期刊
LETTERS IN ORGANIC CHEMISTRY
卷 18, 期 7, 页码 501-506出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1570178617999200517130625
关键词
5-methyl-2-(pyrimidin-2-yl) benzoic acid; synthesis; palladium catalysis; negishi; cross-coupling; anhydrous zinc chloride
资金
- Key Scientific and Technological Projects in Henan Province [182102311040]
- Basic Research Projects of Quality Inspection and Analysis Testing Research Center of Henan Academy of Sciences [190608025]
This study presents a synthetic method for a key molecular fragment of orexin Filorexant, with high yield and simplicity, providing a new approach for the synthesis of the target compound.
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 (MK6096). 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 2chloropyrimidine 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 2chloropyrimidine: 2-bromo-5-methylbenzoic acid molar ratio of 1.1:1 at a reaction temperature of 55 degrees C for 14 h. Under these optimum reaction conditions, the maximum yield of 78.4% is attained for 5methyl-2-(pyrimidin-2-yl) benzoic acid.
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