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【结 构 式】 
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【分子编号】23041 【品名】(2,4-difluorophenyl)(4-piperidinyl)methanone 【CA登记号】 |
【 分 子 式 】C12H13F2NO 【 分 子 量 】225.2381664 【元素组成】C 63.99% H 5.82% F 16.87% N 6.22% O 7.1% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(XII)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 |