Document Type : Original Article


1 Department of Chemistry, Shri Vyankatesh Arts, Commerce and Science College, Deulgaon Raja, Dist. Buldana, Maharashtra, India

2 bDepartment of Chemistry, Savitribai Phule Pune University, Pune, Maharashtra, India

3 cDepartment of Chemistry, Avvaiyar Goverenment College for Women, Karaikal, Puducherry, India


Baclofen, a lipophilic derivative of GABA (gamma-Aminobutyric acid), which acts as an inhibitory neurotransmitter in CNS (central nervous system) was synthesized by Witting olefination-Claisen rearrangement protocol. 4-Chlorobenzaldehyde was subjected to Wittig reaction with ((allyloxy)methylene)triphenyl-phosphane to give 1-(2-(allyloxy)vinyl)-4-chlorobenzene which on heating under reflux condition in toluene underwent Claisen rearrangement to give 2-(4-chlorophenyl)pent-4-enal. Aldehyde was reduced to corresponding alcohol 2-(4-chlorophenyl)pent-4-en-1-ol as an important precursor which can be used for the synthesis of Baclofen and different GABA derivatives. Further tosylation, formation-reduction of azide group and oxidative ozonolysis of terminal double bond yields 4-amino-3-(4-chlorophenyl)butanoic acid in excellent yield. Therefore, an efficient method was developed for the synthesis of (±)-Baclofen in a simple seven step procedure.

Graphical Abstract

Synthesis of (±)-Baclofen using Wittig Olefination–Claisen Rearrangement



Baclofen (Figure 1) is an analog of GABA whichcan cross the blood brain barrier while GABA cannot. Baclofen is a selective and potent agonist for bicuculline-insensitive GABAB receptors. Baclofen is also used clinically as an antispastic as well as muscle relaxant agent [1]. Baclofen reduces the excitatory effect of active compounds such as barbiturates, benzodiazepine, etc[2,3]. Baclofen is also one of the most promising drugs in the control and treatment of the paroxysmal pain of trigeminal neuralgia [4]. Along with this Baclofen is also used for spasticity of spine without influencing the sedation[5]. Significant increment in gastric acid secretion was also observed in rats through the activation of central cholinergic mechanisms. Baclofen is commercialized in its racemic form [6] though R-enantiomer shows biological activity exclusively [7]. The enantiomers of Baclofen differ in their pharmacodynamic and toxicological properties.

Figure 1.Baclofen Stereoisomer’s


Several specific agonists or antagonists at GABA receptor sites have been developed, but 3-(4-chlorophenyl)-4-aminobutyric acid, i.e. Baclofen, is the only clinically useful selective GABAagonists [8]. Baclofen is used in the treatment of paroxysmal pain of trigeminal neuralgia and spasticity of spinal [9].

Enantioselective synthesis of R and/or S form of Baclofen along with their analogues number of methods are reported in the literature. Han et al. (2011) used efficient Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to ethyl-γ-phthalimidocrotonate by using bis-sulfoxide ligand for the synthesis of γ-aminobutyric acid (GABA) derivatives [10].Bae et al. (2011) used highly enantioselective bio mimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitro olefins to produce (S)(+)-Baclofen-HCl salt [11]. Anna et al.(2010) developed a enantioselective biocatalytic reduction of β-aryl-β-cyano-α,β-unsaturated carboxylic acids from anaerobic bacteria for (S)-Balclofen synthesis[12]. Vaselyet al.(2008) used a novel organocatalytic highly enantioselective nitrocyclopropanation reaction of α,β-unsaturated aldehydes as a key step for the synthesis of (S)-Baclofen [13]. Kozo et al.(1998) used Lipase mediated asymmetric acetylation of δ-symmetrical 2-aryl-1,3 propanediols as a key step for the synthesis of (S)-Baclofen [14]. Mahendraet al. (2015) used asymmetric Michael addition of diethyl malonate to 1-chloro-4-(2-nitrovinyl) benzene in the presence of scandium triflate and spartiene as organo catalyst to produce R-(‒)-Baclofen [15]. Yang et al.(2012) used the Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with (E)-3-(4-chlorophenyl)allyl methyl carbonate (monosubstituted allyl substrates) as a key step for the synthesis of (R)- Baclofen [16]. Yongcanet al.(2008) used the enantioselective Michael addition reaction of nitromethane to 3-(4-chlorophenyl)-acrylaldehyde (α,β-unsaturated aldehydes) under the cat

