化合物1是schizophrenia（精神分裂）候选药物，结构如下
工艺配体的筛选研究
-
化合物9和化合物8a制备化合物10a
-
配体的筛选，具体数据如下
-
试验发现开环的配体，例如DPEphos，BINAP和ferrocenylphosphines（entry 2-5），均没有产品，主要产物是脱卤杂质13。这个数据验证了乙醇或者异丙醇，有助于产生脱卤杂质。
-
位阻大的配体（entry 7,8）主要给出了C-O偶联的杂质14。位阻大的，富电子的磷配体，可以抑制β-消除反应（脱卤素杂质），促进醚化反应（杂质14）
-
配体Xantphos（entry 1）结果最好
It is noteworthy that Xantphos seems to be a ligand with unique characteristics, as it is able to hinder unwanted side reactions of primary alcohols such as β-hydride elimination and C−O bond formation and to selectively promote the amidecoupling at very low catalyst loadings.
实验操作
A 250 L reactor previously purged with nitrogen was filled with potassium carbonate (8.68 kg, 62.8 mmol, 1.05 equiv), 8a (12.5 kg, 63.4 mol, 1.06 equiv), and 2 (16.4 kg, 59.8 mol, 1.00 equiv). The reactor was purged with argon, and ethanol (130 L) was added. A 50 L stirrable drumwas filled with Xantphos (0.35 kg, 0.60 mmol, 0.01 equiv) and Pd2dba3 (0.28 kg, 0.30 mol, 0.005 equiv). The drum was purged with nitrogen, and the solid was suspended in THF (20L). The mixture was stirred for 20 min at room temperature and then transferred to the 250 L reactor. The drum was rinsed with THF (20 L). The reaction mixture was heated to 74 °C (Ti, temperature reached in 1 h) and stirred for 3.5 h. IPC control showed 0.09% of 2 remaining (specification ≤1%).
参考文献
Org. Process Res. Dev. 2021, 25, 457−468
