Optical enantiomers of phenyramidol and process for chiral synthesis

Abstract

The present invention discloses optically pure (R) and (S) Phenyramidol enantiomers and their pharmaceutically acceptable salts, a process for synthesizing such enantiomers by means of a styrene oxide based synthesis, and also a clinical evaluation of (R) and (S) enantiomers of Phenyramidol, their salts and compositions thereof for enhanced/newer therapeutic benefits.

1 . An (R) or (S) enantiomer of 2-(.beta.-hydroxyphenethylamino)-pyridine (Phenyramidol) having the structure of Formula 1, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The enantiomer of  claim 1 , wherein the enantiomer has an optical purity of at least 99%. 
     
     
         3 . A pharmaceutical composition comprising the enantiomer or its pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
         4 . A method of using the pharmaceutical composition of  claim 3  as an analgesic or anti-arthritic agent for treating a subject in need of such an agent, comprising administering said agent to the subject. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 4  wherein the composition comprises an (R) enantiomer or a pharmaceutically acceptable salt thereof as an analgesic. 
     
     
         7 . The method of  claim 4  wherein the composition comprises an oxalate salt of the enantiomer as an anti-arthritic agent. 
     
     
         8 . A process of producing (R) or (S) Phenyramidol, or a pharmaceutically acceptable salt thereof, comprising the steps of:
 (a) contacting 2-aminopyridine with an alkali metal amide in an organic solvent to obtain an alkali metal salt of 2-aminopyridine; and   (b) condensing the alkali metal salt of 2-aminopyridine with (R) or (S) styrene oxide to produce a free base of (R) or (S) Phenyramidol, respectively, wherein the (R) or (S) Phenyramidol, or a pharmaceutically acceptable salt thereof, is produced from said free base.   
     
     
         9 . The process of  claim 8 , wherein said alkali metal amide is selected from the group consisting of sodium amide, potassium amide and lithium amide. 
     
     
         10 . The process of  claim 8 , wherein the molar ratio of 2-aminopyridine to alkali metal amide is from 1:1 to 1:1.5. 
     
     
         11 . The process of  claim 8 , wherein the organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), dimethyl sulphoxide (DMSO), methyl tert-butyl ether (MTBE), dimethylacetamide (DMA), dimethylformamide (DMF), and a mixture thereof. 
     
     
         12 . The process of  claim 8 , further comprises the steps of:
 (i) crystallizing the Phenyramidol free base from a solvent; and   (ii) converting the free base into a pharmaceutically acceptable salt by treating the base with an acid to form an acid addition salt.   
     
     
         13 . The process of  claim 12 , wherein the solvent is selected from a group consisting of toluene, benzene, xylene, aqueous methanol or ethanol, 2-propanol, and a mixture thereof. 
     
     
         14 . The process of  claim 12 , wherein the Phenyramidol free base is crystallized from a methanol solvent. 
     
     
         15 . The process of  claim 12 , wherein the free base is treated with oxalic acid in a solvent selected from a group consisting of ester solvents, alcoholic solvents, and a mixture thereof. 
     
     
         16 . The process of  claim 12 , wherein the ester solvents are selected from the group consisting of ethyl acetate, n-butyl acetate and a mixture thereof, and the alcoholic solvents are selected from the group consisting of methanol, ethanol, 2-propanol and a mixture thereof. 
     
     
         17 . An oxalate salt produced by the process of  claim 15 . 
     
     
         18 . The process of  claim 12 , wherein the free base is treated with a hydrochloric acid solution. 
     
     
         19 . A hydrochloride salt produced by the process of  claim 18 .