Intermediate and process for preparing of beta- anomer enriched 21-deoxy,21,21-difluoro-d-ribofuranosyl nucleosides

Abstract

The present invention provides a highly stereoselective, simple and economical glycosylation process for preparation of β-anomer enriched 2 1 -deoxy-2 1 ,2 1 -D-ribofuranosyl difluoronucleosides of formula (II), and physiologically acceptable slats thereof, in particular, the β-enriched anomer of gemcitabine hydrochloride of formula (IIb) in purity of >99% is provided through utilization of a novel trichloroacetimidate of formula (I).

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein, 
 P is hydrogen or a hydroxy protective group.  
 
   
   
       2 . The compound of  claim 1 , wherein P is selected from the group of formyl, 2-chloroacetyl, benzyl, diphenylmethyl, triphenyl methyl, 4-nitrobenzyl, phenoxycarbonyl, tertiary butyl, methoxymethyl, tetyrahydropyranyl, allyl, tetrahydrothienyl, 2-methoxethoxy methyl, methoxy acetyl, phenoxy acetyl, isobutyryl, ethoxy carbonyl, benzyloxy carbonyl, mesyl, trimethylsilyl, isopropyl dimethylsilyl, methyldiisopropyl silyl, triisopropyl silyl, or tertiary butyldimethyl silyl.  
   
   
       3 . A process for preparing a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein, 
 P is hydrogen or a hydroxy protective group;  
 the method comprising:  
 contacting a compound of formula (IV):  
                     
 wherein P is as defined hereinbefore, with trichloroacetonitrile, in an inert organic solvent and in the presence of a base.  
 
   
   
       4 . The process of  claim 3 , wherein the organic solvent is selected from the group of halogenated hydrocarbons, acetic acid, (C 1-4 ) alkyl esters, ethers, aromatic hydrocarbons, and combinations thereof.  
   
   
       5 . The process of  claim 3 , wherein the inert organic solvent is selected from the group of dichloromethane, 1,2-dichloroethane, ethyl acetate, diisopropylether, toluene, and combinations thereof.  
   
   
       6 . The process of  claim 3 , wherein the base is selected from the group of diethylamine, triethylamine, diisopropylethylamine, cyclohexylamine, pyridine, 2,4-dimethylamino pyridine, N-methyl morpholine, and combinations thereof.  
   
   
       7 . The process of  claim 3 , wherein the base is employed in catalytic, equimolar or in molar proportions of about 1 to about 3 moles per mole of the compound of formula (IV).  
   
   
       8 . The process of  claim 3 , wherein the trichloroacetonitrile is employed in equimolar proportions to the compound of formula (IV), in molar proportions of about 1 to about 20 moles per mole of the compound of formula (IV), or in molar proportions of about 1.0 to about 15 moles per mole of the compound of formula (IV).  
   
   
       9 . The process of  claim 3 , wherein the contacting is carried out at a temperature of about −20° C. to about 20° C.  
   
   
       10 . A stereoselective glycosylation process for the preparation of greater than about 99% β-enriched anomer of gemcitabine hydrochloride formula (IIb):  
     
       
         
         
             
             
         
       
     
     comprising the steps of: 
 a) glycosylating a compound of formula (I),  
                     
 wherein P is as defined hereinbefore, with cytosine of formula (Va) or (Vb),  
                     
 wherein R 4  is a nitrogen protective group, and R 5  is a hydroxy protective group, in the presence of an inert organic solvent and optionally in the presence of a Lewis acid catalyst to protected gemcitabine free base of formula (IIa),  
                     
 wherein P and R 4  are as defined hereinbefore;  
 b) removing the protective groups by treating the compound of formula (Ia) with aqueous ammonia in the presence of a C 1-3  alcohol or with hydroxy ion exchanged anion exchange resins, to give the β-enriched anomer of gemcitabine free base of formula (IIc);  
                     
 c) contacting the gemcitabine free base of formula (IIc) with hydrogen chloride in a C 1-3  alcohol to give the β-enriched anomer of gemcitabine hydrochloride of formula (IIb) in a yield of at least about 95% and optionally a purity of at least about 95%; and  
 d) optionally further enriching the β-anomer content of gemcitabine hydrochloride of formula (IIb) to greater than about 99% through crystallization from a mixture of a C 2-3  aliphatic organic acid and water.  
 
   
   
       11 . The process of  claim 10 , wherein the nitrogen protective group R 4  and the hydroxyl group R 5  in the compounds of formula (Va) and (Vb) are acetyl or trialkylsilyl.  
   
   
       12 . The process of  claim 10 , wherein the inert organic solvent is selected from the group of acetonitrile, toluene, xylene and its isomers, chlorobenzene, ortho-dichlorobenzene, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, anisole, and combinations thereof.  
   
   
       13 . The process of  claim 10 , wherein the Lewis acid catalyst is selected from the group of tin tetrachloride, trimethylsilyltrifluoromethanesulphonate, trimethylsilyl nonafluorobutylsulphonate, trimethylsilyl perchlorate, borontrifluoride diethyletherate, and trimethylsilyl tetrafluoroborate.  
   
   
       14 . The process of  claim 10 , wherein the compounds (Va) and (Vb) are employed in molar proportions of about 1 to about 2.0 moles per mole of compound of formula (I).  
   
   
       15 . The process of  claim 10 , wherein the C 1-3  alcohol is selected from the group of methanol, ethanol, 1-propanol, 2-propanol, and combinations thereof.  
   
   
       16 . The process of  claim 10 , wherein the deprotection of protective groups, P, R 4 , and R 5  comprises contacting the compound of formula (IIa) with aqueous ammonia in the presence of a C 1-3  alcohol at a temperature of between ambient to a temperature of about 60° C.  
   
   
       17 . The process of  claim 10 , wherein the anion exchange resin is a strong base anion exchange resin.  
   
   
       18 . The process of  claim 10 , wherein the strong base anion exchange resin is an Amberlite resin.  
   
   
       19 . The process of  claim 18 , wherein the Amberlite resin is selected from the group of FPA40 Cl, FPA90 Cl, FPA91 Cl, FPA97 Cl, FPA98 Cl, IRA 400, IRA402 Cl, and IRA410 Cl.  
   
   
       20 . The process of  claim 10 , wherein the C 2-3  aliphatic organic acid is acetic acid, propionic acid, or a combination thereof.