Patent GB-1491498-A (GB)
Title: 2-(substituted phenyl)-propionic acids and their pharmaceutical compositions
IPC: C07C51/16
Filed: 1974-10-29
Abstract: 1491498 2 - (substituted phenyl) - propionic acids, their preparation and pharmaceutical compositions EISAI CO Ltd 29 Oct 1974 [29 Oct 1973 (2) 16 May 1974] 46851/74 Heading C2C The invention comprises compounds of  Formula I wherein R<SP>1</SP> and R<SP>2</SP> are independently hydrogen or halogen atoms or a CF 3 , C 1-5  alkyl or C 1-5  alkoxy group provided that R<SP>1</SP> and R<SP>2</SP> are not both hydrogen, and pharmaceutically acceptable salts thereof which may be prepared by (a) oxidizing a compound of Formula II where R<SP>1</SP> and R<SP>2</SP> are as defined above; (b) reacting a compound of Formula VI with a compound of Formula VII R<SP>1</SP> and R<SP>2</SP> being as defined above and one of X and Y is halogen, the other being a group OM where M is hydrogen or an alkali metal atom; (c) methylating a compound of Formula XV wherein R<SP>1</SP> and R<SP>2</SP> are as defined above and R<SP>3</SP> is CN or CO 2 R<SP>5</SP> and each of R<SP>4</SP> and R<SP>6</SP> is a hydrogen atom or a C 1-5  alkyl group and hydrolysing the obtained product of Formula XVI with alkali (d) reacting a compound of Formula XIX in which Hal represents a halogen atom with magnesium and reacting the formed Grignard reagent with carbon dioxide or (e) hydrolysing a compound of Formula XXIII and optionally as a final stage of any of the processes (a) to (e) salifying the product to obtain a pharmaceutically acceptable salt thereof. Ethyl 3 - [m - (o - chlorophenoxy)phenyl] - 2,3- epoxybutyrate and the corresponding p - chlorophenoxy compound are prepared by reaction of ethyl chloroacetate with the appropriate 3- (chlorophenoxy)acetophenone in ethanol containing dissolved sodium and these esters are subjected to hydrolysis with ethanolic NaOH to obtain 3-[m-(o-(p-)-chlorophenoxy)phenyl]-2,3- epoxybutyric acid followed by acid hydrolysis to obtain 3-[m-(o-(p-)-chlorophenoxy)phenyl]propionaldehyde. Ethyl m-bromophenylmalonate is obtained by reaction of ethyl m-bromophenylacetate with ethyl carbonate in the presence of ethanolic NaOH and is methylated by reaction with methyliodide and hydrolysed with alcoholic KOH to obtain 2-(m-bromophenyl)propionic acid. 3 - (m - Benzyloxyphenyl) - 2,3 - epoxybutyrate is prepared by reacting ethylchloroacetate with m-benzyloxyacetophenone in the presence of ethanolic NaOH and is hydrolysed with ethanolic KOH to obtain 3-(m-benzyloxyphenyl - 2,3 - epoxybutyric acid; hydrolysis of this acid with HCl gives 2-(m-benzyloxyphenyl)- propionaldehyde which is oxidized by KMnO 4  in acetic acid to obtain 2-(m-benzyloxyphenyl) propionic acid which is finally reduced catalytically to obtain 2-(m-benzyloxyphenyl)propionic acid. 1 - m - (o - Chlorophenoxy)phenethyl alcohol is prepared by reduction of m-(o-chlorophenoxy) acetophenone with NaBH 4  and is reacted with PBr 3  to obtain 1-m-(o-chlorophenoxy)phenethyl bromide. 2 - [m - (o - Chlorophenoxy)phenyl]propionitrile is obtained by reaction of 1-m-(o-chlorophenoxy) phenethyl bromide with NaCN in DMSO. Pharmaceutical compositions having analgesic and anti-inflammatory activity for oral administration comprise a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient.