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【结 构 式】 
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【分子编号】16759 【品名】3-hydroxy-2-methylbenzoic acid 【CA登记号】603-80-5 |
【 分 子 式 】C8H8O3 【 分 子 量 】152.14972 【元素组成】C 63.15% H 5.3% O 31.55% |
合成路线1
该中间体在本合成路线中的序号：(XI)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：(X)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 |