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Synthesis Study On Antipsychotic Drug Quetiapine Hemifumarate And Its Key Intermediates

Posted on:2010-08-06Degree:MasterType:Thesis
Country:ChinaCandidate:Y PanFull Text:PDF
GTID:2121360275974612Subject:Analytical Chemistry
Abstract/Summary:PDF Full Text Request
Quetiapine hemifumarate, commercially named Seroquel, chemically called 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy] ethanol hemifumarate, developed by Zeneca in Britain, which first came into the American market in 1996. And it's the fourth atypical antipsychotic agent following clozapine, risperidone and olanzapine. Quetiapine hemifumarate was strongly efficacious to schizophrenia with lower incidence of extrapyramidal syndroms(EPS), because it has affinities for several neurotransmitter receptors such as D2 receptor and 5-HT receptor. It's one of the first-line drugs for the treatment of schizophrenia in Clinical.The synthetic routes based on references were developed in the thesis. The key intermediate parent nucleus and side-chain compounds were synthesized first, then quetiapine hemifumarate was synthesized with those two key intermediates. In order to improve the yield of quetiapine hemifumarate, lower raw material costs, a great number of experiments have been carried out. First of all, three synthetic routes had been studied for parent nucleus compound. In the first route, the parent nucleus compound was synthesized from 2-amino diphenylsulfide in the process of condensation with phenyl chloroformate, then cyclized in the presence of polyphosphoric acid, with 89.4% yield under optimized reaction conditional. In the second route, the parent nucleus compound with 87.7% overall yield was synthesized from 2-amino diphenylsulfide and triphosgene to give 2-isocyanato diphenylsulfide, which subjected to cyclization in the presence of polyphosphoric acid. In the third route, the parent nucleus compound was synthesized using thiosalicylic acid and o-fluro-nitrobenzene as starting materials, 2-amino-2'-carboxyl diphenylsulfide was synthesized in aqueous phase, which was reduced by ferrous sulfate and cyclized in the medium of sulfuric acid resulting in yield of 78.1%. After investigation of those three synthetic routes, we confirmed the first route was preference. Secondly, side-chain compounds were studied. The method of condensation with 2-(2-Chloroethoxy) ethanol and piperazine hydrochloride was investigated according to references, but the results were not satisfactory. Therefore, a new procedure for the synthesis of side-chain compound was designed by using diethylene glycol as starting material. monosubstituted sulfonate was prepared from diethylene glycol and sulfonating agent, which condensed with anhydrous piperazine to give side-chain compound, the final product with as high as 72.1% yield was obtained from this procedure. Finally, the quetiapine hemifumarate was produced from parent nucleus compound in the process of chlorination with phosphorus oxychloride, then condensed with side-chain compound, and salt formed with fumaric acid in methanol. The overall yield was 65.9% which was higher than the yield of reported in references.Quetiapine hemifumarate, parent nucleus and side-chain compounds synthesized also were confirmed by IR and 1HNMR in the thesis. The route that we reported possesses some merits,such as reaction conditions are all mild, the post treatments are simple, and it is suitable to plant-scale production.
Keywords/Search Tags:Antipsychotic Drug, Quetiapine Hemifumarate, Synthesis
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