Synthesis Of Difluoro Nucleoside Drug Intermediates

Nucleoside drugs with anti-tumor and anti-viral effects are widely used in clinical treatment.Gemcitabine and other difluoro substituted drugs are some important parts of nucleoside drugs.Meanwhile,2-Deoxy-2,2-difluoro-D-ribofuranose-l-Phosphate(F,F-AP)is the important intermediate to synthesize Gemcitabine and other difluoro substituted drugs with biological method.In this issue,we study on the synthesis of F,F-AP through phosphorylation and deprotect benzoyl,which takes 2-deoxy-2,2-difluoro-3,5-dibenzoate-D-ribofuranose(F,F-BzA)as the material.The research contents are as follows:With phosphoric acid as phosphorylating agents to synthesis 2-Deoxy-2,2-difluoro-D-ribofuranose-l-Phosphate.Experiments to determine the solvents and HPLC testing conditions.The HPLC testing conditions is:C18 alkyl silane bonded phase column,mobile phase is ‰5 acetic acid:acetonitrile=40:60(V/V);velocity of flow is 0.5 mL/min;column temperature is 35?;Wavelength of UV detector is 230 nm;retention time is 10 min.Experimental study of the effect of reaction temperature on the reaction.Experimental results show that:reaction temperature in 80?,reaction time was 3 h,the volume of acetonitrile was 15 ml,and feed ratio of n(F,F-AP):n(H3PO4)=3:1.The conversion rate was 14.2%With heterogeneous phosphoric acid as phosphorylating agents,which was prepared by phosphoric acid and phosphorus pentoxide,after a series of reaction with ribose,there produced 2-deoxy-2,2-difluoro-D-ribofuranose-l-phosphate.Experimental study of the effect of reaction temperature on the reaction,experimental results show that:n(F,F-BzA):n(H3P04):n(P205)=1:3.62:5.67,reaction temperature in 70?,reaction time was 3h,the mole of F,F-BzA was 2.1 mmol.The conversion rate was 27.6%.Using phosphorus pentoxide as phosphorylating agents,and carbon tetrachloride and acetonitrile as solvent,to systhsis 2-deoxy-2,2-difluoro-D-ribofuranose-1-phosphate.The conditions of single factor test that the ratio of phosphorus pentoxide and carbon tetrachloride and acetonitrile solution on the conversion rate.And orthogonal experiment showed the optimal conditions is:the mole ratio between ribose and phosphorus pentoxide was 1:0.75,the temperature of phosphorylation was 55?,the reaction time of phosphorylation was 2.5 h,and the dosage of hydrolysis water was 4.5%of the total amount of material.The conversion rate is 60.4%.Researched for the debenzoyl process,the conditions showed that:The amount of phosphorylated product 2.8 mmol,the amount of methanol-tetrahydrofuran is 9 ml,the amount of ? stage ammonia is 6 ml,the reaction time of ? stage is 2 h,the amount of ammonia of ? stage is 12 ml,the reaction time of ? stage is 9 h.The field reached 81.3%.Identified ribose,phosphorylation product and deprotection product respectively by infrared spectroscopy,through the comparison and analysis,proves that the phosphorylation reaction and the debenzoyl reaction are taken off.2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose as a raw material to synthesis of 2-deoxy-2,2-difluoro-D-ribofuranosyl ribose-1-phosphate methods have not been reported.Study of this subject can provide important reference for the synthesis of double-fluoro nucleoside pharmaceutical intermediates.