1063960-83-7

Upstream product

• 13472-85-0 2-methoxy-5-bromopyridine 
• 411235-57-9 cyclopropylboronic acid 
• 67-56-1 methanol 
• 893738-68-6 2-amino-5-cyclopropylpyridine 
• 1072-97-5 5-bromo-2-pyridylamine 
• 1065010-87-8 potassium cyclopropyltrifluoroborate 
• 13473-01-3 5-chloro-2-methoxypyridine 

Downstream Products

• 1159821-42-7 C₈H₉NO 

Relevant academic research and scientific papers

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

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.

Synthesis of bromocyclopropylpyridines via the Sandmeyer reaction

The reactions of 2-amino-5-cyclopropylpyridine with organic nitrites in the presence of copper(II) halides in various organic solvents were investigated. Optimal reaction conditions for the Sandmeyer reaction were developed and successfully applied to the synthesis of useful building blocks, bromo and chlorocyclopropylpyridines. Aminocyclopropylpyridines were synthesized in high yields from the corresponding aminobromopyridines under standard Suzuki coupling conditions.

COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY AND FIBROTIC DISORDERS

Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system.

Cross-coupling of cyclopropyl- and cyclobutyltrifluoroborates with aryl and heteroaryl chlorides

(Chemical Equation Presented) Suitable conditions were found for the Suzuki-Miyaura cross-coupling reaction of potassium cyclopropyl-and cyclobutyltrifluoroborates with aryl chlorides. Both of these secondary alkyl trifluoroborates coupled in moderate to excellent yield with electron-rich, electron-poor, and hindered aryl chlorides to give a variety of substituted aryl cyclopropanes and cyclobutanes.