化合物1是schizophrenia（精神分裂）候選藥物，結構如下
工藝配體的篩選研究
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化合物9和化合物8a製備化合物10a
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配體的篩選，具體數據如下
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試驗發現開環的配體，例如DPEphos，BINAP和ferrocenylphosphines（entry 2-5），均沒有產品，主要產物是脫鹵雜質13。這個數據驗證了乙醇或者異丙醇，有助於產生脫鹵雜質。
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位阻大的配體（entry 7,8）主要給出了C-O偶聯的雜質14。位阻大的，富電子的磷配體，可以抑製β-消除反應（脫鹵素雜質），促進醚化反應（雜質14）
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配體Xantphos（entry 1）結果最好
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.
實驗操作
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%).
參考文獻
Org. Process Res. Dev. 2021, 25, 457−468
