Journal of Applied Organometallic Chemistry

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

Document Type : Original Article

Authors

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

Abstract

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

Keywords

Full Text

Introduction

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

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Journal of Applied Organometallic Chemistry
Volume 1, Issue 3
July 2021
Pages 109-115
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History
  • Receive Date: 30 November 1999
  • Accept Date: 30 November 1999
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