磷脂酰肌醇-3-激酶小分子抑制剂GDC-0941的合成

Synthesis of the small-molecule PI3K inhibitor GDC-0941

目的:改进小分子磷脂酰肌醇-3-激酶(PI3K)抑制剂GDC-0941的合成工艺。方法:以3-氨基-2-噻吩甲酸甲酯为起始原料,经环合、氯代、取代、Suzuki偶联等9步反应制得磷脂酰肌醇-3-激酶抑制剂GDC-0941(2-(1H-吲唑-4-基)-6-[(4-甲磺酰基哌嗪-1-基)甲基]-4-(吗啉-4-基)-噻吩并[3,2-d]嘧啶)。结果与结论:目标产物结构经1H-NMR和ESI-MS确证,总产率为33.2%(以3-氨基-2-噻吩甲酸甲酯计算)。改进后的制备工艺稳定实用、成本低廉,收率显著提高且适合于实验室研究的小规模制备。

Objective： To synthesize GDC-0941, an important small molecular PI3K inhibitor, and optimize the process. Methods： Taking the commercially available methyl 3-amino-2-thiophenecarboxylate as the starting material, 2-（1H-Indazol-4-yl）-6-（（4-（methylsulfonyl）-1-piperazinyl）methyl）-4-（4-morpholinyl）thieno[3,2-d] pyrimidine （GDC-0941） was synthesized via cyclization, chlorination, substitution, Suzuki-coupling reaction and so on. Results and Conclusion： The structure of GDC-0941 was confirmed by 1H-NMR and ESI-MS and the overall yield was 33.2%. The improved process is suitable for lab-scale production since it has lots of advantages, such as stabilization, practical, low cost and high yield.