【结 构 式】 |
【分子编号】65546 【品名】6-Chloro-3-methyluracil; 3-Methyl-6-chlorouracil 【CA登记号】4318-56-3 |
【 分 子 式 】C5H5ClN2O2 【 分 子 量 】160.55968 【元素组成】C 37.4% H 3.14% Cl 22.08% N 17.45% O 19.93% |
合成路线1
该中间体在本合成路线中的序号:(V)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 |