Suzuki-Miyaura Cross-Coupling (SMC): an Adventure Leading to a Green, High Yield and Purity Methylation Route to Pirfenidone and its CD3 Analogue

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1Chemical Development, Discovery & Product Development, Global Innovative R&D, Teva Pharmaceutical Industries Ltd., Netanya, Israel
2Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel

Efficient introduction of methyl or methyl-d3 into aromatic and heteroaromatic systems still presents a synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD3 version of pirfenidone (also known as Pirespa®, Esbriet® or Pirfenex®), one of the two drugs approved to date for retarding idiopathic pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with life expectancy of 3-5 years. The methyl-deuterated version of pirfenidone (also known as SD-560) was designed with the objective of attenuating the rate of drug metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of employing alkyllithium at cryogenic temperatures. Examination of several cross-coupling strategies for introduction of methyl or methyl-d3 into methoxypyridine and pyridone systems culminated in two green and nearly quantitative Suzuki-Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl boronic acid or its CD3 analog; and the second, employing potassium methyl trifluoborate or CD3BF3K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to pirfenidone and its d3 analog, SD-560, at 99% isotopic purity.

Synthetic scheme

* Falb, E.; Ulanenko, K.; Tor, A.; Gottesfeld, R.; Weitman, M.; Afri, M.; Gottlieb, H.; Hassner, A. Green Chem., 2017, 19, 5046-5053

Falb, E.; Ulanenko, K.; Tor, A.; Afri, M.; Gottlieb, H.; Hassner, A. Chem Heterocycl Comp, 2017, 53(9), 979-984









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