Study Of Synthetic Process Of Eluxadoline

Irritable bowel syndrome?IBS?is a common gastrointestinal functional disease.According to statistics,the incidence of IBS is between 5%and 21%worldwide.In China,the incidence of IBS is about 5%to 7%.Among them,15%of young and middle-aged people are more likely to have IBS.The incidence of IBS is higher in women than in men.The highest incidence of IBS is 1:2 in men and women.IBS not only afflicts patients'health,but also affects their work and life,reduces people's quality of life and happiness,and occupies a large number of medical resources,which has a negative impact on the whole society.In recent years,the importance and research efforts of IBS have been strengthened at home and abroad.There are more and more epidemiological surveys on IBS in different countries and regions.Although the results are different,the incidence of IBS generally shows a growing trend.The global IBS market will maintain rapid growth.Therefore,it is necessary to develop new therapies and drugs.At present,the competition of IBS drugs is weak,and the new drugs developed will have broad market prospects.Eluxadoline is the first oral effective,topical treatment of IBS drug,with a unique mechanism,can effectively alleviate diarrhea irritable bowel syndrome?IBS-D?patients with abdominal pain and diarrhea symptoms,and absorption is very small,not easy to produce drug accumulation,fewer adverse reactions,and will not appear constipation side effects.Clinical trials have confirmed that this drug has a definite effect.Compared with placebo,it can make more patients with diarrhea-predominant irritable bowel syndrome get clinical effective response and improve the abdominal pain and fecal hardness comprehensively.In this paper,firstly,the synthetic route of Eluxadoline was designed on the basis of literature,through the laboratory synthesis research,the technological route was opened up,the reaction conditions and process of the key steps were optimized,and the complex purification methods such as column chromatography were not used after the separation and purification of several steps were explored.Finally,a process route for industrial production was obtained.4-amino-3,5-dimethylbenzonitrile?2?was synthesized from 4-bromo-2,6-dimethy-laniline starting material and cuprous cyanide by cyanide substitution reaction.Compound?2?was then diazotized with sodium nitrite and concentrated hydrochloric acid to produce4-iodine-3,5-dimethylbenzonitrile?3?by potassium iodide substitution.Compound?3?was coupled with N-tert-butoxycarbonyl-3-iodine-L-alanine methyl ester to produce(?S?-2-??tert-butoxycarbonyl?amino?-3-?4-cyano-2,6-dimethylphenyl?methyl propionate?6?by Negishi reaction in the presence of tri?o-methylphenyl?phosphorus ligand and catalyst tri?dibenzylidene acetone?palladium?Pd₂?dba?₃?.Compound?6?was hydrolyzed twice to form?S?-2-tert-butoxycarbonyl amino-3-?4-carbamyl-2,6-dimethylphenyl?propionic acid?8?,compound?8?and 2-methoxy-5-[?1S?-1-?5-phenyl-1H-imidazole-2-yl?ethyl]amino]benzoate?9?were joined by condensation agent HATU under alkaline conditions to obtain compound?10?and then hydrolyzed by LiOH.and HCl deprotection Boc finally obtained the target product Eluxadoline two hydrochloride?1?.The chemical structure of its interm-ediates and Eluxadoline product was confirmed by 1H-NMR and MS.The purity of the crude product was 98.7%and the total yield was 28.3%.The reagents used in this synthetic route are cheap and easy to obtain,the reaction process and operation are simple,the yield of the target product is high,each step of the reaction is easy to control,and less"Three Wastes"in Production and Discharge,which is suitable for industrial production.