Synthesis Process Optimization And Quality Research Of Tofacitinib Citrate

Rheumatoid arthritis(RA)is a chronic systemic immune disease mediated by chronic inflammation of joint synovial,rheumatoid factor and the abnormal expression of citrulline peptide antibody.Its clinical symptoms are mainly characterized by synovial hyperplasia,pannus formation,cartilage loss and joint destruction,etc.These symptoms will eventually lead to systemic complications,affect the normal function of the multiple organ,seriously affecting the patient’s quality of life and health of body and mind.At present,there are many treatments for RA,including non-steroidal anti-inflammatory drugs(NSAIDs),glucocorticoids(GCs),slow acting anti-rheumatic drugs(SAARDs),biological drugs and small molecule kinase inhibitors.Tofacitinib citrate is the first small-molecule JAK inhibitor approved for use in human autoimmune diseases.In 2012,FDA first approved 5mg twice daily for adults with moderate to severe active rheumatoid arthritis who did not respond to or tolerate methotrexate.In 2017,EMA also approved the drug for RA treatment and followed up nearly 5,000 patients,and its long-term safety and efficacy data were further confirmed.At present,no domestic enterprises can produce the drug,and there is no quality standard for the API.In this paper,we finished the optimization of the synthesis process of Tofacitinib citrate and the quality research of API to provide the basis for the establishment of quality standardsIn this process,Tofacitinib citrate was synthesized from(3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine dihydrochloride(TF-1)and 4-chloro-7-toluene sulfonyl-7h-pyrrole[2,3-d]pyrimidine(TF-2),through coupling,deprotection,amide condensation,salt formation and re:fining.We controlled the reaction materials and established testing methods and carried out methodological verification.Then we further investigated and optimized the process parameters of each step to realize the synthesis process of Tofacitinib citrate without hydrogen.The whole process was time-consuming,safe and simple,and the yield reached 28%.The structure of product was confirmed by MS,1H-NMR and 13C-NMR.We analysis the impurity spectrurm according to the process route of Tofacitinib citrate.And in quality research section,we established the HPLC analytical method of Tofacitinib citrate by method validation,including isomers,related substances and content determination.And we established the GC analytical method of residual solvents for final product by method validation.The results show that the analytical method is suitable for the determination of isomers,related substances,content and residual solvents.The influence factor test showed that Tofacitinib citrate was stable for 10 days under the conditions of high temperature(60℃)and high humidity(25 ℃,90%±5%RH).Under the condition of light(45001x±5001x)for 10 days,the properties and related substances were stable but the content changed.The quality research of three consecutive batches of Tofacitinib citrate samples was carried out by determining their specific optical rotation,loss on drying,related substances,isomers,residual solvents,content,etc.The results showed that the three batches of samples were all qualified,which also verified the stability of the process.