检查点激酶Bub1抑制剂2OH-BNPP1的合成研究

Synthesis of 2OH-BNPP1,an inhibitor of checkpoint kinase Bub1

目的研究检查点激酶Bub1抑制剂2OH-BNPP1的合成方法。方法将2-羟基苯乙酸转化成苄基保护的酰氯,再与丙二腈缩合得化合物5,经硫酸二甲酯对5的烯醇式甲基化得化合物6,6与叔丁基肼反应完成了吡唑环的构筑以形成化合物7,7与甲酰胺作用构筑并嘧啶环,最后将所得的化合物8脱苄,即得目标物2OH-BNPP1(1)。结果与结论以苄基保护起始原料的2-位酚羟基,使路线中的各步中间体稳定、极性小而易于硅胶柱色谱分离,最后催化脱苄几乎定量完成,保证了终产物的化学纯度。目标物经HPLC检测纯度为98.8%,其结构经ESI-MS和1H-NMR确证。

Aim To investigate a novel synthesis of 2OH-BNPP1, an inhibitor of checkpoint kinase Bubl. Methods 2-Hydroxyphenylacetic acid was first converted into its benzyl-protected acyl chloride, which was then condensed with malononitrile to give compound 5. Methylation of the enol of 5 using Me2 SO4 afforded compound 6 which was further treated with tert-butylhydrazine for the construction of the pyrazole ring to give compound 7. After treating 7 with formamide to form the last pyrimidine ring, the benzyl protecting group of compound 8 was cleanly cleaved via Pd/C-catalyzed hydrogenation to give the target. Results and conclusion Employing the benzyl group for the protection of the phenol in the starting material, the intermediates became stable and could be easily separated by column chromatography on silica gel due to their less polarity, the benzyl-protecting group was almost quantitatively removed via Pd/C-catalyzed hydrogenation to give the target in a 98.8% HPLC purity, and the structure of the target was confirmed by ESI-MS and 1H-NMR.