The asymmetric hydrogenation of a pyridyl benzothiophene alkene has been successfully accomplished using [BoPhoz Rh] catalysts. By tailoring the steric properties of the BoPhoz ligand, the ee of the product could be increased from just 12% to 90%. This research further expands the substrate scope of the conventional class of functionalized alkenes amenable to catalytic asymmetric hydrogenation.

An efficient and scaleable synthesis of (2S,3S)-2-ethyl-3-methylvaleramide (1) has been developed starting from inexpensive and readily available L-isoleucine. The key step in this process is an asymmetric alkylation using (1S,2S)-pseudoephedrine as a chiral auxiliary. A practical procedure was developed to remove the sterically hindered pseudoephedrine auxiliary from the amide. The process consists of eight chemical steps and five isolations without any chromatographic purification. It has been successfully implemented to prepare several multikilogram batches of the target compound 1 in 41% overall yield.

The discovery route and subsequent scale-up routes for NBI-75043 are presented. When traditional batch chemistry was found to limit the scale of a key reaction, a flow reactor was designed and optimized to provide an alternate method of production.

A strategy for the salt selection of NBI-75043 is presented and summarized in a decision-tree format. This is followed by the first scale-up of the process, confirmation of a new polymorph, and description of a method for its conversion to the initial form.