2. Academic Validation
  3. Development of a Scalable Synthesis of a HPK1 Inhibitor Featuring a Direct α-Arylation of Boc-Protected N,N-Dimethylamine by Palladium-Mediated Negishi Cross-Coupling

Development of a Scalable Synthesis of a HPK1 Inhibitor Featuring a Direct α-Arylation of Boc-Protected N,N-Dimethylamine by Palladium-Mediated Negishi Cross-Coupling

  • J Org Chem. 2025 Aug 1;90(30):10690-10701. doi: 10.1021/acs.joc.5c00980.
Dahui Zhou 1,  Matthew Del Bel 2,  Thomas Knauber 1,  Simon Berritt 1,  John Braganza 2,  Adam Brown 1,  Anne-Marie Dechert Schmitt 1,  Rebecca Gallego 2,  Mingying He 2,  Jennifer Lafontaine 2,  Jean Matthews 2,  Peter Morse 1,  Sebastien Monfette 1,  Neal Sach 2,  Joseph Tucker 1,  Lei Zhang 3,  Ru Zhou 2,  Pingyong Liao 4,  Tongnan Liu 4,  Fanxiu Meng 4,  Qiming Mu 4,  Bin Sun 4,  Chaobo Wu 4,  Xin Zhao 5,  Sajiv Nair 2
Affiliations

Affiliations

  • 1 Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
  • 2 Oncology Medicinal Chemistry Worldwide Research and Development, Pfizer, Inc., La Jolla, California 92121, United States.
  • 3 Worldwide Research and Development, Pfizer, Inc., Cambridge, Massachusetts 02139, United States.
  • 4 WuXi Apptec Co., Ltd., No. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
  • 5 Asymchem Life Science (Tianjin) Co., Ltd., No. 71, Seventh Avenue, TEDA, Tianjin 300457, R.R. China.
PMID: 40679277 DOI: 10.1021/acs.joc.5c00980
Abstract

The development of an improved synthesis of the potent HPK1 inhibitor, compound 1, is described. Two primary strategies were explored during this process: metallaphotoredox decarboxylative coupling and Negishi cross-coupling, both focusing on the direct installation of Boc-protected amine in a single step. Through the optimized Pd-catalyzed Negishi cross-coupling, a robust procedure was established for preparing the compound 9 from 3 in a single step on a 20 g scale. This optimization successfully reduced the overall synthesis steps required to produce 1 from 11 to 6, achieving a 28% overall yield.

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