Process for the preparation of amino alcohol derivatives or salts thereof

Abstract

The present invention relates to a process for the preparation of amino alcohol derivatives or salts thereof which may be used as intermediates in the preparation of HIV reverse transcriptase inhibitors, more preferably Carbovir and Abacavir. The present invention more specifically relates to a process for the preparation of (1S, 4R)-4-amino-2-cyclopentene-1-methanol of Formula IIIa.

We claim: 
     
       1. An improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol salt of Formula IIIa 
       
         
           
           
               
               
           
         
         which comprises the steps of 
         i) converting the compound of Formula IVa 
       
       
         
           
           
               
               
           
         
         to the compound of Formula IIIc 
       
       
         
           
           
               
               
           
         
         using a reducing agent in the presence of a base and in a solvent, 
         ii) resolution of the compound obtained in step i) using a chiral acid with D-configuration in a solvent and 
         iii) isolating the compound of Formula IIIa. 
       
     
     
       2. An improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb according to  claim 1 , 
       
         
           
           
               
               
           
         
         which comprises the steps of 
         i) reaction of racemic 2-azabicyclo[2.2.1] hept-5-en-3-one 
       
       
         
           
           
               
               
           
         
         with methanol in the presence of dry HC1 gas followed by resolution with L-(+)-tartaric acid in water in the presence of triethylamine to give (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate L-hydrogen tartrate of Formula IVb, 
       
       
         
           
           
               
               
           
         
         ii) converting the compound of Formula IVb in presence of a base; and using a reducing agent; 
       
       
         
           
           
               
               
           
         
         iii) resolution of the compound obtained in step ii) using a chiral acid with D-configuration in a solvent and 
         iv) isolating the compound of Formula IIIb. 
       
     
     
       3. An improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb according to  claim 2 , 
       
         
           
           
               
               
           
         
         which comprises the steps of 
         i) reaction of racemic 2-azabicyclo[2.2.1] hept-5-en-3-one 
       
       
         
           
           
               
               
           
         
         with methanol in the presence of dry HC1 gas followed by resolution with L-(+)-tartaric acid in water in the presence of triethylamine to give (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate L-hydrogen tartrate of Formula IVb, 
       
       
         
           
           
               
               
           
         
         ii) converting the compound of Formula IVb in presence of sodium hydroxide and sodium borohydride in n-butanol, 
       
       
         
           
           
               
               
           
         
         iii) resolution of the compound obtained in step ii) using D-tartaric acid in methanol and 
         iv) isolating the compound of Formula IIIb. 
       
     
     
       4. The process according to  claim 1 , wherein the base used is alkali metal hydroxides selected from sodium hydroxide, lithium hydroxide or potassium hydroxide or alkali metal carbonates selected from sodium carbonate or potassium carbonate or alkoxides selected from sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide. 
     
     
       5. The process according to  claim 1 , wherein reducing agents used is metal hydrides boron reagents selected from sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride or aluminium reagents selected from diisobutylaluminium hydride, aluminium hydride and lithium aluminium hydride. 
     
     
       6. The process according to  claim 1 , wherein solvents are selected from water, methanol, ethanol, propanol, butanol and the solvents used in resolution are selected from methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol or mixtures thereof. 
     
     
       7. The process according to  claim 1 , wherein the Chiral acid used for resolution are acids having D-configuration selected from malic acid, mandelic acid, tartaric acid, diacetyl tartaric acid, di-p-anisoyl tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid and camphorsulfonic acid. 
     
     
       8. An improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol salt according to  claim 1 , wherein D-Salt is D-tartarate salt and L-salt is L-tartarate salt having the structural formula: