A Simple and Robust Process for Large-Scale Synthesis of 4-Methylenepiperidine Hydrochloride

Author(s): Ao Chen, Ziqian Li, Minghai Li, Keke Liu, Weimin Li, Chen Tan*

Journal Name: Letters in Organic Chemistry

Volume 16 , Issue 10 , 2019

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Graphical Abstract:


4-Methylenepiperidine hydrochloride 1 is a key intermediate for synthesis of the novel antifungal drug efinaconazole 2. In this work, a simple and robust process has been developed to synthesize 4-methylenepiperidine hydrochloride 1, with a high overall yield of 99.1% at a high purity of 99.7% in a large-scale. Moreover, this synthetic process avoided the uses of organolithium reagent and column chromatography process which are not desirable for industrial production.

Keywords: 4-methylenepiperidine hydrochloride, efinaconazole, drug, intermediate, synthetic process, large-scale.

Elewski, B.E.; Rich, P.; Pollak, R.; Pariser, D.M.; Watanabe, S.; Senda, H.; Ieda, C. Smith, Kathleen; Pillai, R.; Ramakrishna, T.; Olin, J.T. J. Am. Acad. Dermatol., 2013, 68, 600-608.
Patel, T.; Dhillon, S. Drugs, 2013, 73, 1977-1983.
Tatsumi, Y.; Nagashima, M.; Shibanushi, T.; Iwata, A.; Kangawa, Y.; Inui, F.; Siu, W.J.; Pillai, R.; Nishiyama, Y. Antimicrob. Agents Chemother., 2013, 57, 2405-2409.
JUBLIA® (efinaconazole) topical solution, 10%, http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf (Accessed May 31, 2018).
Adigun, C.G.; Vlahovic, T.C.; McClellan, M.B.; Thakker, K.D.; Klein, R.R.; Elstrom, T.A.; Ward, D.B. J. Drugs Dermatol., 2016, 15, 1116-1120.
Tamura, K.; Kumagai, N.; Shibasaki, M. J. Org. Chem., 2014, 79, 3272-3278.
Zhu, F.; Aisa, H.A.; Zhang, J.; Hu, T.; Sun, C.; He, Y.; Xie, Y.; Shen, J. Org. Process Res. Dev., 2018, 22, 91-96.
Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.; Iida, Y.; Tamura, M.; Hiyama, Y.; Ohishi, Y. Chem. Pharm. Bull., 1993, 41, 1971-1986.
Mimura, M.; Watanabe, M.; Ishiyama, N.; Yamada, T. Process for producing 1-triazole-2-butanol derivatives. U.S. Patent 20,130,150, 586, June 13, 2013.
Ogura, H.; Kobayashi, H.; Nagai, K.; Nishida, T.; Naito, T.; Tatsumi, Y.; Yokoo, M.; Arika, T. Chem. Pharm. Bull., 1999, 47, 1417-1425.
Naito, T. Process for the preparation of 4-methylenepiperidines. WO Patent 9,711,939, April 3, 1997.
Cooper, J.; Duan, M.; Grimes, R.; Kazmierski, W.; Matthew, T. Preparation of macrocyclic peptides for the treatment of viral infection. US 20,100,196,321, August 5, 2010.
Attolino, E.; Rizzo, E.; Rossi, D. Process for the preparation of piperidine compounds. E.P. Patent 3,091,007, November 9, 2016.
Anderson, N.G. Process Safety.In:Practical Process Research and Development, 2nd ed; Elsevier: Amsterdam, The Netherland, 2012, pp. 23-24.

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Article Details

Year: 2019
Page: [802 - 806]
Pages: 5
DOI: 10.2174/1876402910666181030094143
Price: $65

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