Development of a Scalable Process for the PPAR-α Agonist GW641597X Incorporating Baeyer–Villiger Chemistry and Retrospective ICH M7 Assessment

Abstract

The development of the synthetic process to the PPAR-α receptor antagonist 5-((4-(tert-butoxy)-3-methylphenoxy)methyl)-3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazole (GW641597X) 1 is described. The discussion ranges from the initial supply route, used to deliver early batches for preliminary safety studies to enable dosing in man, to an efficient manufacturing route, which delivered 35 kg of drug substance following on from a pilot plant campaign. The process includes a key oxidative Baeyer−Villiger reaction, where process development identified sodium perborate in acetic acid as a safer alternative to m-chloroperoxybenzoic acid that was used in the initial supply route. Described within is a discussion of impurities, how they are formed, and the process modifications incorporated to either reduce or remove them. There is also a discussion of potential mutagenic impurities within the synthetic process and a retrospective evaluation using ICH M7 control options. Finally, an alternative route to GW641597X is described, which offers the advantage that all intermediates are crystalline facilitating material handling, offering purification opportunities through recrystallization if required, and potentially providing greater controls for the process. This new route was also retrospectively assessed using ICH M7 option controls and highlighted that ICH M7 option 4 controls can be implemented even with excess mutagenic reagents being introduced near to the drug substance as long as the science for its purging is well understood.

Development of a First-Generation Stereocontrolled Manufacturing Process of TRPA1 Inhibitor GDC-6599

“…Reaction optimization by evaluating different bases, solvents, and temperatures offered little improvement and strong bases led to increased formation of a cyclopropane impurity 22 (Table 3) arising from trimerization of 5. 32 DMF and other polar aprotic solvents proved essential for maintaining high solubility of purinone 4 and K 2 CO 3 , while a reaction temperature of 20−25 °C minimized the formation of the undesired N-alkylation and Oalkylation side-products.…”

“…For a typical reaction end point sample, in-process control (IPC) testing showed 79.5 A% of the desired GDC-6599 ( 1 ), 3.5 A% of N -alkylation isomer 20 , and 6.9 A% of O -alkylation isomer 21 by HPLC analysis (Table , entry 1). Reaction optimization by evaluating different bases, solvents, and temperatures offered little improvement and strong bases led to increased formation of a cyclopropane impurity 22 (Table ) arising from trimerization of 5 . DMF and other polar aprotic solvents proved essential for maintaining high solubility of purinone 4 and K 2 CO 3 , while a reaction temperature of 20–25 °C minimized the formation of the undesired N -alkylation and O -alkylation side-products.…”

Leveraging ICH M7 Control Options 3 and 4: Discussion and Clarification Using Industrial Case Studies

“…There have been numerous publications discussing the use of ICH M7 Option 4 purge rationales to justify PMI purging through the application of process understanding on the fate and effect to specific impurities. − Additionally, a Lhasa Limited led industry consortium published a best practice paper to highlight the types of Supporting Information, which should accompany a regulatory submission to justify a proposed purge rationale . The later publication of the ICH M7 Questions and Answers (ICH M7 Q&A) document provided additional guidance for when the above control options can be applied .…”

Establishing Best Practice for the Application and Support of Solubility Purge Factors

“…Purge arguments therefore allow chemists familiar with the drug manufacturing process to utilize their experience and expertise of their synthetic process to justify an option 4 approach. The general application of these principles has been demonstrated across entire syntheses in numerous publications − and has led to the cross-industry development of in silico software designed to standardize the reporting and application of purge assessments . More recently, Borths et al clearly highlighted the impact of purge arguments through a survey of pharmaceutical companies identifying that 76% of impurities included in approved submissions between 2011 and 2018 were being suitably controlled through process understanding (option 3 or 4) rather than testing alone.…”