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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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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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. 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Process Res. Dev</addtitle><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. 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Process Res. Dev</addtitle><date>2024-07-19</date><risdate>2024</risdate><volume>28</volume><issue>7</issue><spage>2702</spage><epage>2707</epage><pages>2702-2707</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>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%.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.oprd.4c00085</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-7151-8032</orcidid><orcidid>https://orcid.org/0000-0001-8042-5225</orcidid><orcidid>https://orcid.org/0000-0002-8683-0691</orcidid><orcidid>https://orcid.org/0000-0002-6950-5045</orcidid><orcidid>https://orcid.org/0000-0002-7972-9966</orcidid><orcidid>https://orcid.org/0000-0003-4228-768X</orcidid></addata></record> |
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title | Chemoselective Saponification in the Synthesis of Danuglipron Facilitated with Trifluoroethanol |
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