| Gout is a lens associated arthropathy caused by Monosodium urate（MSU）,which is directly related to hyperuricemia caused by the disturbance of purine metabolism and/or reduction of uric acid excretion.As the second major metabolic disease,gout is endangering human health.Topiroxostat,a new type of acid depressant was developed in Japan.The molecular structure of topiroxostat is obviously different with febuxostat.It is also a xanthine oxidase inhibitor.However,topiroxostat has a highly selective inhibitory effect.Topiroxostat has better curative effect and less side effects than allopurinol and febuxostat.At present,China has no import or production of topiroxostat and it’s preparations.Thus,it is more important to study the synthesis of topiroxostat.A new synthetic route is designed by referencing multiple documents.The target product topiroxostat was synthesized from isonicotinic acid.There are five steps reaction in this synthetic route which are hydrogen peroxide oxidation,methanol esterification,hydrazinolysis by hydrazine hydrate,reaction with 4-cyanopyridine and cyclization reaction,cyanidation of trimethylcyanosilane.But when we open up the experimental route,the reaction of reaction with 4-cyanopyridine and cyclization reaction can not reach it at one step.We combine theoretical analysis with experiments.And a series of comparative experiments were carried out.Finally,the reasons for the success or failure of the experiment were found.The different density of electron cloud caused by the different structure of the intermediate state of the reaction,and the different density of electron cloud lead to the failure of the cyclization reaction.After the reaction of addition reaction with 4-cyanopyridine,cyano group was introduced to reduce the electron cloud density of the electrophilic group,so that thecyclization reaction could proceed smoothly.Therefore,we have developed a new experimental route that has not been reported.The final experimental route:The target product topiroxostat was synthesized from isonicotinic acid which cheap and easily obtained.There are six steps reaction in this synthetic route which are hydrogen peroxide oxidation,methanol esterification,hydrazinolysis by hydrazine hydrate,reaction with 4-cyanopyridine,cyanidation of trimethylcyanosilane and cyclization reaction.The route has the following advantages:The starting materials and various reagents are cheap and easy to obtain.The experimental operation is simple and controllable,and there is no extreme reaction conditions.It is suitable for laboratory development and industrial production in the future.The higher total yield,the lower the cost of finished products.The purity of the finished product is guaranteed.Avoid conflicts with other patents so as to make the generic drug of topiroxostat to product smoothly.The synthetic process has also been optimized.For example,in the hydrogen peroxide oxidation step,the operation is simplified by simplifying the post-treatment method,and the process has stable repeatability.In the methanol esterification step,the yield of the reaction is greatly improved by optimizing the post-treatment method.The yield was increased from 47.3%to 91.7%.In this step,the use of solvent was reduced and greatly reducing the production cost.In order to reduce the production cost,reduce the production of pollutants,improve the purity and yield of the reaction.The amount of reagent and reactant was reduced as much as possible in the three steps of hydrazine hydrate,addition reaction with 4-cyanopyridine,cyanidation of trimethylcyanosilane.And the yield of the cyanidation was increased from 66%in the literature to 87.5%.In the step of cyclization reaction,using polyphosphoric acid as catalyst and the operation is safe.And a recrystallization method of finished product has been found out,which can steadily obtain topiroxostat with purity over 99.5%.The optimised synthetic route of topiroxostat contains such highlights:the total yield was 51.4%,experimental operation is simple and controllable,relative friendly process to the environment,extreme reaction conditions were avoided and it is suitable for research and development in the laboratory and industrial production in the future.The structure of the product was confirmed by MS and 1HNMR. |
