This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba)₂ with BINAP and Cs₂CO₃ in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound (S)-3.

中文翻译：

---

Kiloscale Buchwald–Hartwig胺化：碱敏感的6-溴异喹啉-1-腈与（S）-3-氨基-2-甲基丙烷-1-醇的优化偶联

这项工作描述了用于制备药物中间体的布赫瓦尔德-哈特维格胺胺化反应的优化和规模放大。使用手性伯胺会挑战这种C–N键的形成，这既增加了成本，又有利于联芳基副产物的形成。为了开发可扩展的方法，必须研究许多因素，包括催化剂的选择和手性胺的化学计量。所有这些都需要进行优化，同时在分离出的产品中保持较低的钯含量。发现将Pd（dba）₂与BINAP和Cs ₂ CO ₃一起使用是最有效的在THF中。当以2.5千克规模执行时，这些条件以80％的收率提供了2.06千克所需的产品，而钯的残留量仅为73 ppm。迄今为止，已经成功地进行了该过程以生产超过12kg的化合物（S）-3。