Study On Separation And Amplification Of Synthesis And Purification Of Tofacitinib Citrate

Tofacitinib citrate is a novel janus kinase(JAK)inhibitor that is clinically useful for the treatment of rheumatoid arthritis and has the advantages of being orally available.This medicine can help the patients of moderate to serious active classes that are refractory to methotrexate Rheumatoid arthritis get better treatment,reduce the pain and improve their life qualities.Therefore,the synthesis purification and scale-up production of this medicine are of great significance.In this thesis,according to the comparison and screeing of the synthesis routes of tofacitinib citrate reported in the references,the synthesis process suitable for the industrial production of tofacitinib citrate was established.The synthesis conditions were optimized and improved,and then the crude tofacitin citrate was prepared successfullu by the optimized process.The purification and separation of impurities were carried out and the final product was obtained.The scale-up process was also investigated.The contents and main results are summarized as following.1.After screening the reported synthesis routes of tofacitinib citrate,the synthesis process relatively suitable for industrial production was obtained.In this process,4-chloro-7h-pyrrolo[2,3-d]pyrimidine was employed as the starting material,and N-p-toluenesulfonyl protection reaction with p-toluenesulfonyl chloride under basic conditions was used.The resulting group protected product,followed by reaction with bis[(3R,4R)-1-benzyl-N,Piperidin-3-amine]-di-p-toluoyI-L-tartaric acid salt was subjected to a nucleophilic substitution reaction in an aqueous potassium carbonate solution,and the product was subjected to an amide hydrolysis reaction in a strongly alkaline aqueous solution to remove the p-toluenesulfonyl group.The resulting product was subjected to debenzylic protection reaction with hydrogen to give N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]Pyrimidin-4-amine,which was then reacted with cyanoacetic acid,oxalyl chloride or 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]Pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile,and finally salified with citric acid to obtain tofacitin citrate.2.The selected process was optimized,in which the substitution of(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride in the nucleophilic substitution reaction was used to replace the deliquescence-yellowing bis[(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine]-di-p-toluoyl-L-tartaric acid salt.Hydrogen source was replaced by hydrazine hydrate to reduce the risk of the reaction operation.In the amidation reaction,ethyl cyanoacetate was used to instead of cyanoacetic acid,which reduced the probability of impurities in the reaction.The optimal process parameters were obtained by the optimization and improvement of the reaction temperature in each step,the solvents,the reaction time as well as the post-processing techniques.3.The purification of the crude tofacitinib citrate was investigated and then the lab-scale test was carried out to prepare tofacitinib citrate.The crude product obtained had the appearance of gray-pink in color,and did not match the quality requirements after detected by HPLC.However,by the purification stragety using 20 times(volume ratio)of 50%ethanol in water(volume ratio),discoloring twice and recrystallization of the mixture,a white high-purity product with a liquid chromatographic purity of 99.82%and no more than 0.1%mono-miscellaneous,was obtained.4.The scale-up process based on the optimization and improvement of the whole lab-scale process was investigated.A number of anomalies occurred during the pilot-scale test.However,all the anomalies were eventually solved in time.Finally,the pilot scale was achieved successfully and the total revenue rate of 34.66%.The final product of tofacitinib citrate had impurities of not more than 0.1%each and the total purity of 99.93%was observed by HPLC,elemental analysis,infrared,mass spectrometry,nuclear magnetic resonance,differential thermal and thermogravimetric analysis.X-ray diffraction was used in the characterization and crystal form determination of the final product.