The Synthetic method of Larotrectinib (LOXO-101)

Description

Larotrectinib (LOXO-101) is the first highly potent and selective small molecule ATP competitive inhibitor of all three TRK kinases (TRKA, TRKB, and TRKC) to enter clinical development[1]. Discovered by Array BioPharma and Loxo Oncology and later developed in collaboration with Bayer AG, larotrectinib was approved in November 2018 by the USFDA for the treatment of solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion that do not have a known acquired resistance mutation, are metastatic, or where surgical treatment is likely to result in morbidity.

Synthetic method

A synthetic route to the larotrectinib was disclosed in a patent filed by Array Biopharma in 2017, and this approach is depicted in below[2]. The synthesis began with condensation of 2,5-difluorobenzaldehyde (298) with Ellman' auxiliary to form transient sulfinyl imine 299, which was then treated with the Grignard reagent formed from alkyl bromide 300. This sequence gave rise to sulfinamide 301 in 81% yield over 2 steps, although no diastereoselectivity was reported. Treatment with TFA and triethylsilane triggered removal of the chiral auxiliary and concomitant deprotection−cyclization to form pyrrolidine 302, which was isolated as the D- (+)-maleate salt. SNAr reaction of pyrrolidine 302 with nitropyrazolopyridimine 303 formed intermediate arene 304.

The final sequence to furnish larotrectinib involved nitro reduction of 304 to form aminopyrazolopyrimidine 305, which was isolated as a fumarate salt in 83% yield. Exposure to phenyl chloroformate, pyrrolidinol 307, then sulfuric acid provided larotrectinib as the hydrogen sulfate salt in 92% yield.

References

[1] Theodore W Laetsch, Douglas S Hawkins. “Larotrectinib for the treatment of TRK fusion solid tumors.” Expert Review of Anticancer Therapy 19 1 (2019): 1–10.

[2] Andrew C. Flick. “Synthetic Approaches to New Drugs Approved during 2018.” Journal of Medicinal Chemistry 63 19 (2020): 10652–10704.

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