Login Register Cart 0
Generic placeholder image

Letters in Organic Chemistry

Editor-in-Chief

ISSN (Print): 1570-1786
ISSN (Online): 1875-6255

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Letter Article

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

Author(s): Fei Liu*, Shengyong Zhao, Linpo Yu and Haibiao Liu

Volume 18, Issue 7, 2021

Published on: 17 May, 2020

Page: [501 - 506] Pages: 6

DOI: 10.2174/1570178617999200517130625

Price: $65

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.

Next »
Graphical Abstract

[1]
Ohayon, M.M. Sleep Med. Rev., 2002, 6(2), 97-111.
[http://dx.doi.org/10.1053/smrv.2002.0186] [PMID: 12531146]
[2]
Sharon, S.R.; Lauren, B.; Daniel, B.; Cynthia, D.; Michael, S. J. Clin. Sleep Med., 2008, 4, 487-504.
[http://dx.doi.org/10.5664/jcsm.27286] [PMID: 18853708]
[3]
Damien, L.; Virginie, B. Sleep Med. Rev., 2010, 14, 379-389.
[http://dx.doi.org/10.1016/j.smrv.2010.01.003] [PMID: 20359916]
[4]
Winrow, C.J.; Gotter, A.L.; Cox, C.D.; Doran, S.M.; Tannenbaum, P.L.; Breslin, M.J.; Garson, S.L.; Fox, S.V.; Harrell, C.M.; Stevens, J.; Reiss, D.R.; Cui, D.; Coleman, P.J.; Renger, J.J. J. Neurogenet., 2011, 25(1-2), 52-61.
[http://dx.doi.org/10.3109/01677063.2011.566953] [PMID: 21473737]
[5]
Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.M.; Tanaka, H.; Williams, S.C.; Richardson, J.A.; Kozlowski, G.P.; Wilson, S.; Arch, J.R.S.; Buckingham, R.E.; Haynes, A.C.; Carr, S.A.; Annan, R.S.; McNulty, D.E.; Liu, W.S.; Terrett, J.A.; Elshourbagy, N.A.; Bergsma, D.J.; Yanagisawa, M. Cell, 1998, 92(4), 573-585.
[http://dx.doi.org/10.1016/S0092-8674(00)80949-6] [PMID: 9491897]
[6]
Xu, T.R.; Yang, Y.; Ward, R.; Gao, L.; Liu, Y. Cell. Signal., 2013, 25(12), 2413-2423.
[http://dx.doi.org/10.1016/j.cellsig.2013.07.025] [PMID: 23917208]
[7]
Winrow, C.J.; Gotter, A.L.; Cox, C.D.; Tannenbaum, P.L.; Garson, S.L.; Doran, S.M.; Breslin, M.J.; Schreier, J.D.; Fox, S.V.; Harrell, C.M.; Stevens, J.; Reiss, D.R.; Cui, D.; Coleman, P.J.; Renger, J.J. Neuropharmacology, 2012, 62(2), 978-987.
[http://dx.doi.org/10.1016/j.neuropharm.2011.10.003] [PMID: 22019562]
[8]
Lin, L.; Faraco, J.; Li, R.; Kadotani, H.; Rogers, W.; Lin, X.; Qiu, X.; de Jong, P.J.; Nishino, S.; Mignot, E. Cell, 1999, 98(3), 365-376.
[http://dx.doi.org/10.1016/S0092-8674(00)81965-0] [PMID: 10458611]
[9]
Girardin, M.; Ouellet, S.G.; Gauvreau, D.; Moore, J.C.; Hughes, G.; Devine, P.N.; O’Shea, P.D.; Campeau, L.C. Org. Process Res. Dev., 2013, 17, 61-68.
[http://dx.doi.org/10.1021/op3002678]
[10]
Chung, J.Y.L.; Zhong, Y.L.; Maloney, K.M.; Reamer, R.A.; Moore, J.C.; Strotman, H.; Kalinin, A.; Feng, R.; Strotman, N.A.; Xiang, B.; Yasuda, N. Org. Lett., 2014, 16(22), 5890-5893.
[http://dx.doi.org/10.1021/ol5028249] [PMID: 25365229]

Rights & Permissions Print Cite
Article Metrics
11
1
© 2024 Bentham Science Publishers | Privacy Policy