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Synthese of R(－)-Baclofen and Resolution of Baclofen Intermediate (±)-GAM

Author: DuanZhenYing
Tutor: YanTingRen
School: Hebei Medical University
Course: Medicinal Chemistry
Keywords: Baclofen γ-Amino-butyric acid Spasmolysis Ammonolysis Hoffmann degradation Enantiomer Resolution Racemization Synthesis
CLC: R914
Type: Master's thesis
Year: 2003
Downloads: 184
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Abstract


Baclofen, [β - (p-chlorophenyl) -γ -amino-butyric acid], or Lioresal for its commercial name , is the first selective GABAB receptor agonist in clinical. Y -aminobutyric acid (GAB A), the major inhibitory amino acid transmitter in the central nervous system of mammalians, exerts its physiological actions through the interaction with three receptor subtypes, that is GABAA, GABAB and GABAC. Baclofen is the first liophilic analogue of GABA and is used clinically for the treatment of spasticity of spinal and cerebral origin. Some more recent studies have described many new uses of baclofen , including antitussis , antiepilepty, treating intractable hiccup, pain caused by apoplexy and myelopathy, trigeminal neuralgia, etc. Baclofen can also improve the hypermyotonia and myoclonia in case of cerebrovascular diseases. Beside , it was applied successfully to cure gastroesophageal reflux, which opened up a new way to treat gastroesophageal reflux whithout inhibitting gastric secretion. There is another report that baclofen has effective application in the treatment of the cocaine addication, which has great significance in treating drug addication.The biological activity and physical properties of racemic baclofen are well documented in the literature. Further extensive pharmacological tests have concluded that biological activity of the drug resides with the R-enantiomer (R (-) baclofen) . These selective activites have led to extensive research concerning methods of separating the optical isomers of baclofen. It is very important in augmenting effect, reducing toxic and secondary action and treating many other diseases.Objective: To synthese R- (-) - β - (p-chlorophenyl) - Y -aminobutyric acid (R (-) -baclofen ) through resolution of its intermediate, (± )-GAM. To deveplop a modification of the general route for the synthesis of R (-) -baclofen and find a suitable method for industrialization. For purpose of saving raw material, reducing production costs and shortening reaction cycle and exploring a reusable route through racemization of S (-) -GAM.Methods: 3- ( p-chlorophenyl ) glutaric acid was synthesized by using two different compounds as raw materials through two different synthetic routes respectively: (1)3- (p-chlorophenyl) glutaric acid was synthesized by using p-chlorobenzaldehyde and ethyl acetoacetate as raw materials through esterification , acid-decomposition , dehydration and condensation. (2) 3- ( p-chlorophenyl ) glutaric acid was obtained through esterification , hydrolysis , decarboxylation , and condensation withp-chlorobenzaldehyde and diethyl malonate as raw materials. The second route was not reported previously.3- (p-chlorophenyl) glutaramic acid was synthesized through two different synthetic routes respectively. According to the literature, 3- (p-chlorophenyl) -glutaric anhydride reacted with ammonia at 185癈 to gave 3-( p-chlorophenyl) glutarimide, then subjected to basic hydrolysis to obtain 3- (p-chlorophenyl) glutaramic acid. It was synthesized only through one step in the improved method.R- (-) - 0 - (p-chlorophenyl) - y -aminobutyric acid (R(-) -baclofen) was synthesized as follows: (±) -GAM was resolved by the reaction with S- (-) -a -phenylethylamine(S-PEA) to form two enantioners R ( + ) -GAM and S (-) -GAM. The R(+)-GAM was subsepuently converted to R( -) -baclofen with sodium hypochlorite via a Hoffmann degradation. S ( - ) -GAM was racemizated through dehydration and condensation to afford 3- (p-chlorophenyl) glutarimide followed the basic hydrolysis to obtain (±) -GAM.Owing to the very low value of the optical rotation of R(-)-baclofen, ([alpha]22D= - 1.2(c=0.24 in H2O)), its optical purity was assessed by the transformation of a sample into the corresponding lactame: R- (-) -4- (p-chlorophenyl) pyrrolidin-2-one, ([alpha]25D= -39 (c=0.5 in EtOH) ) . Results: (±)-3- (p-chlorophenyl) glutaramic acid IR(KBr, cm-1) : 3428.55, 32

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