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【结 构 式】 
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【分子编号】52326 【品名】1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate 【CA登记号】 |
【 分 子 式 】C27H46BrNO4Si 【 分 子 量 】556.65608 【元素组成】C 58.26% H 8.33% Br 14.35% N 2.52% O 11.5% Si 5.05% |
合成路线1
该中间体在本合成路线中的序号：(X)Hydroxy amino ester (I) was protected as the oxazolidine (III) upon heating with 2,2-dimethoxypropane (II) in the presence of p-toluenesulfonic acid. Conversion of the ester group of (III) into aldehyde (V) was accomplished by reduction to alcohol (IV) with LiAlH4, followed by NaOCl oxidation catalyzed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr. Addition of 3-(benzyloxy)propylmagnesium bromide (VI) to aldehyde (V) furnished carbinol (VII), which was further protected as the silyl ether (VIII) by treatment with tert-butyldimethylsilyl chloride and imidazole. After hydrogenolysis of the O-benzyl protecting group of (VIII), the resultant primary alcohol (IX) was converted to bromide (X) employing the N-bromosuccinimide/triphenylphosphine reagent.
| 【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323. |
| 【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 . |
| 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) | 52327 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxy-4-phenylbutanoate | C16H23NO5 | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 52319 | 3-(1,1-dimethylethyl) 5-methyl 2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3,5-dicarboxylate | C19H27NO5 | 详情 | 详情 | |
| (IV) | 52320 | 1,1-dimethylethyl 5-(hydroxymethyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C18H27NO4 | 详情 | 详情 | |
| (V) | 52321 | 1,1-dimethylethyl 5-formyl-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C18H25NO4 | 详情 | 详情 | |
| (VI) | 52322 | bromo{3-[(phenylmethyl)oxy]propyl}magnesium | C10H13BrMgO | 详情 | 详情 | |
| (VII) | 52323 | 1,1-dimethylethyl 5-{1-hydroxy-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C28H39NO5 | 详情 | 详情 | |
| (VIII) | 52324 | 1,1-dimethylethyl 5-{1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C34H53NO5Si | 详情 | 详情 | |
| (IX) | 52325 | 1,1-dimethylethyl 5-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-hydroxybutyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C27H47NO5Si | 详情 | 详情 | |
| (X) | 52326 | 1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C27H46BrNO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Alkylation of 2-hydroxypyridine (XI) with bromide (X) produced a mixture of the N-alkylated pyridone (XII) and the pyridyl ether (XIII), which were separated by column chromatography. The required minor regioisomer (XIII) was desilylated with tetrabutylammonium fluoride, and the resultant alcohol (XIV) was oxidized under Swern conditions to the ketone (XV). Acidic hydrolysis of the cyclic aminal function of (XV) furnished amino alcohol (XVI). This was then coupled with the pyrimidinylacetic acid (XVII) to yield amide (XVIII). The free hydroxyl group of (XVIII) was subsequently esterified with acetic anhydride giving ester (XIX).
| 【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323. |
| 【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 52326 | 1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C27H46BrNO4Si | 详情 | 详情 | |
| (XI) | 52328 | 2-pyridinol | C5H5NO | 详情 | 详情 | |
| (XII) | 52329 | 1,1-dimethylethyl 5-{1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-[2-oxo-1(2H)-pyridinyl]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C32H50N2O5Si | 详情 | 详情 | |
| (XIII) | 52330 | 1,1-dimethylethyl 5-[1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(2-pyridinyloxy)butyl]-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C32H50N2O5Si | 详情 | 详情 | |
| (XIV) | 52331 | 1,1-dimethylethyl 5-[1-hydroxy-4-(2-pyridinyloxy)butyl]-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C26H36N2O5 | 详情 | 详情 | |
| (XV) | 52332 | 1,1-dimethylethyl 2,2-dimethyl-4-(phenylmethyl)-5-[4-(2-pyridinyloxy)butanoyl]-1,3-oxazolidine-3-carboxylate | C26H34N2O5 | 详情 | 详情 | |
| (XVI) | 52333 | 2-amino-3-hydroxy-1-phenyl-7-(2-pyridinyloxy)-4-heptanone | C18H22N2O3 | 详情 | 详情 | |
| (XVII) | 52334 | 2-[5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid | C17H19N3O5 | 详情 | 详情 | |
| (XVIII) | 52335 | 1,1-dimethylethyl 1-(2-{[2-hydroxy-3-oxo-1-(phenylmethyl)-6-(2-pyridinyloxy)hexyl]amino}-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate | C35H39N5O7 | 详情 | 详情 | |
| (XIX) | 52336 | 1-[1-({2-[5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetyl}amino)-2-phenylethyl]-2-oxo-5-(2-pyridinyloxy)pentyl acetate | C37H41N5O8 | 详情 | 详情 |