Synthetic Technology Development Of Calcium Dobesilate And Direct N-Glycosylation Of D-galactal By Pd-catalysis

Calcium dobesilate was firstly developed and listed by Galenica AG company in Switzerland,which is widely used for the treatment of diabetic nephropathy,chronic interstitial nephritis,microvascular disease and varicose syndrome.The sulfonation of hydroquinone technology is widely used for the industural preparation of calcium dobesilate in our country.However,there are always accompanied by many side reactions,large amount of waste water and low yield.An improved sulfonating technology for the synthesis of calcium dobesilate was reported in this work.Firstly,the optimal reaction conditions were obtained by orthogonal screening experiments:1 equivalent of hydroquinone reacts with 2.5 equivalent of sulfuric acid at the temperature range of 60-65℃ for 2 hours.The best solvent system for recrystallization of crude the calcium dobesilate was found to be ethanol and n-hexane(1:1.6,V/V),and our products could meet the requirement of Chinese Pharmacopoeia with the purity of 99.92%by HPLC.The possible impurity in this technology was obtained by direction synthesis,which was characterized as calcium 2,5-dihydroxybenzene-1,4-disulfonate by NMR,HRMS and comparative HPLC analysis.The synthetic route of this project was as follows:#12N-Glycoside exists broadly in nature and clinical drugs.The most well-known N-glycosides arguably are nucleotides.The stereose-lective N-glycosylation is still highly challenging.In this paper,two kinds of catalytic methods for the synthesis of single configuration β-glycoside from 3,4-O-carbonate D-galactal were reported.Glycosyl donor was synthesized by galactose through six steps of nucleophilic substitution,elimination and hydroxyl protection,and then it was stereoselective coupling with nucleophilic reagent containing nitrogen to obtain β-glycoside.The strategy could tolerate various amines/amides with high yields and exclusive regioselectivity and diastereoselectivity.#12It was worth noting that the preliminary evaluation of biological activity showed that the target compounds(3a、3e、3j、3k、5i)can significantly inhibit the proliferation of liver cancer cells(27.8μM<IC50<45.1μM)and were safe for normal cells.The synthetic rout a of this project and the structure of the active compound are as follows:(?)...