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【结 构 式】

【分子编号】68611

【品名】(4R,12aS)-7-chloro-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

【CA登记号】　

【 分 子 式 】C13H13ClN2O5

【 分 子 量 】312.709

【元素组成】C 49.93% H 4.19% Cl 11.34% N 8.96% O 25.58%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(LVI)

Condensation of ethyl 4-chloro-3-oxobutyrate (XXX) with N,Ndimethylformamide dimethylacetal (XXXII) in EtOAc results in ethyl 2-(chloroacetyl)-3-(dimethylamino)-2-propenoate (LI), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF affords diethyl 3-chloro-4-oxopyran-2,5-dicarboxylate (LII). Condensation of pyranone (LII) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LIII), which is then hydrolyzed using HCOOH and H2SO4 in CH2Cl2 to yield the corresponding aldehyde (LIV). Cyclization of compound (LIV) with 3(R)-amino-1-butanol (XI) and AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LV), which by hydrolysis with KOSiMe3 in DME affords the hydroxy acid (LVI). Finally, acid (LVI) is coupled with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .

参考文献 中间体
合成目标
【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
(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
(XXI) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(XXVI) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(XXX) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 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
(LI) 68607 ethyl 2-(chloroacetyl)-3-(dimethylamino)-2- propenoate;(E)-ethyl 4-chloro-2-((dimethylamino)methylene)-3-oxobutanoate 　 C9H14ClNO3 详情 详情
(LII) 68608 diethyl 3-chloro-4-oxo-4H-pyran-2,5-dicarboxylate 　 C11H11ClO6 详情 详情
(LIII) 68609 diethyl 3-chloro-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate 　 C15H20ClNO7 详情 详情
(LIV) 68610 diethyl 3-chloro-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate 　 C13H14ClNO6 详情 详情
(LV) 68612 (4R,12aS)-ethyl 7-chloro-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 　 C15H17ClN2O5 详情 详情
(LVI) 68611 (4R,12aS)-7-chloro-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 　 C13H13ClN2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(LVI)

Condensation of ethyl 3-oxobutyrate (LVII) with N,N-dimethylformamide dimethylacetal (XXXII) in EtOAc affords ethyl 2-acetyl-3-(dimethylamino)-2-propenoate (LVIII), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF provides diethyl 4-oxopyran-2,5-dicarboxylate (LIX). Condensation of pyranone derivative (LIX) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LX), which is then brominated with NBS in DMF to yield the 3-bromopyridin-4-one derivative (LXI). Hydrolysis of acetal (LXI) using HCOOH and H2SO4 in CH2Cl2 yields the corresponding aldehyde (LXII), which is cyclized with 3(R)-aminobutan-1-ol (XI) in the presence of AcOH in refluxing MeOH/toluene to afford the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LXIII). Finally, bromo ester (LXIII) is submitted to treatment with KOSiMe3 in DME .

参考文献 中间体
合成目标
【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
(XI) 68577 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol 61477-39-2 C4H11NO 详情 详情
(XXI) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 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
(LVI) 68611 (4R,12aS)-7-chloro-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 　 C13H13ClN2O5 详情 详情
(LVII) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(LVIII) 68613 ethyl 2-acetyl-3-(dimethylamino)-2-propenoate;Ethyl 2-acetyl-3-(dimethylamino)acrylate;Ethyl (2E)-2-(dimethylaminomethylidene)-3-oxobutanoate 51145-57-4 C9H15NO3 详情 详情
(LIX) 68614 diethyl 4-oxopyran-2,5-dicarboxylate;diethyl 4-oxo-4H-pyran-2,5-dicarboxylate 　 C11H12O6 详情 详情
(LX) 68615 diethyl 1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate 　 C15H21NO7 详情 详情
(LXI) 68616 diethyl 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate 　 C15H20BrNO7 详情 详情
(LXII) 68617 diethyl 3-bromo-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate 　 C13H14BrNO6 详情 详情
(LXIII) 68618 (4R,12aS)-ethyl 7-bromo-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 　 C15H17BrN2O5 详情 详情
Extended Information