Preparation of nucleosides ribofuranosyl pyrimidines

Abstract

The present process provides an improved method for converting 2′-deoxy-2′-fluoro-2′-methyl-D-ribonolactones derivatives to 3-fluoro-3-methyl-2-chlorofuran compounds which are useful for the synthesis of nucleosides and improved processes for the synthesis of the D-ribonolactone compounds.

1 . A process for the preparation of a nucleoside of formula I comprising the steps of: 
       
         
           
           
               
               
           
         
         (i) contacting an (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxymethyl-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl ester (II; R=aryl or alkyl) with RED-AL/TFE (1:1) in DCM/PhMe (6:1) at a temperature of −10 to −5° C.; 
         (ii) contacting the mixture with a chlorinating agent selected from sulfuryl chloride, thionyl chloride or phosphorus oxychloride and tetrabutylammonium bromide to afford an 
         (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester (III; R=aryl or alkyl); and, 
         (iii) contacting III with N-(2-trimethylsilanyloxy-pyrimidin-4-yl)-benzamide, SnCl 4  and PhCl to afford an (aryl)alkanoic acid (2R,3R,4R,5R)-3-(aryl)alkanoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (I; R=aryl or alkyl). 
       
     
     
         2 . A process according to  claim 1  said process further comprising the step of hydrolysis of the protected nucleoside I to 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (IV). 
       
         
           
           
               
               
           
         
       
     
     
         3 . A process according to  claim 2  wherein R is C 6 H 5 . 
     
     
         4 . A process according to  claim 3  said process further comprising the steps of: 
       
         
           
           
               
               
           
         
         (i) contacting (E)-3-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-2-methyl-acrylic acid ethyl ester (V) with aqueous sodium permanganate, ethylene glycol, sodium bicarbonate and acetone at −20 to 0° C., then quenching the reaction with aqueous sodium bisulfite, partitioning the product between EtOAc and water and recovering (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (VI) from the organic phase; 
       
       
         
           
           
               
               
           
         
         (ii) contacting a solution of (VI) and TEA in iso-propyl acetate and MeCN with thionyl chloride to afford (VII); 
       
       
         
           
           
               
               
           
         
         (iii) contacting a solution of (VII) in iso-propyl acetate and MeCN with NaHCO 3  and aqueous NaOCl to afford (VIII); 
       
       
         
           
           
               
               
           
         
         (iv) contacting (VIII) with TEA and triethylamine-trihydrofluoride to afford (IX) followed by HCl, BaCl 2  and water to afford (X); 
       
       
         
           
           
               
               
           
         
         (v) contacting a solution of (X) in MeCN with TEA, DMAP and benzoyl chloride to afford II (R═C 6 H 5 ). 
       
     
     
         5 . A process for the preparation of an (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester (III, R=aryl or alkyl) from an (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxymethyl-4-fluoro-4-methyl-5-oxo-tetrahydro-furan-3-yl ester (II, R=aryl or alkyl) comprising the steps of: 
       
         
           
           
               
               
           
         
         (i) contacting II with RED-AL/TFE (1:1) in DCM/PhMe (6:1) at a temperature of −10 to −5° C.; and, subsequently 
         (ii) treating the mixture with sulfuryl chloride and tetrabutylammonium bromide to afford (III).