Condition Optimization for Synthesis of 5-methyl-2(pyrimidin-2-yl) Benzoic Acid

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.