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【结 构 式】 
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【分子编号】68593 【品名】(E)-methyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate;methyl 2-[(benzyloxy)acetyl]-3-aminoacrylate 【CA登记号】 |
【 分 子 式 】C15H19NO4 【 分 子 量 】277.3202 【元素组成】C 64.97% H 6.91% N 5.05% O 23.08% |
合成路线1
该中间体在本合成路线中的序号：(XXXV)Condensation of methyl 4-chloroacetoacetate (XXXIII) with PhCH2OH in the presence of t-AmONa in THF gives the benzyl ether (XXXIV), which is then condensed with N,N-dimethylformamide dimethyl acetal (XXXII) in dioxane to give methyl 2-[(benzyloxy) acetyl]-3-aminoacrylate (XXXV). Cyclocondensation of acrylate (XXXV) with dimethyl oxalate by means of t-BuONa provides the pyranone derivative (XXXVII), which is then reacted with aminoacetaldehyde dimethyl acetal (XXVI) at reflux to yield pyridone (XXXVIII). Hydrolysis of acetal (XXXVIII) with H2SO4 and HCOOH affords aldehyde (XXXIX), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene gives the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XL). Finally, methyl ester (XL) is condensed with 2,4-difluorobenzylamine (XIV) in the presence of AcOH in toluene .
Alternatively, coupling of methyl ester (XXXVIII) with 2,4-difluorobenzylamine (XIV) by means of AcOH in toluene/MeOH gives amide (XLI), which upon acetal hydrolysis with H2SO4 and HCOOH in toluene yields aldehyde (XLII). Finally, aldehyde (XLII) is submitted to cyclocondensation with 3(R)-amino-1-butanol (XI) in the presence of AcOH in refluxing MeOH/toluene .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XL) | 68597 | (4R,12aS)-methyl 7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate | C21H22N2O6 | 详情 | 详情 | |
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XIV) | 68578 | 2,4-difluorobenzylamine | 72235-52-0 | C7H7F2N | 详情 | 详情 |
| (XV) | 68579 | (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C27H25F2N3O5 | 详情 | 详情 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XXXIII) | 68591 | methyl 4-chloro-3-oxobutanoate；Methyl 4-chloro-3-oxo-butanoate;Methyl 4-chloro-3-oxobutyrate；Methyl 4-chloroacetoacetate | 32807-28-6 | C5H7ClO3 | 详情 | 详情 |
| (XXXIV) | 68592 | methyl 4-(benzyloxy)-3-oxobutanoate | C12H14O4 | 详情 | 详情 | |
| (XXXV) | 68593 | (E)-methyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate;methyl 2-[(benzyloxy)acetyl]-3-aminoacrylate | C15H19NO4 | 详情 | 详情 | |
| (XXXVI) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (XXXVII) | 68594 | dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate | C16H14O7 | 详情 | 详情 | |
| (XXXVIII) | 68595 | dimethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C20H23NO8 | 详情 | 详情 | |
| (XXXIX) | 68596 | dimethyl 3-(benzyloxy)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C18H17NO7 | 详情 | 详情 | |
| (XLI) | 68598 | methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate | C26H26F2N2O7 | 详情 | 详情 | |
| (XLII) | 68599 | methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate | C24H20F2N2O6 | 详情 | 详情 |