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

Abstract

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 Cs 2 CO 3 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.

Light‐Promoted Nickel Catalysis: Etherification of Aryl Electrophiles with Alcohols Catalyzed by a NiII‐Aryl Complex

“…It is noted that functionalities such as ester and cyano groups may not be compatible with the conventional strongly‐basic conditions. Indeed, owing to the use of strong bases, transesterification in copper catalysis and the formation of impurities in palladium catalysis due to the cyano group have been reported. In contrast, all tested ester‐ and cyano‐containing electrophiles were suitable for this new method, thus demonstrating the advantage of using organic amines as base.…”

The Buchwald–Hartwig Amination After 25 Years

“…Chemists at Pfizer reported in 2014 the scale‐up of the coupling of 6‐bromoisoquinoline‐1‐carbonitrile ( 28 ), featuring a potentially base‐labile nitrile group, with ( S )‐3‐amino‐2‐methylpropan‐1‐ol ( 29 ) to provide pharmaceutical intermediate 30 in 80 % yield on a 2.5 kilogram scale (Scheme ) . Notably, the competing formation of the corresponding diarylated amine was significantly circumvented and 30 was obtained in 94.8 % purity, containing less than 5 % of this byproduct.…”

Light‐Promoted Nickel Catalysis: Etherification of Aryl Electrophiles with Alcohols Catalyzed by a NiII‐Aryl Complex

“…Notably, for aryl chloride bearing a chloro substituent, the mono-etherified product (10) was dominant, thus providing the possibility for subsequent transformation. Of further interest is that a range of (hetero)aryl chlorides were compatible, delivering the desired products containing quinolines (12)(13)(14)(15), pyridine (16,17), benzothiophene (18), benzoxazole (19), and benzothiazole (20), which are important building blocks in drug molecules, with good to excellent yields. As shown in Scheme 2, various alcohols can be used.…”

“…It is noted that functionalities such as ester and cyano groups may not be compatible with the conventional strongly-basic conditions. Indeed, owing to the use of strong bases, transesterification in copper catalysis [7f] and the formation of impurities in palladium catalysis due to the cyano group [16] have been reported. In contrast, all tested ester-and cyano-containing electro-…”