which is reduced with NaBH4 in ethanol to yield the diol (IV). The reaction of (IV) with Ts-OH and TEA affords the ditosylate (V), whose acetonide is cleaved with HCl to provide the diol (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the cyclic sulfite (VII), which is oxidized with NaIO4 and RuCl3 to yield the cyclic sulfate (VIII). The reaction of (VIII) with sodium azide in acetone/water affords the azide (IX), which is treated with sulfuric acid in THF/water to provide the azido alcohol (X). The reduction of the azido group of (X) with H2 over Pd/C affords the amino alcohol (XI), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XII) by means of TEA in THF, providing the intermediate amide (XIII). Spontaneous cyclization of the amide (XIII) under the reaction conditions gives the oxazoline (XIV), which is condensed with the perhydroisoquinoline (XV) by means of K2CO3 in isopropanol to yield the oxazoline intermediate (XVI). Finally, the cleavage of the oxazoline ring of (XVI) by means of thiophenol (XVII) affords the target compound.
【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
(II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
(III) | 55018 | (4S,5S)-1,3-dioxolane-4,5-dicarboxylic acid | C5H6O6 | 详情 | 详情 | |
(IV) | 55019 | [(4R,5R)-5-(hydroxymethyl)-1,3-dioxolan-4-yl]methanol | C5H10O4 | 详情 | 详情 | |
(V) | 55020 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | C19H22O8S2 | 详情 | 详情 | |
(VI) | 55021 | (2R,3R)-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H22O8S2 | 详情 | 详情 | |
(VII) | 55022 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxo-1,3,2lambda~4~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O9S3 | 详情 | 详情 | |
(VIII) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
(IX) | 55024 | C18H20N3NaO10S3 | 详情 | 详情 | ||
(X) | 55025 | (2S,3S)-3-azido-2-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H21N3O7S2 | 详情 | 详情 | |
(XI) | 55026 | (2S,3S)-2-amino-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H23NO7S2 | 详情 | 详情 | |
(XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
(XIII) | 55027 | 3-({[(1S,2S)-2-hydroxy-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}carbonyl)-2-methylphenyl acetate | C28H31NO10S2 | 详情 | 详情 | |
(XIV) | 55028 | 3-[(4S)-4-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-methylphenyl acetate | C21H23NO7S | 详情 | 详情 | |
(XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
(XVI) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
(XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |