Strategic use of preparative chiral chromatography for the synthesis of a preclinical pharmaceutical candidate

Abstract

The modern use of preparative chromatography in pharmaceutical development is illustrated by the case of a recent preclinical candidate from these laboratories. The synthesis of the candidate employed a coupling of two enantiopure intermediates, each of which could be resolved using preparative chiral chromatography. SFC screening was employed to identify the enantioselective stationary phases, and semipreparative SFC methods derived from this screening were used to produce gram amounts of enantiopure intermediate for initial studies. However, initial larger scale resolution required the translation of the SFC methods to HPLC conditions. Preparative chiral HPLC on a 30-cm i.d. column was then used to produce enantiopure intermediates which were coupled to give 170 g of the preclinical candidate. Subsequent preparation of the candidate at larger scale for later-stage clinical evaluation employed an improved synthesis in which one component was constructed by asymmetric synthesis. Resolution of the other component, now a more advanced intermediate, was carried out using newly obtained large-scale SFC equipment. Some discussion is presented on the varying strategies whereby preparative chiral chromatography can be used to support either short-term or long-term synthetic goals in preclinical pharmaceutical development.

The comparison in enantioseparation ability of the chiral stationary phases with single and mixed selector—The selectors derived from two D‐tartrates

“…The toluene layer was neutralized with diluted hydrochloric acid under vigorous stir and was then washed with water till aqueous phase became neutral in pH. The organic phase was dried over anhydrous MgSO 4 . Yellow oil was given after toluene was removed in vacuo.…”

“…[1][2][3][4] Chiral stationary phases (CSPs) are essential absorbent materials for chiral HPLC columns. 5 In this technique, enantioseparation results from the difference of the interactions between a pair of enantiomers and CSPs.…”

9.06 The Use of Preparative Chiral Chromatography for Accessing Enantiopurity in Pharmaceutical Discovery and Development

“…The example illustrated in Figure 19 highlights the different criteria for route optimization in early versus late development of a pharmaceutical candidate. 77 The synthetic route for initial preparation of the candidate on kilogram scale involved a reasonably productive (0.34 kkd) chromatographic resolution of a doubly protected BOC/CBZ intermediate followed by a four-step transformation to the desired product. Although this route was suitable for early development, a more cost-effective synthesis was required for late development and commercialization.…”

Use of Enantioselective Synthesis and Preparative Chiral Chromatography to Access a Challenging Enantiopure Pharmaceutical Candidate from a Mixture of Four Stereoisomers

“…Modern chromatographic method development is substantially automated, often making identification of candidate separation conditions routine and straightforward [4]. Small-scale loading studies allow fast evaluation of different candidate separation conditions, enabling rapid optimization of chromatographic productivity (the amount of purified product that can be obtained with a given amount of stationary phase in a given time) [5]. Scale-up from small-to production-scale chromatography is also relatively straightforward and highly predictable [6].…”