Title:Condition Optimization for Synthesis of 5-methyl-2(pyrimidin-2-yl) Benzoic Acid
Volume: 18
Issue: 7
Author(s): Fei Liu*, Shengyong Zhao, Linpo Yu and Haibiao Liu
Affiliation:
- Henan Chemical Industry Research Institute Co., Ltd., and Henan Engineering Technology Research Center for Industrial Wastewater Adsorption and Separation, Zhengzhou,China
Keywords:
5-methyl-2-(pyrimidin-2-yl) benzoic acid, synthesis, palladium catalysis, negishi, cross-coupling, anhydrous zinc
chloride.
Abstract: Orexin has been emerged as a hot and frontier research theme in the close relationship with
sleep-wake regulation. In this paper, we report a synthetic method for the preparation of 5-methyl-2-
(pyrimidin-2-yl)benzoic acid, which is an important molecular fragment of orexin Filorexant (MK-
6096). Compared to the previously reported methods, the current route has the advantages of a short
synthetic pathway, simple post-treatment, and high yield that provide an effective new methodology
for the synthesis of the target compound. Using 2-bromo-5-methyl benzoic acid and 2-
chloropyrimidine as raw materials, PdCl2(PPh3)2 is used as a metal catalyst to mediate one-pot generation
of 5-methyl-2-(pyrimidin-2-yl)benzoic acid using the Negishi cross-coupling method. The optimum
condition involves 2-bromo-5-methylbenzoic acid (10.00 g) and anhydrous zinc chloride powder
(6.32 g) together with the catalyst: 2-bromo-5-methylbenzoic acid molar ratio of 0.02 and 2-
chloropyrimidine: 2-bromo-5-methylbenzoic acid molar ratio of 1.1:1 at a reaction temperature of 55°C
for 14 h. Under these optimum reaction conditions, the maximum yield of 78.4% is attained for 5-
methyl-2-(pyrimidin-2-yl) benzoic acid.
