Synthesis Process Optimization Of A3 Adenosine Receptor Agonist CF102 And Synthesis Of BMN-673 Analogues

CF102 is a selective A3 adenosine receptor agonist developed by Can-Fite's,which is mainly used for the treatment of NAFLD,NASH and HCC.In the future,it has a broad market research prospect.BMN-673 analogues are designed and synthesized by the parent structure of BMN-673.It is desirable to screen for PARP inhibitors with low toxicity and high biological activity.The main work in this thesis can be summarized as follows:?1?Synthesis process optimization of CF102:Dichloropurine and tetraacetylribose as starting materials,CF102 was prepared through seven steps:Vorbruggen reaction,nucleophilic substitution,reduction,hydroxyl protection,TEMPO oxidation and Pinnick reaction,methylamine nucleophilic substitution and deprotection.The purity of CF102was 99.0%and the overall yield increased from 26.9%to 38.8%.The intermediates and product were confirmed by ¹H nuclear magnetic resonance spectroscopy and mass spectrometry.The optimization results shows that solids are produced by adjust p H with sodium bicarbonate and increase the stirring time,the purity is up to 98.9%and the yield is 85.6%.In the nucleophilic substitution,the reaction time is shortened from 48 hours to6 hours by raising the temperature to 40?and the yield is 91.7%.In hydroxy protection,the reaction time is shortened from 12 hours to 4 hours by using acetone as solvent.In the methylamine nucleophilic substitution,using dichloromethane as a solvent can effectively save costs.?2?Synthesis of BMN-673 analogues:6-fluoro-4-nitro-3H-isobenzofuran-1-ketone and 1-methyl-1H-1,2,4-triazol-5-formaldehyde were synthesized by the raw materials of5-fluoro-2-methyl-3-methyl nitrobenzoate and 1-methyl-1,2,4-triazole.And Then the compound 2a were synthesized by the nucleophilic addition and lactone ring-opening.Next the seven novel BMN-673 analogues were produced by aldol condensation and cyclization of the keto-ester compounds with aldehydes R₂=benzofuran-5-yl,indole-5-yl,4-methoxybenzo[d][1,3]dioxole-6-yl,pyridine-3-yl,phenyl,4-cyanophenyl,3-bromophenyl?R₂CHO?.The overall yields of the analogues range from 47.1%to 52.6%,and the molecular structures of the synthesized compounds are confirmed by ¹H nuclear magnetic resonance spectroscopy and mass spectrometry.The condition of nucleophilic addition is optimized and the result shows that the reaction time from 10 h reduced to 4 h and the yield is up to 90%with 1,4-dioxane as solvent.Currently,these BMN-673analogues are undergoing bioactivity testing.