  1. I.A. Mohamed, H. Claus, B.O. Hans, Molecules, 2013, 18, 10266-10284.[Crossref], [Google Scholar], [Publisher]
  2. F.K. Pier, P.Zimmerrman, Brain Res, 1973, 54, 376.[Crossref], [Google Scholar], [Publisher]
  3. P.Polc, W.Haefely, NaunynSchmiedbergs Arch Pharmacol, 1976, 294, 121.[crossref], [Google Scholar], [Publisher]
  4. G.H. Fromm, C.F.Terrenc, H.S.Chaftha, J.D. Glass, Arch Neural,1980, 37, 768.[crossref], [Google Scholar], [Publisher]
  5. B.A.Sachais, J.N. Logue, Arc Neural, 1977, 34, 422. [crossref], [Google Scholar], [Publisher]
  6. 6.                  V.V. Thakur, A.S.Paraskar, A.Sudalai, Indian Journal of Chemistry-Section B, 2007,46B(2), 326-330.[crossref], [Google Scholar], [Publisher]
  7. 7.                  E.M.Jorgensen,GABA (August 31, 2005), WormBook, [crossref], [Google Scholar], [Publisher]
  8. W.Sieghart,Pharmacol Rev.,1995,47(2), 181-234. PMID: 7568326.[PDF], [Google Scholar], [Publisher]
  9. L. Ji, Y. Ma, J. Li, L. Zhang, L.Zhang,Tetrahedron Letters, 2009, 50, 6166–6168. [crossref], [Google Scholar], [Publisher]
  10. F. Han, J. Chen, X. Zhang, J. Liu, L.Cun, J. Zhu, J. Deng, J.Liao,Tetrahedron Lett., 2011, 52, 830.[crossref], [Google Scholar], [Publisher]
  11. H.Y. Bae, S. Some, J.H. Lee, J.Y. Kim, M.J. Song, S. Lee, Y.J. Zhang, C.E.Songa,Adv. Synth. Catal., 2011, 353, 3196. [crossref], [Google Scholar], [Publisher]
  12. A.Fryszkowska, K. Fisher, J.M.Gardinera, G.M.Stephens,Org.Biomol. Chem., 2010, 8, 533.[crossref], [Google Scholar], [Publisher]
  13. J.Vesely, G.L. Zhao, A.Bartoszewicz, A.Córdova,Tetrahedron Lett., 2008, 49, 4209. [crossref], [Google Scholar], [Publisher]
  14. S. Kozo, B.Toshikazu,J. Mol. Cat. B: Enzymatic,1998, 5, 183.[crossref], [Google Scholar], [Publisher]
  15. M. N. Lokhande, M. D. Nikalge, IJCPS,2015, 4, 487. [crossref], [Google Scholar], [Publisher]
  16. X. F. Yang, C. H. Ding, X. H. Li, J. Q. Huang, X. L. Hou, L. X. Dai, P. J. Wang, J. Org. Chem., 2012,77, 8980.[crossref], [Google Scholar], [Publisher]
  17. Y. Wang, P. Li, X. Liang, T. Y. Zhangc, J.Ye, Chem.Commun.,2008, 1232. [crossref], [Google Scholar], [Publisher]
  18. V.V. Thakur, M. D. Nikalje, A. Sudalai,Tetrahedron Asymm., 2003, 14, 581. [crossref], [Google Scholar], [Publisher]
  19. M. Claudio, L. Jacques, V.R.Alphand, F. Roland,Tetrahedron Lett.,1997,38, 1195. [crossref], [Google Scholar], [Publisher]
  20. F. Fabricio, D.Z.Vargas, C. Vargas, R. M. D’Oca, C.M. Celso, R. Dennis, New J. Chem., 2015, 39, 1643. [crossref], [Google Scholar],[Publisher]
  21. K. Biswas, R. Gholap, P. Srinivas, S.Kanyal, K.D.Sarma, RSC Adv.,2014, 4, 2538. [crossref], [Google Scholar], [Publisher]
  22. M.Y. Chang, C.L.Paib, Y.H. Kunga,Tetrahedron Lett.,2006, 47, 855. [crossref], [Google Scholar], [Publisher]
  23. R.Varala, S. R. Adapa, Syn. Commun.,2006, 36, 3743. [crossref], [Google Scholar], [Publisher]
  24. Z. Chen, Z. Chen, Y. Jiang, W. Hu, Tetrahedron, 2005, 61, 1579. [crossref], [Google Scholar], [Publisher]
  25. H. Mohammad, T. Houshdar, F. Morteza, S.Massoud, T. Nazer, Iranian Journal of Pharmaceutical Research,2003, 1.  [crossref], [Google Scholar], [Publisher]
