Chemoselective Saponification in the Synthesis of Danuglipron Facilitated with Trifluoroethanol

Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (J. Med. Chem. 2022, 65, 8208–8226; JAMA Netw. Open. 2023; 6(5): e2314493). The earlier syn...

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Veröffentlicht in:Organic process research & development 2024-07, Vol.28 (7), p.2702-2707
Hauptverfasser: Han, Lu, Li, Bryan, Wang, Ke, Damon, David B., Magano, Javier, Maloney, Mark T., Mustakis, Jason, Post, Ronald J., Li, Ruizhi, Nguyen, Truong
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container_end_page 2707
container_issue 7
container_start_page 2702
container_title Organic process research & development
container_volume 28
creator Han, Lu
Li, Bryan
Wang, Ke
Damon, David B.
Magano, Javier
Maloney, Mark T.
Mustakis, Jason
Post, Ronald J.
Li, Ruizhi
Nguyen, Truong
description Danuglipron (PF-06882961), a potent, orally bioavailable small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, is currently being developed for glycemic control among patients with Type-2 diabetes (J. Med. Chem. 2022, 65, 8208–8226; JAMA Netw. Open. 2023; 6(5): e2314493). The earlier synthesis of danuglipron suffered from chemoselective issues due to the competing nitrile hydrolysis in the final saponification step, which resulted in highly convoluted operations and extensive chromatographic purifications. We found that the methyl ester could be converted to trifluoroethyl ester, and the latter underwent hydrolysis to carboxylic acid in a much cleaner reaction profile. A thorough design of experiments (DOE) was conducted to expand the operating time window of the process to aid the process robustness during manufacturing. The improved process increased the yield by ∼20% and reduced the process mass intensity (PMI) by 86%.
doi_str_mv 10.1021/acs.oprd.4c00085
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title Chemoselective Saponification in the Synthesis of Danuglipron Facilitated with Trifluoroethanol
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