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【结 构 式】 
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【分子编号】16597 【品名】(2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid 【CA登记号】 |
【 分 子 式 】C14H23N3O3S 【 分 子 量 】313.42104 【元素组成】C 53.65% H 7.4% N 13.41% O 15.31% S 10.23% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The oxidation of N-(benzyloxycarbonyl)-L-phenylalaninol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which by dimerization with Zn dust in dichloromethane yields (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexane-3,4-diol (III) [along with the (2S,3S,4S,5S)-isomer]. The reaction of (III) with alpha-acetoxyisobutyryl bromide (IV) in hexane/dichloromethane affords (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexan-3-ol acetate ester (V), which is converted into the corresponding epoxide (VI) with NaOH in dioxane/water. The reduction of the epoxide (VI) with NaBH4 in THF affords (2S,3S,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexan-3-ol (VII), which is deprotected with Ba(OH)2 in refluxing dioxane/water yielding the corresponding diamine (VIII). The cyclization of (VIII) with phenylboronic acid (IX) in refluxing toluene gives (4S,6S)-6-[1(S)-amino-2-phenylethyl]-4-benzyl-2-phenyl-1,3,2-oxaazaborinane (X), which is condensed with (5-thiazolylmethyl)(4-nitrophenyl)carbonate (XI) in THF to afford (2S,3S,5S)-5-amino-1,6-diphenyl-2-(5-thiazolylmethoxycarbonylamino) hexan-3-ol (XII). Finally, this compound is condensed with N-[N-(2-isopropylthiazol-4-ylmethyl)-N-methylaminocarbonyl]-L-valine (XIII) by means of 1-hydroxybenzotriazole (HBT) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (DEC) in THF.
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【3】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 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) | 16585 | benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (III) | 16587 | benzyl (1S,2R,3R,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (IV) | 12806 | 2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide | 40635-67-4 | C6H9BrO3 | 详情 | 详情 |
| (V) | 16589 | (1R,2R,3S)-3-[[(benzyloxy)carbonyl]amino]-1-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2-bromo-4-phenylbutyl acetate | C36H37BrN2O6 | 详情 | 详情 | |
| (VI) | 16590 | benzyl (1S)-1-[(2R,3R)-3-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)oxiranyl]-2-phenylethylcarbamate | C34H34N2O5 | 详情 | 详情 | |
| (VII) | 16591 | benzyl (1S,2S,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2-hydroxy-5-phenylpentylcarbamate | C34H36N2O5 | 详情 | 详情 | |
| (VIII) | 16592 | (2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol | C18H24N2O | 详情 | 详情 | |
| (IX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (X) | 16594 | (1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenylethylamine; (1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenyl-1-ethanamine | C24H27BN2O | 详情 | 详情 | |
| (XI) | 16595 | 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate | 144163-97-3 | C11H8N2O5S | 详情 | 详情 |
| (XII) | 16596 | 1,3-thiazol-5-ylmethyl N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]carbamate | C23H27N3O3S | 详情 | 详情 | |
| (XIII) | 16597 | (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid | C14H23N3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The N-substituted valine (XIII) has been synthesized as follows: The reaction of isobutyramide (XXII) with phosphorus pentasulfide (P4S10) in ethyl ether gives the corresponding thioamide (XXIII), which is cyclized with 1,3-dichloroacetone (XXIV) by means of MgSO4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (XXV). The reaction of (XXV) with methylamine in water affords N-(2-isopropylthiazol-4-ylmethyl)-N-methylamine (XXVI), which is condensed with N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) by means of 4-(dimethylamino)pyridine (DMAP) and triethylamine in refluxing THF to give the thiazol-substituted L-valine ester (XXVIII). Finally, this compound is converted into the corresponding free acid with LiOH in dioxane/water. The N-(4-nitrophenoxycarbonyl)-L-valine methyl ester (XXVII) has been synthesized by reaction of chloroformate (XXI) with L-valine methyl ester (XXIX) by means of 4-methylmorpholine (MPH) in dichloromethane.
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 16597 | (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid | C14H23N3O3S | 详情 | 详情 | |
| (XXI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XXII) | 16606 | Isobutyramide; 2-methylpropanamide | 563-83-7 | C4H9NO | 详情 | 详情 |
| (XXIII) | 16607 | 2-methylpropanethioamide | 13515-65-6 | C4H9NS | 详情 | 详情 |
| (XXIV) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XXV) | 16609 | 4-(chloromethyl)-2-isopropyl-1,3-thiazole | C7H10ClNS | 详情 | 详情 | |
| (XXVI) | 16610 | (2-isopropyl-1,3-thiazol-4-yl)-N-methylmethanamine; N-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-N-methylamine | 154212-60-9 | C8H14N2S | 详情 | 详情 |
| (XXVII) | 16611 | methyl (2S)-3-methyl-2-[[(4-nitrophenoxy)carbonyl]amino]butanoate | C13H16N2O6 | 详情 | 详情 | |
| (XXVIII) | 16612 | methyl (2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutanoate | C15H25N3O3S | 详情 | 详情 | |
| (XXIX) | 16613 | methyl (2S)-2-amino-3-methylbutanoate | C6H13NO2 | 详情 | 详情 |