  26. M. Y. Chang, P. P. Sun, S. T. Cgena, N. C. Chang,Tetrahedron Lett., 2003, 44, 5271. [crossref], [Google Scholar], [Publisher]
  27. J. Marcos, S. Carpes, R. Carlos, D.Correia, Tetrahedron Lett., 2002, 43, 741. [crossref], [Google Scholar], [Publisher]
  28. A. Alcindo, D. Santos, C. Giuliano, C.F. Simonelli, R. M. Alfredo, D. Oliveira, D. Francisco, A. Marques, H. Paulo, G.Zarbin, J. Braz. Chem. Soc., 2001, 12, 673. [PDF], [crossref], [Google Scholar], [Publisher]
  29. F. Coelho, B. Mariangela, M. De Azevedo, R. Boschiero, P. Resende, Syn. Commun.,1997, 27, 2455. [crossref], [Google Scholar], [Publisher]
  30. M. G. Kulkarni, S. I. Davawala, M. P. Shinde, A. P. Dhondge, A. S. Borhade, S. W. Chavhan, D. D. Gaikwad, Tetrahedron Lett., 2006,47, 3027. [crossref], [Google Scholar], [Publisher]
  31. M. G. Kulkarni, S. I. Davawala, A. K. Doke, D. S. Pendharkar, Synthesis, 2004, 2919. [crossref], [Google Scholar], [Publisher]
  32. M. G. Kulkarni, S. I. Davawala, A. P. Dhondge, A. S. Borhade, S. W. Chavhan, D. D. Gaikwad, Tetrahedron Lett., 2006, 47, 1003. [crossref], [Google Scholar], [Publisher]
  33. M. G. Kulkarni, A. P. Dhondge, A. S. Borhade,, D. D. Gaikwad, S. W. Chavhan, Y. B. Shaikh, V. B. Ningdale, M. P. Desai, D. R. Birhade, M. P. Shinde, Tetrahedron Lett., 2009, 50, 2411. [crossref], [Google Scholar], [Publisher]
  34. M. G. Kulkarni, D. D. Gaikwad, A. S. Borhade, Y. B. Shaikh, V. B. Ningdale, S. W. Chavhan, A. P. Dhondge, M. P. Desai, D. R. Birhade, Synth. Commun., 2010, 40, 423. [crossref], [Google Scholar], [Publisher]
  35. H. Bräuner-Osborne, B. Nielsen, P. Krogsgaard-Larsen, Eur. J. Pharmacol.,1998350, 311. [crossref], [Google Scholar], [Publisher]
  36. A. Kamal, S. R.Vangala, N. V. Subba Reddy, V. Santhosh Reddy, Tetrahedron: Asymmtry, 2009, 20, 2589-2593. [crossref], [Google Scholar], [Publisher]
  37. N. B. Kalamkar, V. M. Kasture, D. D. Dhavale, Journal of Organic Chemistry,2008, 73, 3619-3622.[crossref], [Google Scholar], [Publisher]
  38. R. M. Schelkun, P. Yuen, Wustrow, J. Kinsora, SuTi-Zhi, M. G. Vartanian, Bioorganic & Medicinal Chemistry Letters, 2006, 16, 2329-2332.[crossref], [Google Scholar], [Publisher]
  39. O. K. Taedong, J. Aram, L.Joohee, H. L. Jung, S. H. Chang, S. L. Hee, Journal of Organic Chemistry,2007, 72, 7390-7393.[crossref], [Google Scholar], [Publisher]
  40. N. G. Bowery, B. Bettler, W. Froestl, J. P. Gallagher, F. Marshall, M. Raiteri, T. I. Bonner, S.J. Enna, Pharmacol. Rev., 2002, 54, 247. [crossref], [Google Scholar], [Publisher]
  41. P. Krogsgaard-Larsen, E. Falch, H. Hjeds, Prog. Med. Chem., 1985, 22, 67.[crossref], [Google Scholar], [Publisher]
  42. Y. Ma, G. Marston, Phys. Chem. Chem. Phys., 2009, 11, 4198–4209. [crossref], [Google Scholar], [Publisher]
  43. P. Hannen, H. Haeger, M. Roos, United States Patent, Patent No.:US 8,703,993 B2, Apr. 22, 2014.
  44. M. G. Kulkarni, A. P. Dhondge, A. S. Borhade, D. D. Gaikwad, S. W. Chavhan, Y. B. Shaikh, , V. B. Ningdale, , M. P. Desai, , D. R. Birhade, M. Shinde, Eur. J. Org. Chem., 2009, 23, 3875.[crossref], [Google Scholar], [Publisher]
  45. D. Zhang, Z. H. Pan, M. Awobuluyi, S. A. Lipton, Trends Pharmacol. Sci., 2001, 22, 121. [crossref], [Google Scholar], [Publisher]