Evolution of the Process for the Preparation of a Selective ErbB VEGF Receptor Inhibitor

Abstract

An efficient synthetic route to the potent and selective ErbB VEGF receptor inhibitor, BMS-690514 (1) is described. Strategic modifications in both approach and procedure addressed several issues, which led to a safe, efficient, and economical process for the preparation of multi-kilogram quantities of 1. The convergent route involves alkylation of a suitably protected (3R,4R)-4-aminopiperidin-3-ol with the triethyl(alkyl)ammonium salt of a functionalized pyrrolotriazine 3a followed by deprotection to provide 1 as the crystalline free base.

Key words

antitumor agents - protected piperidines - protecting groups - heterocycles - Schiff bases

• References and Notes

• 1 New address: Celgene Corp., Basking Ridge, NJ, USA.
• 2 New address: Dupont, Newark, DE, USA.

For Bristol-Myers Squibb patents covering 1, see:
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• 3b Fink BE, Gavai AV, Vite GD, Chen P, Mastalerz H, Norris DJ, Tokarshi JS, Zhao Y, Han W.-C. Preparation of pyrrolo[2,1-f][1,2,4]triazine derivatives as HER1, HER2, HER4 kinase inhibitors and antiproliferative agents; . WO Patent 066176, 2005
• 3c Fink BE, Gavai AV, Vite GD, Chen P, Mastalerz H, Norris DJ, Tokarski JS, Zhao Y, Han W.-C Pyrrolotriazine Compounds as Kinase Inhibitors; US Patent 7,141,571 B2, 2006

For earlier discovery work in the HER and VEGFR program, see:
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• 9 The structure of 8 was proposed based on LCMS data. Specifically, the C–N connectivity cannot be confirmed.
• 10 Loss of acetonitrile and triethylamine, which form a low-boiling azeotrope (b.p. 55 °C), was attributed to the nitrogen sweep used to ensure efficient inertion and prevent formation of colored impurities. This issue was resolved during development runs by using a nitrogen blanket, and was not observed in the pilot plant batches.
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• 15 In general, impurities (organic, residual solvents, or inorganic) do not add any therapeutic value, may present toxicity concerns and are therefore controlled to very low levels in the active pharmaceutical ingredient.
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• 22 First generation: three steps, 62% yield, three N-alkyl impurities. Second generation: two steps, 67% yield, no N-alkyl impurities. Number of steps refers to number of intermediates that could be isolated.