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【结 构 式】

【分子编号】68604

【品名】5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid

【CA登记号】 

【 分 子 式 】C11H11NO7

【 分 子 量 】269.21088

【元素组成】C 49.08% H 4.12% N 5.2% O 41.6%

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:(XLVIII)

Condensation of methyl 4-methoxyacetoacetate (XLIII) with N,N-dimethylformamide dimethyl acetal (XXXII) produces methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate (XLIV), which by reaction with 2,2-dimethoxyethylamine (XXVI) in MeOH affords the N-(dimethyoxyethyl)enamine (XLV). Cyclization of enaminoketone (XLV) with dimethyl oxalate (XXXVI) by means of LiH at 40 °C gives the dimethyl pyridone-dicarboxylate (XLVI), which by selective hydrolysis with LiOH yields the monocarboxylic acid (XLVII). Hydrolysis of acetal (XLVII) with MsOH and AcOH in acetonitrile at 58-65 °C followed by in situ cyclization of the resulting aldehyde (XLVIII) with 3(R)-amino-1-butanol (XI) in acetonitrile at 64 °C affords the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XLIX). Activation of acid (XLIX) with CDI in DME at 80 °C and subsequent coupling with 2,4-difluorobenzylamine (XIV) gives amide (L), which is finally O-demethylated with either MgBr2 in hot acetonitrile or LiBr in refluxing THF .

1 Wang, H., Goodman, S.N., Mans, D., Kowalski, M. (GlaxoSmithKline, Inc.). Process for preparing carbamoylpyridone derivatives and intermediates. WO 2011119566.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XXXVI) 37412 methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate 553-90-2 C4H6O4 详情 详情
(XLIII) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(XLIV) 68600 methyl 3-(dimethylamino)-2-(methoxyacetyl)-2-propenoate;(Z)-methyl 2-((dimethylamino)methylene)-4-methoxy-3-oxobutanoate   C9H15NO4 详情 详情
(XLV) 68601 (Z)-methyl 2-(((2,2-dimethoxyethyl)amino)methylene)-4-methoxy-3-oxobutanoate   C11H19NO6 详情 详情
(XLVI) 68602 dimethyl 1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate   C14H19NO8 详情 详情
(XLVII) 68603 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid   C13H17NO8 详情 详情
(XLVIII) 68604 5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid   C11H11NO7 详情 详情
(XLIX) 68606 (4R,12aS)-7-methoxy-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-carboxylic acid   C14H16N2O6 详情 详情
(L) 68605 (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-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   C21H21F2N3O5 详情 详情
Extended Information