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

[ Vol. 18 , Issue. 7 ]

Author(s):

Fei Liu*, Shengyong Zhao, Linpo Yu and Haibiao Liu   Pages 501 - 506 ( 6 )

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.

Keywords:

5-methyl-2-(pyrimidin-2-yl) benzoic acid, synthesis, palladium catalysis, negishi, cross-coupling, anhydrous zinc chloride.

Affiliation:

Henan Chemical Industry Research Institute Co., Ltd., and Henan Engineering Technology Research Center for Industrial Wastewater Adsorption and Separation, Zhengzhou, Henan Chemical Industry Research Institute Co., Ltd., and Henan Engineering Technology Research Center for Industrial Wastewater Adsorption and Separation, Zhengzhou, Department of Chemical and Environmental Engineering, Faculty of Science and Engineering, and Key Laboratory of More Electric Aircraft Technology of Zhejiang Province, University of Nottingham Ningbo China, Ningbo, Henan Chemical Industry Research Institute Co., Ltd., and Henan Engineering Technology Research Center for Industrial Wastewater Adsorption and Separation, Zhengzhou



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