Kiloscale Buchwald鈥揌artwig Amination: Optimized Coupling of Base-Sensitive 6-Bromoisoquinoline-1-carbonitrile with (S)-3-Amino-2-methylpropan-1-ol

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• 作者：Jeffrey B. Sperry ; Kristin E. Price Wiglesworth ; Ian Edmonds ; Phillip Fiore ; David C. Boyles ; David B. Damon ; Roberta L. Dorow ; Eugene L. Piatnitski Chekler ; Jonathan Langille ; Jotham W. Coe
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：December 19, 2014
• 年：2014
• 卷：18
• 期：12
• 页码：1752-1758
• 全文大小：361K
• ISSN：1520-586X

文摘

This work describes the optimization and scale-up of a Buchwald鈥揌artwig amination reaction for the preparation of a pharmaceutical intermediate. This C鈥揘 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.