Study On The Synthesis Technology Of Lurasidone Hydrochloride

Schizophrenia is a severe mental disease with high recurrence rate and high disability rate.Its symptoms mainly include positive symptoms such as hallucinations,auditory hallucinations,and paranoia,and negative symptoms such as hypovolemia,uncoordinated emotional responses,social fear,and cognitive dysfunction.The cause of the disease is not clear,which seriously affects the work and life of patients.At present,antipsychotic drugs are still the first choice for the treatment of schizophrenia.In 1993,Japan Sumitomo Pharmaceutical Co.,Ltd.first synthesized the second generation of non-classical antipsychotic drug lulasidone hydrochloride.In 2010,it was approved by the US Food and Drug Administration（FDA）for the treatment of schizophrenia in the United States.In 2013,it was approved for the treatment of bipolarⅠdisorder.In 2019,lurasidone hydrochloride was launched in China with the approval of the National Medical Products Administration（NMPA）.Lulasidone hydrochloride can be used in the treatment of schizophrenia patients of different ages and genders,and extrapyramidal side effects are rare,and the drug is safer.The drug is one of the most advantageous drugs in the second generation antipsychotic drugs currently on the market,and has broad market prospects.In this paper,the existing synthesis routes and refining methods of lurasidone hydrochloride were comprehensively analyzed,and the synthesis route was reasonably designed.The optical raw material（1R,2R）-cyclohexane dimethanol was used as the starting material for synthesis.After three nucleophilic substitution reactions,the crude product of lurasidone was obtained,and then the antipsychotic drug lurasidone hydrochloride was finally synthesized by refining into salt.After that,we carefully screened and optimized the reaction conditions of each reaction step in the experiment.On the basis of reducing the cost of raw materials,we simplified the post-processing operation of products and made them more suitable for industrial production.Based on the preliminary synthesis experiment of lurasidone hydrochloride intermediateⅠ,the reaction solvent,feeding molar ratio,reaction temperature,reaction time,crystallization temperature,refining method and baking temperature used in the process development of lurasidone hydrochloride intermediateⅠwere carefully screened,and the optimal reaction conditions for the synthesis of lurasidone hydrochloride intermediateⅠwere obtained.Based on the preliminary synthesis experiment of lurasidone hydrochloride intermediateⅡ,the acid binder,reaction solvent,reaction temperature,feeding molar ratio,refining method and crystallization temperature used in the process development were carefully screened,and the optimal reaction conditions for the synthesis of lurasidone hydrochloride intermediateⅡwere obtained.Based on the preliminary synthesis experiment of lurasidone crude product,the amount of acid binder,reaction time,feeding molar ratio and refining method used in the process of development were carefully screened,and the optimal reaction conditions for the synthesis of lurasidone crude product were obtained.Based on the preliminary synthesis experiment of lurasidone hydrochloride product,the reaction solvent,hydrochloric acid diluent,hydrochloric acid concentration,hydrochloric acid dosage,hydrochloric acid drop temperature and baking temperature used in the process of its development were carefully screened,and the optimal reaction conditions for the synthesis of lurasidone hydrochloride product were obtained.After that,we conducted different levels of scale-up versatility experiments under optimal conditions as well as three batches of stable experiments to verify the stability of the obtained conditions.In the process of optimizing the synthesis process of key intermediates and finished products,we innovatively used a simpler refining method,which effectively controlled the purity of the resulting products and the largest single impurity.The optimized production process is more mature than traditional processes such as one-pot synthesis and racemic chiral separation.The total yield of the finished product of lurasidone hydrochloride can reach up to 73.20%,the purity of the finished product can reach more than 99.99%,and the yield and impurities are stable,and the maximum single impurity is less than 0.01%.The impurity limit,solvent residue,moisture and other testing items of the finished product are in line with the drug COA standard.We confirmed the structure of the finished product and intermediates by ¹H NMR,¹³C NMR,HRMS,HPLC,X-ray and other characterization methods.