Jump to main content
Jump to site search

Issue 21, 2017
Previous Article Next Article

A highly efficient Suzuki–Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)

Author affiliations

Abstract

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 (4d, 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 a life expectancy of 3–5 years. The methyl-deuterated version of pirfenidone (4e, 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. The examination of several cross-coupling strategies for the 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 trifluoroborate or CD3BF3K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to the synthesis of pirfenidone (4d) and its d3 analog, SD-560 (4e), at 99% isotopic purity.

Graphical abstract: A highly efficient Suzuki–Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)

Back to tab navigation

Supplementary files

Article information


Submitted
14 Jun 2017
Accepted
11 Sep 2017
First published
11 Sep 2017

Green Chem., 2017,19, 5046-5053
Article type
Communication

A highly efficient Suzuki–Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)

E. Falb, K. Ulanenko, A. Tor, R. Gottesfeld, M. Weitman, M. Afri, H. Gottlieb and A. Hassner, Green Chem., 2017, 19, 5046 DOI: 10.1039/C7GC01740E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.


Social activity

Search articles by author

Spotlight

Advertisements