The Research On New Synthetic Process Of Crisaborole And The Synthesis Of Nilotinib

Based on the high selectivity,low toxicity and other excellent characteristics of small molecule inhibitors,it has important theoretical and practical research significance in drug production in recent decades.It has always been a low-cost,high-yield,green and environmentally friendly synthesis method.The goal pursued by production.In this paper,two small molecule inhibitors of crisaborole and nilotinib were studied,and the synthesis process was optimized and improved.New ideas and design schemes were studied to find a better synthetic route.The research content of the thesis is divided into two parts.The first part is to design the target molecule crisaborole by 5-step reaction using 2-bromo-5-hydroxybenzaldehyde as the raw material through literature and patent research.The final product was characterized and the low yield unit reaction was optimized and screened.Compared with the process conditions of the research literature,the total yield of crisaborole was improved by about 6%after optimization.The method of synthesizing aryl borate has also been studied and analyzed,and two new routes using 2-amino-5-fluorobenzoic acid and 4-fluoro-2-methylaniline as raw materials have been redesigned.The raw materials used in the new route are more It is cheap and easy to obtain,and the synthesis step is shortened.The new method is to obtain an aryl boronate by the SN2Ar route from sodium nitrite and hydrochloric acid as a diazotizing agent under the promotion of a protic solvent by using an arylamine.Compared with the Suzuki-Miyaura coupling reaction,the base reagent and the lithium material and the palladium catalyst not only avoid the use of the transition metal palladium and lithium,but also the reaction conditions are milder,environmentally friendly and energy-saving,and more suitable for industrial regulations.The total yield after improvement and optimization has also increased by 11%and 9%respectively.The second part was designed with 3-acetylpyridine,4-methylbenzoic acid and 3-bromo-5-(trifluoromethyl)aniline.As a raw material,the target product nilotinib was synth-esized by a 8-step reaction,and the process of key intermediates was explored,optimized and improved.Compared with the process conditions of the research literature,the total yield of nilotinib was optimized.The rate is increased by about 1.6%.In addition,the pyrimidine ring synthesis and copper-catalyzed carbon-nitrog-en coupling method in the key intermediate N7 are studied and analyzed.After the improvement,the urea synthesis of the pyrimidine ring and the nucleophil-ic substitution by acid catalysis to obtain the secondary amine can effectively reduce the reaction temperature and time,save energy utilization,and the total yield is also improved by 6.5%,and the post-treatment method is simplified and more efficient safety.By exploring the synthesis process of two small molecule inhibitor drugs,not only the total synthesis yield of crisaborole and nilotinib is improved,but also a new,more gentle,low-cost,green environment has been redesigned.The new route provides important theoretical significance and practical application value for the technological transformation and scale-up of the enterprise.