Overview

Pexidartinib (PLX3397) is a novel, orally available small molecule tyrosine kinase inhibitor (TKI) with potent and selective activity against the colony-stimulating factor 1 (CSF1) receptor. CSF1, expressed in high levels in several types of solid tumors, facilitates the differentiation of monocytes into tumor-associated macrophages (TAMs) and the survival of TAMs within the tumor microenvironment. TAMs, in turn, have immunosuppressive effects and promote tumor growth and metastases. Pexidartinib also inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3, harboring an internal tandem duplication mutation (FLT3-ITD). Daiichi Sankyo has developed this drug for the treatment of tenosynovial giant cell tumor (TGCT, also known as giant cell tumor of the tendon sheath or pigmented villonodular synovitis). Most commonly arising in the synovium of joints or tendon sheaths of young adults, TGCT is a rare and locally aggressive neoplasm that overexpresses CSF1[1].

Synthesis method

The preparation of pexidartinib and its derivatives has been described previously. However, a relatively short kilogram scale synthesis of the drug was disseminated by researchers at Daiichi-Sankyo, and this sequence is depicted above. A nucleophilic attack of chloroazaindole 285 on pyridine aldehyde 284 in the presence of tetrabutylammonium hydrogen sulfate resulted in alcohol 286, which was reduced with triethylsilane. Subsequent treatment with TFA removed both Boc groups to afford aminopyridine 287 in good yield. The side chain was introduced by reductive amination with aldehyde 288 and subsequent exposure to TFA-delivered pexidartinib. The following step can obtain its hydrochloride: neutralizing the obtained solution, and then, the free-base form of the drug was obtained and converted into the HCl salt in 90% yield using concentrated HCl and ethanol.

References

[1] Lamb, Yvette N. “Pexidartinib: First Approval.” Drugs 79 1 (2019): 1805–1812.

[2] Andrew C. Flick. “Synthetic Approaches to the New Drugs Approved during 2019.” Journal of Medicinal Chemistry 64 7 (2021): 3604–3657.