Large‐scale chiral supercritical fluid chromatography of a key intermediate in the synthesis of two S1P₁ final active pharmaceutical ingredients

Abstract

Large‐scale preparation of two sphingosine‐1‐phosphate‐subtype 1 (S1P1) active pharmaceutical ingredients, BMS‐986166 and compound 2, was achieved through a scalable supercritical fluid chromatography separation of a key common diastereomeric intermediate. Multi‐gram scale chiral supercritical fluid chromatography of the final active pharmaceutical ingredients was time‐consuming and not economical due to low throughput and recovery. An efficient large‐scale chiral supercritical fluid chromatography method was developed to rapidly obtain multi‐gram quantities of a chirally pure (>99% de) common intermediate for the preparation of the two S1P1 active pharmaceutical ingredients in reduced time and cost. Extensive column screening was conducted on two shared chiral intermediates: a methyl ester and an alcohol derivative. The subsequent sample loading comparison of these two compounds indicated that the methyl ester was the preferred intermediate for large‐scale chiral purification. The finalized supercritical fluid chromatography method for the methyl ester was readily scaled up onto a 3 cm I. D. Chiralpak IC column at a total flow rate of 180 mL/min with 52% methanol as co‐solvent in CO2, resulting in a high throughput of 4 g/h, which was equivalent to 96 g/day. In total, 1 kg of the ester intermediate was purified with a recovery of >90%. This efficient chiral supercritical fluid chromatography purification enabled large‐scale preparation of the two S1P1 compounds to support toxicology studies in Discovery Chemistry.

Semi-continuous and continuous processes for enantiomeric separation

“…310 The advantages and applications of supercritical fluid chromatography for enantioseparation are described in the following reviews. [311][312][313][314][315][316][317][318][319][320] When merging simulated moving bed with supercritical fluid chromatography technologies it leads to a purification procedure with unique characteristics with advantages of both techniques, named Supercritical fluid simulated moving bed (SFC-SMB). In 1996, Clavier et al 321 described for the first time the fusion between the two chromatography methods.…”

“…310 The advantages and applications of supercritical fluid chromatography for enantioseparation are described in the following reviews. 311–320…”