Novel and Highly Stereoselective Process for Preparing Gemcitabine and Intermediates Thereof

Abstract

The present invention provides a novel and highly stereoselective process for preparing gemcitabine, which is suitable for industrial production, wherein, it includes the following reactions. Additionally, the invention discloses the key intermediates. The definition for the groups of G1, G2, G3, G4, and G5 are described in the specification.

1 . The following formula compound, which includes its α-anomer or β-anomer, or mixture thereof: 
       
         
           
           
               
               
           
         
         wherein, the substitutions of G1 and G2 are independently the radicals defined by the following structure: 
       
       
         
           
           
               
               
           
         
         wherein, R1 is selected from the group consisting of C1-C3 alkyl and null; 
         R2 is selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl and substituted phenyl; 
         and with the provision that at lest one of R2 in the G1 and G2 is phenyl or substituted phenyl; 
         the said substituted phenyl is the one substituted by C1-C4 alkyl, or halogen; 
         G3 is selected from the group consisting of alkylsulfonyl, arylsulfonyl, substituted alkylsulfonyl and substituted arylsulfonyl. 
       
     
     
         2 . The compound of  claim 1 , wherein, G1 and G2 are independently selected from the group consisting of benzoyl, phenylacetyl, biphenylcarbonyl, and biphenylacetyl;
 with the provision that at least one of R2 in the G1 and G2 is selected from the group consisting of phenyl and substituted phenyl;   G3 is selected from the group consisting of methylsulphonyl, benzylsulphonyl, p-toluenesulphonyl and p-nitrobenzenesulphonyl.   
     
     
         3 . The compound of  claim 1 , wherein G 1  and G 2  are biphenylcarbonyl, G3 is methylsulphonyl. 
     
     
         4 . The compound of  claim 1 , wherein G 1  is benzoyl, and G 2  is biphenylcarbonyl, G3 is methylsulphonyl. 
     
     
         5 . The compound of  claim 1 , which is selected from the following compounds:
 2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-methanesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-ethanesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-benzenesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-p-nitrobenzenesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-methanesulphonate;   1α-2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-methanesulphonate;   1β-2-deoxy-2,2-difluoro-D-arabinofuranose-3,5-di-(4-phenyl)benzoate-1-methanesulphonate;   1α-2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-methanesulphonate;   1β-2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-methanesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-ethanesulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-benzylsulphonate;   2-deoxy-2,2-difluoro-D-arabinofuranose-5-benzoate-3-(4-phenyl)benzoate-1-p-nitrobenzenesulphonate.   
     
     
         6 . The process for preparing compound of  claim 1 , it may adopt the following scheme 1: 
       
         
           
           
               
               
           
         
         firstly, in the present of acid scavenger, formula 3 compound reacts with an acylating agent in organic solvent to prepare hydroxyl group protected formula 4 compound; the acylating agent is preferably selected from the group consisting of benzoyl chloride, phenylacetyl chloride, biphenylcarbonyl chloride and biphenylacetyl chloride; the acid scavenger is preferably selected from the group consisting of pyridine, triethylamine and N,N-dimethyl-4-aminopyridine; 
         secondly, in the present of trifluoroacetic acid and water, formula 4 compound in acetonitrile is hydrolyzed into formula 5 compound, then formula 5 is dehydrated and lactonized by refluxing to yield formula 6 compound; 
         thirdly, in the present of acid scavenger, formula 6 compound reacts with acylating agent in an organic solvent to prepare 5′-hydroxyl group protected formula 7 compound, and was then purified by ethyl acetate and n-hexane to give pure erythro-structure thereof; the acylating agent is preferably selected from the group consisting of benzoyl chloride, phenylacetyl chloride, biphenylcarbonyl chloride and biphenylacetyl chloride; the acid scavenger is preferably selected from the group consisting of pyridine, triethylamine and N,N-dimethyl-4-aminopyridine; 
         finally, formula 7 compound is reduced into formula 10 compound in the present of a reducing agent, then formula 10 compound reacts with a sulphonating agent and acid scavenger to give alpha-anomer enriched (α:β up to 2-2.5:1) formula 11 compound, the said sulphonating agent is selected from the group consisting of C1-04 alkylsulphonyl, arylsulphonyl, substituted alkylsulphonyl and substituted arylsulphonyl, preferably, methylsulphonyl, ethylsulphonyl, benzylsulphonyl, p-nitrobenzensulphonyl; 
         wherein, G1, G2 and G3 is defined as  claim 1 . 
       
     
     
         7 . The process for preparing compound of  claim 1 , where the hydroxyl protected groups of formula 11 compound are same, the following scheme 2 may be adopted to prepare it: 
       
         
           
           
               
               
           
         
         firstly, formula 9 compound reacts with acylating agent in organic solvent in the present of acid scavenger to prepare the hydoxyl group protected formula 7 compound, which was then purified by toluene and n-hexane to get pure erythro-structure of compound 7; the acylating agent is preferably the group consisting of from benzoyl chloride, phenylacetyl chloride, biphenylcarbonyl chloride and biphenylacetyl chloride; the acid scavenger is preferably selected from the group consisting of pyridine, triethylamine and N,N-dimethyl-4-aminopyridine; 
         secondly, formula 7 compound is reduced into formula 10 compound in the present of a reducing agent, then formula 10 compound reacts with a sulphonating agent and acid scavenger to get alpha-anomer enriched formula 11 compound; the said sulphonating agent is selected from the group consisting of C1-C4 alkylsulphonyl, arylsulphonyl, substituted alkylsulphonyl and substituted arylsulphonyl; 
         wherein, the groups of G1 and G3 are same, furthermore, G1, G2 and G3 are defined as claim  9 .