title: 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.
authors.affiliation: Separation and Analysis Technologies, Department of Process Research, Merck Research Laboratories, Rahway, NJ 07065, USA. william_leonard@merck.com
authors.forename: William R
authors.initials: WR
authors.lastname: Leonard
authors.forename: Derek W
authors.initials: DW
authors.lastname: Henderson
authors.forename: Ross A
authors.initials: RA
authors.lastname: Miller
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Spencer
authors.forename: Osama S
authors.initials: OS
authors.lastname: Sudah
authors.forename: Mirlinda
authors.initials: M
authors.lastname: Biba
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Welch
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013237:Stereoisomerism; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D004364:Pharmaceutical Preparations