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【结 构 式】 
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【分子编号】46596 【品名】3-(chlorocarbonyl)-2-methylphenyl acetate 【CA登记号】 |
【 分 子 式 】C10H9ClO3 【 分 子 量 】212.63236 【元素组成】C 56.49% H 4.27% Cl 16.67% O 22.57% |
合成路线1
该中间体在本合成路线中的序号：(XIII)A new synthesis of nelfinavir has been described: The protection of the amino group of the dioxolane derivative (I) with benzyl chloroformate and K2CO3 in toluene gives the carbamate (II), which is mesylated with MsCl and triethylamine in toluene yielding the mesylate (III). Reaction of compound (III) with thiophenol (IV) by means of tetrabutylammonium bromide and NaOH in toluene/water affords the thioether (V), which is treated with HCl in methanol/water to provide diol (VI). Protection of the primary OH group of (VI) with p-nitrobenzoyl chloride and 2-picoline yields the p-nitrobenzoate (VII), which is mesylated as before to afford the protected compound (VIII). The reaction of (VIII) with KOH in dioxane gives epoxide (IX), which is condensed with N-tert-butylperhydroisoquinoline-3-carboxamide (X) in refluxing methanol to yield the addition product (XI). This compound (XI) can also be obtained by direct condensation of compound (VIII) with isoquinoline (X) by means of K2CO3 in methanol/water. Removal of the benzyloxycarbonyl group of (XI) with KOH in hot isopropanol affords compound (XII), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XIII) by means of NaHCO3 in ethyl acetate to give the corresponding amide (XIV). Finally, this compound is deacetylated with ammonia in methanol.
| 【1】 Schaus, S.E.; et al.; Practical synthesis of enantiopure cyclic 1,2-amino alcohols via catalytic asymmetric ring opening of meso epoxides. J Org Chem 1997, 62, 12, 4197. |
| 【2】 Busse, J.K.; Borer, B.C.; Zook, S.E.; A concise synthesis of the HIV-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement. Tetrahedron Lett 2000, 41, 36, 7017. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 | |
| (I) | 46589 | (2S)-2-amino-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol | C7H15NO3 | 详情 | 详情 | |
| (II) | 46590 | benzyl (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylcarbamate | C15H21NO5 | 详情 | 详情 | |
| (III) | 46591 | (2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl methanesulfonate | C16H23NO7S | 详情 | 详情 | |
| (IV) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (V) | 46592 | benzyl (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(phenylsulfanyl)ethylcarbamate | C21H25NO4S | 详情 | 详情 | |
| (VI) | 46593 | benzyl (1R,2R)-2,3-dihydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C18H21NO4S | 详情 | 详情 | |
| (VII) | 46594 | (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-(phenylsulfanyl)butyl 4-nitrobenzoate | C25H24N2O7S | 详情 | 详情 | |
| (VIII) | 46595 | (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(methylsulfonyl)oxy]-4-(phenylsulfanyl)butyl 4-nitrobenzoate | C26H26N2O9S2 | 详情 | 详情 | |
| (IX) | 16755 | benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate | C18H19NO3S | 详情 | 详情 | |
| (X) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XI) | 16757 | benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C32H45N3O4S | 详情 | 详情 | |
| (XII) | 16758 | (3S,4aS,8aS)-2-[(2R,3R)-3-amino-2-hydroxy-4-(phenylsulfanyl)butyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2S | 详情 | 详情 | |
| (XIII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XIV) | 46597 | 3-[([(1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]amino)carbonyl]-2-methylphenyl acetate | C34H47N3O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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3
该中间体在本合成路线中的序号：(XII)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 |
合成路线4
该中间体在本合成路线中的序号：(XII)Alternatively, the reaction of the cyclic sulfate (VIII) with potassium phthalimide (XVIII) gives the N-substituted phthalimide (XIX), whose sulfate group is cleaved with sulfuric acid to yield the alcohol (XX). The reaction of (XX) with the perhydroisoquinoline (XV) by means of K2CO3 in acetonitrile/methanol affords the oxazoline (XXI), whose ring is opened with thiophenol (XVII) and KHCO3 in THF, providing a mixture of the two sulfides (XXII) and (XXIII) that are not isolated. The cleavage of the phthalimido group with refluxing ethanolamine followed by a treatment with benzoic acid gives a mixture of ammonium salts that is separated by crystallization, yielding the desired isomer (XXIV). The reaction of (XXIV) with acid chloride (XII) affords the precursor (XXV), which is finally deacetylated with NaOH to provide 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (XVIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XIX) | 55029 | potassium 2-[(1S,2S)-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-(sulfonatooxy)propyl]-1,3-dioxoisoindoline | C26H24KNO12S3 | 详情 | 详情 | |
| (XX) | 55030 | (2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C26H25NO9S2 | 详情 | 详情 | |
| (XXI) | 55031 | methyl 2-((4S)-4-{(1R)-2-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-hydroxyethyl}-4,5-dihydro-1,3-oxazol-2-yl)benzoate | C27H39N3O5 | 详情 | 详情 | |
| (XXII) | 55032 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R,3R)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIII) | 55033 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2S,3S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide | C32H41N3O4S | 详情 | 详情 | |
| (XXIV) | 55034 | (2R,3R)-4-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-3-hydroxy-1-(phenylsulfanyl)-2-butanaminium benzoate | C31H45N3O4S | 详情 | 详情 | |
| (XXV) | 46497 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butanenitrile | C16H20N2O2 | 详情 | 详情 |