The Synthesis Of Antipsychotic Drug--Aripiprazole

Schizophrenia is a kind of mental illness. It is characterizedby positive, negative and cognitive symptoms. Positivesymptoms include hallucinations, delusions, disorganizedthought and behavior. Negative symptoms include depressionand withdrawing the society relationships. Schizophrenia hasbrought great pains to the patients. Now, there areapproximately 1% persons in the world who are suffering fromschizophrenia, most of them are 15-45 years old. In 1952, thediscovery of chlorpromazine started the modern treatment ofschizophrenia, soon after that many new antipsychotic drugssuch as haloperidol, trifluoperazine and loxapine emerged, theywere called as typical antipsychotic drugs. Their mechanism ofaction was to block the dopamine D2 receptor in limbic systemand striatum. Blocking the dopamine D2 receptor in limbicsystem was the base of antipsychotic action, but when thedopamine D2 receptor in striatum was blocked, adverse effectssuch as Extrapyramidal side effects (EPS), hyperprolactinemiaand weight gain were caused, patients'negative and cognitivesymptoms could not release. Evidence suggested that thisgeneration of agents had no efficacy to 15-30% patients.In 1970's clozapine was discovered. It was stronglyefficacious to schizophrenia and with lower incidence of EPS,because it had affinity for several receptors it was called asatypical antipsychotic drug. In the past decade many new drugsin the class such as risperidone, olanzapine, and ziprasidoneemerged. This generation of drugs could select to work inlimbic system but not basal ganglia, so they were moreefficacious and carried lower incidence of EPS, and they weremore selective to serotonine 5-HT receptors which couldrelease the negative symptoms. However, more and moreevidence suggested that this generation of drugs might beassociated with significant weight gain, DM, hyperlipidemiaand QTc prolongation. According to the statistics, there were50% patients who were suffering from weight gain.In 2002, a new antipsychotic drug----aripiprazole (OPC-14597) came into the market in America, which was discoveredby Bristol-Mayer Squibb Company and Otsuka Company. Itwas described as "the 3rd generation of antipsychotic drug"and "dopamine system stabilizer"for it's unique mechanismsof action. Aripiprazole was a partial agonist at dopamine D2and serotonine 5-HT_1A receptors, and also an antagonist at theserotonine 5-HT_2A receptor. A lot of trials confirmed thataripiprazole was obviously efficacious to positive, negativesymptoms, acute exacerbations of schizophrenia andschizoaffective disorder. Compared with other drugs,aripiprazole was safer and had lower propensity for adverseeffects. So the discovery of aripiprazole will have significantimpression on the treatment of schizophrenia and theimprovement in people's life.Objective: To synthesize the antipsychotic drug---aripip-razole, optimize the synthetic conditions, explore other sy-nthetic routes.Methods: The target compound 1 was obtained via sixsteps. First, 3-aminophenol reacted with 3-chloropropionyl-chloride to form 3-chloro-N-(3-hydroxyphenyl)-propionami-de(2), which was cyclized into 7-hydroxy-3,4-dihydro-2(1H)-quinolinone(3) in the presence of AlCl3 under solvent-freeconditions. Then, 3 was treated with 1,4-dibromobutane togive 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone(4). N,N-dibromethylamine(5) was synthesized from diethanolami-ne, which was easily converted into 1-(2,3-dichlorophenyl)piperazine(6) by the reaction with 2,3-dichlorophenylamine.Finally, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone(1) was obtained by the conde-nsation of 4 and 6.Results: The synthesis was accomplished and the synth-etic conditions was optimized. Another route to synthesize1 was explored. IR,1H-NMR,13C-NMR,DEPT-NMR a-nd MS-FAB spectral data were found to be fully consiste-nt with reference. IR (KBr) ν(cm-1): 3401(NH);3191,3104,3052(Ar); 1676(C=O); 1173(C-N=); 1047(C-O). H-NMR 1(CDCl3)(δ, ppm) 1.676-1.736(2H, m, c-H),1.795-1.851(2H, m, b-H),2.485 (2H, t, d-H), 2.600-2.630(2H, m, 4-H),...