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【结 构 式】 
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【分子编号】16757 【品名】benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate 【CA登记号】 |
【 分 子 式 】C32H45N3O4S 【 分 子 量 】567.79312 【元素组成】C 67.69% H 7.99% N 7.4% O 11.27% S 5.65% |
合成路线1
该中间体在本合成路线中的序号：(IX)The addition of thiophenol (II) to N-(benzyloxycarbonyl)-L-serine beta-lactone (I) by means of NaH in THF gives N-(benzyloxycarbonyl)-(S-phenyl)-L-cysteine (III), which is treated with isobutyl chloroformate, diazomethane and N-nitro-N-nitrosoguanidine in ethyl acetate/ethyl ether to yield the diazo intermediate (IV). The treatment of (IV) with dry HCl in ethyl ether affords the chloromethyl derivative (V), which is reduced with NaBH4 in THF giving the secondary alcohol (VI). The dehydrochlorination of (VI) with KOH in ethanol yields the corresponding epoxide (VII), which is submitted to ring opening with (3S,4aS,8aS)-N-(tert-butyl)decahydroisoquinoline-3-carboxamide (VIII) in hot isopropanol to afford the condensation product (IX). The deprotection of (IX) with 30% HBr in acetic acid gives compound (X) with a free amino group, which is finally acylated with 3-hydroxy-2-methylbenzoic acid (XI) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in THF. The benzoic acid (XI) has been obtained by the following sequence: The condensation of 3-methoxybenzoyl chloride (XII) with aniline (XIII) gives the corresponding anilide (XIV), which is methylated with butyllithium and methyl iodide in THF yielding 2-methyl-3-methoxybenzanilide (XV). Finally, this compound is treated with 5N HCl and 30% HBr in refluxing acetic acid.
| 【1】 Rabasseda, X.; Martel, A.M.; Castañer, J.; Nelfinavir Mesylate. Drugs Fut 1997, 22, 4, 371. |
| 【2】 Dressman, B.A.; Fritz, J.E.; Hammond, M.; Hornback, W.J.; Kaldor, S.W.; Kalish, V.J.; Munroe, J.E.; Reich, S.H.; Tatlock, J.H.; Shepherd, T.A.; Rodriguez, M.J. (Agouron Pharmaceuticals, Inc.); HIV protease inhibitors. EP 0889036; JP 1997501443; JP 1999310573; US 5484926; WO 9509843 . |
| 【3】 Jungheim, L.N.; Shepherd, T.A. (Eli Lilly and Company); Intermediate and process for making. WO 9521164 . |
| 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) | 16749 | benzyl N-[(3S)-2-oxooxetanyl]carbamate | C11H11NO4 | 详情 | 详情 | |
| (II) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (III) | 16751 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(phenylsulfanyl)propionic acid | 159453-24-4 | C17H17NO4S | 详情 | 详情 |
| (IV) | 16752 | benzyl N-[(1R)-3-diazo-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H17N3O3S | 详情 | 详情 | |
| (V) | 16753 | benzyl N-[(1R)-3-chloro-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H18ClNO3S | 详情 | 详情 | |
| (VI) | 16754 | benzyl N-[(1R,2S)-3-chloro-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H20ClNO3S | 详情 | 详情 | |
| (VII) | 16755 | benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate | C18H19NO3S | 详情 | 详情 | |
| (VIII) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 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 | |
| (XI) | 16759 | 3-hydroxy-2-methylbenzoic acid | 603-80-5 | C8H8O3 | 详情 | 详情 |
| (XII) | 16760 | 3-methoxybenzoyl chloride | 1711-05-3 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (XIV) | 16762 | 3-methoxy-N-phenylbenzamide | C14H13NO2 | 详情 | 详情 | |
| (XV) | 16763 | 3-methoxy-2-methyl-N-phenylbenzamide | C15H15NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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 |