Study On Synthesis Process Of Glycoside Drugs Capecitabine And Sotagliflozin

Capecitabine is a nucleoside antitumor drug developed by Roche,which is mainly used for the treatment of colorectal cancer.It has a broad anti-tumor and is also effective in the treatment of gastric cancer and breast cancer.Sotagliflozin is a dual SGLT 1/2 inhibitor developed by Lexicon/Sanofi,and was approved by the European Union in April 2019 for the adjuvant insulin therapy of type 1 diabetes.Also,clinical studies have proved its therapeutic effect on cardiovascular.In this work,the synthesis processes of Capecitabine and Sotagliflozin are studied,and the process improvement is achieved through reaction conditions screening,which provides a practical guidance for the development and industrialization of these 2 API projects.The following are the main research contents.1.Study on the Synthesis of Capecitabine1,2,3-Tri-O-acetyl-5-deoxy-D-furanribose(6)was obtained by protection,sulfonic esterification,reduction,hydrolysis and acetyl protection with D-ribose(2)as the starting material.Capecitabine(1)was obtained by glycosylation,amidation,and deprotection.The overall yield was 23.2%and the purity was 99.94%.The main research results are listed as follows:i.Intermediate methane sulfonate 4 was replaced with benzene sulfonate 10,which was obtained by using a new acid binding agent 1,4-diazabicyclo[2.2.2]octane(DABCO),and the yield and purity was 87.7%and 98.02%of compound 10 respectively after recrystallized in absolute ethanol;ii.Optimize the silyl reaction conditions and greatly shorten the reaction time.Using new Lewis’s acid trimethylsilyl trifluoromethanesulfonate(TMSOTf),the yield was increased to 81%(from 7),and confirmed that it was recrystallized with isopropanol,and the purity was 100%;iii.The forced degradation study of capecitabine was conducted,and 7 specific impurities listed in the European Pharmacopoeia were designed and synthesized,and a total of 12 different types of related substances were obtained.The purities of the degradation products were all greater than 95%,and the purity of the impurities were higher than 98%.2.Study on the Synthesis of Sotagliflozin((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro-[2,3-d][1,3]dioxol-5yl)(morpholino)methanone(22)was obtained by protection,selective hydrolysis,oxidation of the primary alcohol,crystallization with morpholine,and amidation with L-xylose(40)as the starting material.22 is coupled with aryl iodide 26 to obtain ketone 50.Sotagliflozin(21)was finally obtained by carbonyl reduction,ring expansion,protection,thiolation,and deprotection.The total yield of the key intermediate morpholine amide 22 was 44%,and the purity was 100%;the total yield of sotagliflozin was 50%,and the purity was 99.92%.The main research results are as follows:i.Using phosphoric acid/water(pH 2)as the selective hydrolysis system of 41,and improved the extraction efficiency by salting out effect;ii.31%sodium chlorite/2%sodium hypochlorite was used for the primary alcohol oxidation,the solvent was quantitatively 3 times the volume,and the buffer was quantitatively 6 times the volume,and overcame the problems that the compound was difficult to extract due to its good water solubility;iii.When preparing 22,the reaction solution was concentrated after filtration and solidified with n-heptane,the purity was 100%,and the yield was 85%;iv.Replace the aryl iodide 27 with the aryl bromide 26,and confirm that isopropyl magnesium chloride is used as the coupling reagent.The work-up method is simplified,pulping with petroleum ether,then recrystallization with mixed solvent,the purity was 100%,and the yield was 82%;v.In the process of thiolation of tetraacetate 53,the Lewis’s acid was changed from BF3·Et2O to TMSOTf(1.5 eq),the solvent was changed to 1,2-dichloroethane,and DIPEA was added after methyl iodide,the yield was 91.3%;vi.The deprotection of 35 was changed to use ammonia water in methanol,avoiding the use of sodium methoxide,and the conditions were milder.After optimization,capecitabine and sotagliflozin have undergone three batches of verification experiments.The process parameters are stable,the operation is simple,the raw materials are relatively cheap and easy to obtain,the yields of each reaction are stable,and the product with high purity,which suits the quality requirements,and have the potential of industrial production.