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【结 构 式】 
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【分子编号】65547 【品名】(R)-3-Aminopiperidine dihydrochloride 【CA登记号】 |
【 分 子 式 】C5H12N2.2HCl 【 分 子 量 】137.632 【元素组成】C 43.63% H 10.25% N 20.35% Cl 25.76% |
合成路线1
该中间体在本合成路线中的序号：(VI)6-Chlorouracil (I) is alkylated with 2-(bromomethyl)benzonitrile (II) in the presence of NaH and LiBr in DMF/DMSO to produce the N-benzyluracil derivative (III), which is further alkylated with iodomethane and NaH in DMF/THF to yield the 1,3-disubstituted uracil (IV) (1-3). Intermediate (IV) is alternatively obtained by alkylation of 6-chloro-3-methyluracil (V) with 2-(bromomethyl)benzonitrile (II) by means of diisopropylethylamine in hot NMP (3). Subsequent displacement of chlorouracil (IV) with 3(R)-aminopiperidine dihydrochloride (VI) in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (1-3), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol (3). Scheme 1.
| 【1】 Feng, J., Gwaltney, S.L., Stafford, J.A. et al. (Takeda San Diego, Inc.). Dipeptidyl peptidase inhibitors. EP 1586571, JP 2005263780, US2005261271, WO 2005095381. |
| 【2】 Feng, J., Zhang, Z., Wallace, M.B. et al. Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 2007, 50(10): 2297-300. |
| 【3】 Feng, J., Gwaltney, S.L., Stafford, J.A. et al. (Takeda Pharmaceutical Co., Ltd.). WO 2007035629. |
| 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) | 65543 | 6-Chloro-2,4-Pyrimidinediol | 107577-09-3 | C4H3ClN2O2 | 详情 | 详情 |
| (II) | 33303 | 2-(bromomethyl)benzonitrile | 22115-41-9 | C8H6BrN | 详情 | 详情 |
| (III) | 65544 | 2-((6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile | 865758-95-8 | C12H8ClN3O2 | 详情 | 详情 |
| (IV) | 65545 | 2-((6-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile | C13H10N3O2 | 详情 | 详情 | |
| (V) | 65546 | 6-Chloro-3-methyluracil; 3-Methyl-6-chlorouracil | 4318-56-3 | C5H5ClN2O2 | 详情 | 详情 |
| (VI) | 65547 | (R)-3-Aminopiperidine dihydrochloride | C5H12N2.2HCl | 详情 | 详情 |