Enabling the First Scale-Up of the Selective HER2 Inhibitor BI-4142
The enabling synthesis of the first route to HER2 inhibitor BI-4142 (1) to deliver a drug substance in kilogram quantity is reported. The synthetic route involves (1) a fit-for-purpose synthesis of pyrimido[5,4-d]pyrimidine 2; (2) a high yielding, scalable synthesis of aniline 3; (3) a safer sodium tungstate-catalyzed sulfide oxidation; (4) SNAr reactions to form C–N bonds; and (5) amidation via Schotten–Baumann conditions. With the speed of delivery prioritized, a purification protocol using silica gel filtration and crystallizations was developed in time to control the quality of API. The overall yield of the delivery route was improved from 22% to 46% over a prior route starting from 2.
Authors
- Frédéric G. Buono (ORCID: https://orcid.org/0000-0001-7585-0438)
- Maxim V. Chevliakov
- Max Sarvestani
- Eugene Chong (ORCID: https://orcid.org/0000-0002-5038-0131)
- Earl Spinelli
- Scott Pennino
- Ruoshi Li (ORCID: https://orcid.org/0000-0001-9422-8927)
- Yongda Zhang (ORCID: https://orcid.org/0000-0002-2575-7590)
- Nizar Haddad (ORCID: https://orcid.org/0000-0001-7068-7897)
- Shutao Yao (ORCID: https://orcid.org/0000-0002-6059-2963)
- Birgit Wilding (ORCID: https://orcid.org/0000-0002-1896-3708)
- Donghong A. Gao
- Thomas G. Tampone
- Weitong Dong (ORCID: https://orcid.org/0000-0002-0125-7102)
- Jon C. Lorenz
- Bo Qu (ORCID: https://orcid.org/0000-0001-7347-0108)
- Heewon Lee (ORCID: https://orcid.org/0000-0002-3086-9263)
- Huayu Li (ORCID: https://orcid.org/0000-0003-1292-297X)
- Jinhua J. Song
- Ling Wu
- Joe Gao
- Thuraya Omar
Institutions
- Boehringer Ingelheim (Germany) (DE)
- Boehringer Ingelheim (Taiwan) (TW)
Publication Details
- Journal
- Organic Process Research & Development
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1021/acs.oprd.5c00127
- Citations
- 3
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14