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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information