Processes for the preparation of linezolid intermediate

Abstract

The present invention provides improved methods of converting R—N-(4-morpholiyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to the intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) that involve the production of fewer by-products than previous methods. The amine (II) may then be converted into linezolid (I) of high chemical purity with respect to the inactive R-enantiomer and bis-linezolid (IV), and is in high yield, without the need for tedious, complicated purification steps, such as chromatography.

1 . A process for preparation of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) from R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) by catalytic hydrogenation comprising: combining R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) and a linear or branched-chain aliphatic C 1  to C 8  alcohol or a biphasic solvent system to obtain a reaction mixture; and reducing the said azide (III) using a reducing agent selected from the group of formic acid and salts thereof to obtain S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II).  
   
   
       2 . The process of  claim 1 , wherein the alcohol is ethanol or butanol.  
   
   
       3 . The process of  claim 1 , wherein the amount of alcohol is about 10 volumes to about 25 volumes relative to the said azide.  
   
   
       4 . The process of  claim 1 , wherein the amount of alcohol is about 15 volumes (g/mL) relative the said azide.  
   
   
       5 . The process of  claim 1 , wherein the aqueous solvent of the biphasic solvent is water.  
   
   
       6 . The process of  claim 1 , wherein the organic solvent of the biphasic solvent is ethylacetate.  
   
   
       7 . The process of  claim 1 , wherein the ratio of organic solvent:water of the biphasic solvent is from about 0.1:1 to about 10:1  
   
   
       8 . The process of  claim 7 , wherein the ratio of organic solvent:water of the biphasic solvent is about 1:1.  
   
   
       9 . The process of  claim 1 , wherein the process comprises a phase transfer agent and the phase transfer agent is tetrabutylammonium bromide (TBAB) or Aliquot 336.  
   
   
       10 . The process of  claim 1 , wherein the reducing agent is ammonium formate.  
   
   
       11 . The process of  claim 1 , wherein reduction conducted in the presence of zinc or a noble metal catalyst on an inert support such as carbon, activated carbon, alumina or zinc.  
   
   
       12 . The process in  claim 11 , wherein the noble metal catalyst is palladium on carbon (“Pd/C”).  
   
   
       13 . The process in  claim 11 , wherein the noble metal catalyst is in an amount of about 2-20% compared to the azide.  
   
   
       14 . The process in  claim 11 , wherein the zinc is in an amount of about 1 to 2 equivalents, relative to the azide.  
   
   
       15 . The process in  claim 11 , wherein the reduction is carried out to completion as judged by using periodic TLC or HPLC analysis.  
   
   
       16 . The process in  claim 1  further comprising converting the said amine (II) into linezolid.  
   
   
       17 . The process of  claim 16 , wherein the linezolid (I) produced comprises less than about 3.2% of bis-linezolid (IV).  
   
   
       18 . The process of  claim 17 , wherein the linezolid (I) produced comprises less than about 1% of bis-linezolid (IV).  
   
   
       19 . The process of  claim 18 , wherein the linezolid (I) produced comprises less than about 0.1% of bis-linezolid (IV).  
   
   
       20 . The process of  claim 16 , wherein the linezolid (I) produced comprises less than about 0.05% of bis-linezolid (IV).  
   
   
       21 . The process of  claim 16 , wherein pure linezolid (I) is produced having a purity of more than about 95% with respect to reaction by-product impurities.  
   
   
       22 . The process of  claim 16 , wherein pure linezolid (I) is produced having a purity of more than about 98% with respect to reaction by-product impurities.  
   
   
       23 . The process of  claim 22 , wherein pure linezolid (I) is produced having a purity of more than about 99% with respect to reaction by-product impurities.