(2R)-2-[di(2-propyl)phosphonyylmethoxy]-3-P-toluenesulfonyloxy-1-trimethylacetoxypropane, its preparation and use

Abstract

The invention relates to the new compound (2R)-2-[di(2-propyl)phosphonylmethoxy]-3-p-toluenesulfonyloxy-1-trimethylacetoxypropane and the method of producing it. The compound may be used for producing (S)-N-(3-hydroxy-2-phosphonylmethoxypropyl) derivatives of the heterocyclic purine and pyrimidine bases of antiviral activity.

What we claim is: 
     
       1. (2R)-2-[Di(2-propyl)phosphonylmethoxy]-3-p-toluenesulfonyloxy-1-trimethylacetoxypropane of the formula I ##STR7## 
     
     
       2. The method of producing the compound of the formula I in claim 1 consisting in the reaction of (2R)-3-O-p-toluenesulfonyloxy-1,2-propandiol of the formula II ##STR8## with an equimolar amount of N-trimethylacetylimidazole in the inert organic aprotic solvent in the presence of a tertiary amine, whereupon the obtained (2R)-3-p-toluenesulfonyloxy-1-trimethylacetoxy-2-propanol of the formula III ##STR9## is reacted with dimethoxymethane and phosphorus pentoxide in an inert organic solvent and the (2R)-2-methoxymethoxy-3-p-toluenesulfonyloxy-1-trimethylacetoxypropane of the formula IV ##STR10## is treated with acetic anhydride in the presence of a Lewis acid, at temperatures -5° C. to 5° C. and the obtained (2R)-2-acetoxymethoxy-3-p-toluenesulfonyloxy-1-trimethylacetoxypropane of the formula V ##STR11## is heated with bromotrimethylsilane at temperatures 100° C. to 120° C., the volatile components are evaporated in vacuo, the residue is heated with tri(2-propyl)phosphite to 100°-120° C. and the product of the formula I is obtained by chromatography or distillation. 
     
     
       3. The method of utilization of the compound of the formula I according to claim 1 for the production of (S)-N-(3-hydroxy-2-phosphonylmethoxypropyl) derivatives of the heterocyclic purine and pyrimidine bases of the general formula VI ##STR12## where B is a substituted purin-9-yl, purin-7-yl, or pyrimidin-1-yl, or pyrimidin-3-yl residue and their aza and deaza analogues consisting in the reaction of the compound of the formula I with a sodium salt of the heterocyclic purine or pyrimidine base or its aza or deaza analogue, or with a mixture of such base and alkali carbonate in dimethylformamide at temperatures 60° C. to 120° C., whereupon the solvent is evaporated in vacuo and the mixture treated with sodium methoxide in methanol and subsequently with bromotrimethylsilane in an inert organic solvent and the product of the general formula VI is isolated by chromatography. 
     
     
       4. A method according to claim 2, wherein the solvent is dichloro methane, the tertiary amine comprising triethylamine, the Lewis acid comprising boron trifluoridediethylether complex, the compound of formula V being heated in toluene. 
     
     
       5. A method according to claim 3, wherein the alkali carbonate comprises cesium carbonate, the inert inorganic solvent comprising acetonitrile, the chromatography being ion-exchange chromatography. .Iadd.6. A compound of the general formula VI ##STR13##.Iaddend. wherein B is purin-9-yl, purin-7-yl, pyrimidin-1-yl selected from the group consisting of 6-methylthiopurine, 2-amino-6-chloropurine, 2-amino-6-chloropurine, 2-amino-6-azidopurine, 4-alkoxy-2-pyrimidinone, 
     
     
        and 2-chloroadenine. .Iadd.7.  A compound of claim 6 which is the (S) enantiomer at an optical purity higher than 95%. .Iaddend..Iadd.8. The compound of claim 7 wherein B is 2-amino-6-chloropurine. .Iaddend..Iadd.9. The compound of claim 7 wherein B is 2-amino-6-azidopurine. .Iaddend..Iadd.10. The compound of claim 7 wherein B is 6-methylthiopurine. .Iaddend..Iadd.11. The compound 9-(S)-(2-phosphonylmethoxy-3-hydroxypropyl)-2-chloroadenine diisopropyl ester. .Iaddend.