Dissertation > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug

Synthesis of Alosetron Hydrochloride

Author LiWei
Tutor XiaZhiNing;HaoGuangFu
School Chongqing University
Course Pharmaceutical Engineering
Keywords Irritable bowel syndrome (IBS) Alosetron hyd
Type Master's thesis
Year 2007
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Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterised by abdominal pain (bloating,abdominal distension,sensation of incomplete evacuation) and diarrhea,constipation,or alternating diarrhea and constipation.At present the cause of IBS is unknown.Alosetron hydrochloride is a potent and highly selective serotonin 5-HT3 receptor antagonist which became the first agent approved by the United States Food and Drug Administration (FDA) for the treatment of non-constipated women with the irritable bowel syndrome(IBS).Alosetron hydrochloride,brand Lotronex,made by GlaxoWellcome company in English,which first came into the American market in march 2000.The chemical name of alosetron hydrochloride is 2,3,4,5-tetrahydro-5-methyl-1H-2[-(5-methyl-1H-imidazole-4-yl) methyl]-1H-pyrido[4,3-b] indol-1-one hydrochloride.This paper is a study about the synthesis of alosetron hydrochloride and refer to relevant synthesis documents before improving the preparation process of alosetron hydrochloride on a large scale production.Alosetron hydrochloride was synthesized from 2,4-dioxopiperidine in the process of condensation with N-methyl -2- phenylhydrazine , then cyclization in sulfuric acid ,and condensation with 4-hydroxymethyl-5-methy imidazole hydrochloride ,and salt formatiom with hydrochloric acid. The total yield is approximate 40.7% which is higher than the total yield of the reported process.In order to improve the yield of alosetron hydrochloride,lower raw material costs,a great quantity synthesis experiments have been carried out,the mechanism and optimization of every step have been discussed in this paper,In-process control requirements have been established.In the synthesis experiment process,makes the improvement to the intermediate post-processing,obtains the very good effect.Among them,N,N-dimethylformamide substitutes ethanol for intermediate 2,3,4,5-tetahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one recrystallization,the purity of the intermediate has been improved by 10% .Ethyl acetate extracts aqueous layer recycling raw material 2,3,4,5-tetahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one that make the yield of alosetron hydrochloride increased 2%.Alosetron hydrochloride has been confirmed by element analysis,IR,UV,1HNMR,H-H COSY,13CNMR,C-H COSY,MS.Therefore ,The improved synthesis craft is safe,convenient and higher-yield,for synthesis of alosetron hydrochloride providing the new synthesis craft for reference.

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