Exploratory Process Development of Pexidartinib through the Tandem Tsuji–Trost Reaction and Heck Coupling

Abstract

A novel synthetic route to CSF1R inhibitor pexidartinib was designed and demonstrated. Crucial to the successful synthesis is a tandem Tsuji–Trost reaction and Heck coupling in combination with palladium and silver catalysis. The final product was obtained via five steps in 49% yield with purity as high as 99.2%. The cheap and available materials and reagents and easy operations for workup and purification make this route more practical.

Key words

pexidartinib - palladium-silver-catalyzed - tandem - Tsuji–Trost reaction - Heck coupling

• References

• 1a Bertoni F, Unni KK, Beabout JW, Sim FH. Am. J. Surg. Pathol. 1997; 21: 153
• 1b West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, Zhu S, Marinelli RJ, De Luca A, Downs-Kelly E, Goldblum JR, Corless CL, Brown PO, Gilks CB, Nielsen TO, Huntsman D, van de Rijn M. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 690
• 2a Giustini N, Bernthal NM, Bukata SV, Singh AS. Clin. Sarcoma. Res. 2018; 8: 14
• 2b Tap WD, Gelderblom H, Stacchiotti S, Palmerini E, Ferrari S, Desai J, Bauer S, Blay J, Alcindor T, Ganjoo KN, Broto JM, Ryan CW, Shuster DE, Zhang L, Wang Q, Hsu H, Lin PS, Tong S, Wagner AJ. J. Clin. Oncol. 2018; 11502
• 3a Zhang C, Zhang J, Ibrahim PN, Artis DR, Bremer R, Wu G, Zhu H, Nespi M. PCT Int. Appl WO 2008064255 A2 20080529, 2008
• 3b Ibrahim PN, Jin M, Matsuura S. PCT Int. Appl WO 2016179412 A1 20161110, 2016
• 4 Chen D, Chen Y, Ma Z, Zou L, Li J, Liu Y. J. Org. Chem. 2018; 83: 6805
• 5a Tsuji J, Takahashi H, Morikawa M. Tetrahedron Lett. 1965; 4387
• 5b Trost BM, Fullerton TJ. J. Am. Chem. Soc. 1973; 95: 292
• 5c Frost CG, Howarth J, Williams JM. Tetrahedron: Asymmetry 1992; 3: 1089
• 5d Kljajic M, Puschnig JG, Weber H, Breinbauer R. Org. Lett. 2017; 19: 126
• 5e Braun J, Ariens MI, Matsuo BT, de Vries S, van Wordragen ED. H, Ellenbroek BD, Van de Velde CM. L, Orru RV. A, Ruijter E. Org. Lett. 2018; 20: 6611
• 6a Mizoroki T, Mori K, Ozaki A. Bull. Chem. Soc. Jpn. 1971; 44: 581
• 6b Heck RF, Nolley JP. J. Org. Chem. 1972; 37: 2320
• 6c Nallapati SB, Adepu R, Ashfaq MA, Sreenivas BY, Mukkanti K, Pal M. RSC Adv. 2015; 5: 88686
• 6d Yue G, Lei K, Hirao H, Zhou JS. Angew. Chem. Int. Ed. 2015; 54: 6531
• 6e Pires MJ. D, Poeira DL, Purificação SI, Marques MM. B. Org. Lett. 2016; 18: 3250
• 7a D’Errico S, Oliviero G, Borbone N, Nici F, Piccialli V, Pinto B, D’Alonzo D, Mayol L, Piccialli G. Eur. J. Org. Chem. 2015; 2244
• 7b Wang Y, Przyuski K, Roemmele RC, Hudkins RL, Bakale RP. Org. Process Res. Dev. 2013; 17: 846
• 8a Xu J, Jain N, Sui Z. Tetrahedron Lett. 2004; 45: 6399
• 8b Struk L, Sosnicki JG. Synthesis 2012; 44: 735
• 8c Tian Q, Shang S, Wang H, Shi G, Li Z, Yuan J. Molecules 2017; 22: 1952
• 9a Crisp GT. Chem. Soc. Rev. 1998; 27: 427
• 9b Amatore C, Jutand A. Acc. Chem. Res. 2000; 33: 314
• 10 Tanaka D, Romeril SP, Myers AG. J. Am. Chem. Soc. 2005; 127: 10323
• 11a Beller M, Fischer H, Kühlein K, Reisinger C.-P, Herrmann WJ. J. Organomet. Chem. 1996; 520: 257
• 11b Reetz MT, Maase M. Adv. Mater. 1999; 11: 773
• 11c Reetz MT, Westermann E. Angew. Chem. Int. Ed. 2000; 39: 165
• 12a Beletskaya IP, Cheprakov AV. Chem. Rev. 2000; 100: 3009
• 12b Jeong S, Chen X, Harran PG. J. Org. Chem. 1998; 63: 8640
• 13 Zhou Q, Phoa AF, Abbassi RH, Hoque M, Reekie TA, Font JS, Ryan RM, Stringer BW, Day BW, Johns TG, Munoz L, Kassiou M. J. Med. Chem. 2017; 60: 2052
• 14 Xing L, Petitjean A, Schmidt R, Cuccia L. Synth. Commun. 2007; 37: 2349
• 15 The preparation of compound 16 is described in the Supporting Information.
• 16 The preparation of compound 12 is described in the Supporting Information.