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Strategic use of preparative chiral chromatography for the synthesis of a preclinical pharmaceutical candidate
Author(s) -
Leonard William R.,
Henderson Derek W.,
Miller Ross A.,
Spencer Glenn A.,
Sudah Osama S.,
Biba Mirlinda,
Welch Christopher J.
Publication year - 2007
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20378
Subject(s) - enantiopure drug , chemistry , high performance liquid chromatography , enantioselective synthesis , chromatography , chirality (physics) , chiral column chromatography , chiral stationary phase , resolution (logic) , organic chemistry , computer science , artificial intelligence , chiral symmetry , quantum mechanics , physics , quark , nambu–jona lasinio model , catalysis
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. Chirality, 2007. © 2007 Wiley‐Liss, Inc.