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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information