A concise synthesis of Fingolimod: an orally available drug for treating multiple sclerosis

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• 作者：Ning Yan (1)
  Kai Chen (1)
  Xinfa Bai (1)
  Lei Bi (2)
  Lei Yao (1)
  
  1. School of Pharmacy ; Yantai University ; Yantai ; Shandong ; 264005 ; China
  2. School of Chemistry and Chemical Engineering ; Anhui University of Technology ; Maanshan ; Anhui ; 243002 ; China
  
• 关键词：Fingolimod ; 3 ; nitropropionic acid ; Immunosuppressant
• 刊名：Chemistry Central Journal
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：9
• 期：1
• 全文大小：417 KB
• 参考文献：1. Adachi K, Kohara T, Nakao N, Arita M, Chiba K, Mishina T, et al. Design, synthesis, and structure-activity-relationship of 2-substituted-2-amino-1,3-propanediols:discovery of a novel immunosuppressant, FTY720. Bioorg Med Chem Lett. 1995;5:853. CrossRef
  2. Strader CR, Pearce CJ, Oberlies NH. Fingolimod (FTY720): a recently approved multiple sclerosis drug based on a fungal secondary metabolite. J Nat Prod. 2011;74:900. CrossRef
  3. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346. CrossRef
  4. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine-1-phosphate receptors. J Biol Chem. 2002;277:21453. CrossRef
  5. Durand P, Peralba P, Sierra F, Renaut P. A new efficient synthesis of the immunosuppressive agent FTY-720. Synthesis. 2000;4:505鈥?. CrossRef
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  10. Hale J, Yan L, Neway W, Hajdu R, Bergstrom J, Milligan J, et al. Synthesis, stereochemical determination and biochemical characterization of the enantiomeric phosphate esters of the novel immunosuppressive agent FTY720. Bioorg Med Chem. 2004;12:4803. CrossRef
  11. Hale J, Neway W, Mills S, Hajdu R, Keohane A, Rosenbach M, et al. Potent S1P receptor agonists replicate the pharmacologic actions of the novel immune modulator FTY720. Bioorg Med Chem Lett. 2004;14:3351. CrossRef
  12. Hinterding K, Cottens S, Albert R, Zecri F, Buehlmayer P, Spanka C, et al. Synthesis of chiral analogues of FTY720 and its phosphate. Synthesis. 2003. p. 1667.
  13. Feng X, Yang X, Luo Y, Li X, Tang W, Zuo J, et al. Synthesis and immunomodulating activity of new analogues of Fingolimod. Arch Pharm Chem Life Sci. 2012;345:93. CrossRef
  14. Mulakayala N, Rao P, Iqbal J, Bandichhor R, Orugant S. Synthesis of novel therapeutic agents for the treatment of multiple sclerosis / : a brief overview. Eur J Med Chem. 2013;60:170. CrossRef
  15. Kandagatla B, Raju VV, Kumar NS, Reddy GM, Srinivas K, Iqbal J, et al. Practical synthesis of fingolimod from diethyl acetamidomalonate. RSC Adv. 2013;3:9678. CrossRef
  16. Compound 4 has been reported in the following patents: WO2012146980; WO2012056458; CN1765872.
  17. In patent WO2012/146980, the compound 6 was obtained by a similar sequence: Friedel-Crafts reaction of / n-octylbenzene and 3-chloropropanyl chloride, then displacement of Cl with nitro group, followed a reduction of carbonyl by triethylsilane and TiCl₄.
  18. 3-nitropropionic acid is toxic especially to the central nervous system. Fortunately, it is solid and easily to handle. The operator was strongly recommended to ware glove and mask.
  
• 刊物类别：Chemistry and Materials Science
• 出版者：Chemistry Central Ltd
• ISSN：1752-153X

文摘

A concise route for the synthesis of Fingolimod is reported. Starting from n-octylbenzene and 3-nitropropionic acid, a sequence of reactions consisting of Friedel-Crafts acylation, reduction, and double Henry reaction, followed by hydrogenation were applied to prepare Fingolimod with a yield of 31%, and an overall atom economy of 82.7%. Graphical Abstract Starting from 3-nitropropanyl chloride, Fingolimod was obtained in 4 steps with an overall yield of 31%.