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【结 构 式】

【分子编号】23044

【品名】3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

【CA登记号】63234-80-0

【 分 子 式 】C11H15ClN2O

【 分 子 量 】226.70568

【元素组成】C 58.28% H 6.67% Cl 15.64% N 12.36% O 7.06%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(VII)

The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III), which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV). The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V), which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI). Finally, this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.

1 Kennis, L.E.J.; Vandenberk, J. (Janssen Pharmaceutica NV); Novel 1,2-benzisoxazol-3-yl and 1, 2-benzisothiazo. EP 0196132; ES 8705881; JP 1986221186; US 4804663 .
2 Diller, D.; Krochmal, B.; Dolitzky, B.-Z.; Aronhime, J. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Preparation of risperidone. WO 0212200; WO 0214286 .
3 Castaner, J.; Prous, J.; Risperidone. Drugs Fut 1988, 13, 12, 1052.
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) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 13700 1-Acetyl-4-piperidinecarbonyl chloride C8H12ClNO2 详情 详情
(III) 23040 1-[4-(2,4-difluorobenzoyl)-1-piperidinyl]-1-ethanone C14H15F2NO2 详情 详情
(IV) 23041 (2,4-difluorophenyl)(4-piperidinyl)methanone C12H13F2NO 详情 详情
(V) 23042 (2,4-difluorophenyl)(4-piperidinyl)methanone oxime C12H14F2N2O 详情 详情
(VI) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(VII) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

The intermediate 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (IV) has been obtained as follows: The condensation of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (I) with dibenzylamine (II) by means of NaHCO3 in refluxing acetonitrile gives the tertiary amine (III), which is debenzylated by hydrogenation with H2 over Pd/C in warm ethanol to afford the target intermediate (IV).

1 Huguet-Clotet, J.; Marquillas Olondriz, F.; Caldero Ges, J.M.; Del Castillo Nieto, J.C.; Dalmases Barjoan, P.; Bosch Rovira, A. (Vita-Invest, SA); Process for obtaining 3-2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine-4-one. ES 2074966 .
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) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情
(II) 12361 N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine 103-49-1 C14H15N 详情 详情
(III) 50858 3-[2-(dibenzylamino)ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C25H29N3O 详情 详情
(IV) 50859 3-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C11H17N3O 详情 详情

合成路线3

该中间体在本合成路线中的序号:(V)

The intermediate 3-(2-chloroethyl)-2-methyl-6, 7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (V) has been obtained as follows: The cyclization of 2-aminopyridine (I) with 3-acetyltetrahydrofuran-2-one (II) by means of polyphosphoric acid (PPA) at 160 C gives 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (III), which is hydrogenated with H2 over Pd/C in ethanol/water to yield the tetrahydro derivative (IV). Finally, the OH group of (IV) is treated with SOCl2 in dichloromethane to afford the target 2-chloroethyl intermediate (V).

1 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 .
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) 11305 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine 504-29-0 C5H6N2 详情 详情
(II) 24709 3-acetyldihydro-2(3H)-furanone 517-23-7 C6H8O3 详情 详情
(III) 50866 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one C11H12N2O2 详情 详情
(IV) 50867 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C11H16N2O2 详情 详情
(V) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情

合成路线4

该中间体在本合成路线中的序号:(V)

The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII), which is treated with SOCl2 to yield the corresponding acyl chloride (IX). The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI), which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII). The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII), which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV). Finally, this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.

1 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情
(VI) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(VII) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(VIII) 50868 1-(ethoxycarbonyl)-4-piperidinecarboxylic acid C9H15NO4 详情 详情
(IX) 50869 ethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate C9H14ClNO3 详情 详情
(X) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(XI) 50870 ethyl 4-(2,4-difluorobenzoyl)-1-piperidinecarboxylate C15H17F2NO3 详情 详情
(XII) 23041 (2,4-difluorophenyl)(4-piperidinyl)methanone C12H13F2NO 详情 详情
(XIII) 50871 3-[2-[4-(2,4-difluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C23H27F2N3O2 详情 详情
(XIV) 50872 3-(2-[4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinyl]ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one C23H28F2N4O2 详情 详情

合成路线5

该中间体在本合成路线中的序号:(IV)

 

1 Smet KD, Dun JV, Stokbroekx B.et aL 2005. Selectivity gontrol by use of near-IR for a hydrogenation process. Org Proc Res Dev,9: 344一347
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) 66563 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one   C11H11ClN2O2 详情 详情
(II) 66561 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 130049-82-0 C11H15ClN2O2 详情 详情
(III) 66564 9-hydroxy-2-methyl-3-propyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one   C12H18N2O2 详情 详情
(IV) 23044 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one 63234-80-0 C11H15ClN2O 详情 详情
(V) 66565 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one   C11H16N2O3 详情 详情
(VI) 66566 3-ethyl-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one   C11H12N2O2 详情 详情
Extended Information