The Synthesis Of 1, 3-dihydro-2H-indol-2-one And It' Analogues

Schizophrenia is a serious form of mental illness resulting in human health. Now there are approximately 1% persons among the total population of the world who are suffering from schizophrenia, most of them are 15-45 years old. Schizophrenia is to have the positive symptoms with hallucination, delusion, the disturbance in thinking, behavior and negative symptoms with indifference in affection, poverty in thinking, DEC in volition.At present, the antipsychotic drug in clinical application educes therapeutical effect, simultaneously, genesising untoward reaction. For instance EPS, raise in mass, change in ECG(as prolongation in QTC), hypertension, hyperlipemia. All kinds of antipsychotic drugs' mechanisms of action are different, because their structures are different. The typical antipsychotic drugs for the representation of chlorpromazine act on central dopamine D₂ receptor, reduce the transmission in ocular region'dopamine. The therapeutic effect is true, but existing serious EPS. Nevertheless, atypical antipsychotics for the representation of clozapine produce a marked effect by antagonisming 5-HT, NE receptor and adjusting glutamic acid receptor.In 1990's, ziprasidone and aripiprazole were developed. Ziprasidone is a 5-HT and dopamine-receptor antagonist, especially 5-HT_2A and D₂ receptor. It's peroral dosage form and dosage form of intramuscular injection go on the market in 1998 and 2000 in Sweden. Compared with typical antipsychotic drugs, ziprasidone is efficacious to positive and negative symptoms, elevate cognition, induce EPS, elevate toleration conspicuously; Compared with olanzapine, quetiapine, risperidone, is better in negative symptoms or suitable, not to cause weight gain and prolactin heighten. Aripiprazole treated in Schizophrenia through FDA'permission in 2002. Aripiprazole possesses high affinity with D₂, D₃, 5-HT_1A and 5-HT_2a receptor, moderate affinity with D₄, 5-HT_2c, 5-HT₇, a₁, H₁ and 5-HT reabsorb site. Aripiprazole produces a marked antipsychotic effect by partly agitating D₂ and 5-HT_1A as well as antagonisming 5-HT_2A. clinical test III data means therapeutic effect is as well as little dependency, good tolerance. Aripiprazole is efficacious to positive and negative symptoms, insensibly change in body weight, seldom take EPS and sedative. Otherwise QTc interval prolongation is similar to placebo.Indoles and their analogues are among of paying people'attention to heterocyclic compound because of their molecular diversity and wide biological activity in large quantity of natural products and synthesis drugs. Pharmacological activities and chemical synthesis of indoles and their analogues attract technology worker'attention all through. Object: To synthesize indole-2-one and its analogues from 6-chloro-5-(2-chloroethyl)-2-oxindole based on twin drug theory.Methods: the synthesis reaction refers to three important intermediate. First, 6-chloro-5-(2-chloroethyl)-2-oxindole was synthesized through eight steps from 1,2,4-trichlorobenzene. Then, 1-(3-Nitrophenyl)piperazine was prepaired by the reaction of 3-nitroaniline and bis(2-chloroethyl)aminehydrochloride. Third,5-[2-[4-( 1,2-dichlorobenzene-3-yl)-1 -piperazinyl)ethyl)-6 -chloro-1,3-dihydro-2H-indol-2-one was obtained by the condensation of the 6-chloro-5-(2-chloroethyl)-2-oxindole with 1-(2,3-Dichlorophenyl)piperazine.Finally,5-[2-[4-(3-Nitropheny 1)-1 -piperazinyl] ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one prepared by the reaction of the 6-chloro-5-(2-chloroethyl)-2-oxindole with l-(3-Nitrophenyl)piperazine.Results: The synthesis was accomplished and the synthetic conditions were optimized. The intermediate 6-chloro-5-(2-chloroethyl)-2-oxindole was synthesized and the yield was 84.0% .The melting point of it was found in the range of 204.2-205.7℃. The structure was confirmed by ¹H-NMR. 1-(3-Nitrophenyl)piperazine was synthesized and the yield was 64.8%, The melting point of it was found in the range of 224.0-226.0℃. The compound 5-[2-[4-(3-Nitrophenyl)-1-pipe razinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one was synthe sized. mp:214.4-215.6℃. ¹H-NMR(d-DMSO, 500 MHz): 10.41(s, 1H, NH); 7.29-7.33 (m, 2H, 2ArH); 7.22 (s, 1H, ArH); 7.15 (dd, 1H, J₁=7.00 Hz, J₂=3.00 Hz, ArH); 6.80 (s, 1H, ArH); 3.46 (s, 2H, CH₂CO); 3.00 (br s, 4H, -NCH₂CH₂N-); 2.63 (br s, 4H, -NCH₂CH₂N-); 2.83(t, 2H, J=8.00 Hz, -CH₂CH₂N-); 2.53(t, 2H, J=8.00 Hz, -CH₂CH₂N-). The structure was confirmed by ¹H-NMR.Conclusion:1 The monomer 6-chloro-5-(2-chloroethyl)-2-oxindole was synthesized. We developed the individual steps in the synthetic route. Synthesis can be run smoothly and efficiently on a production scale. The starting materials were cheap and available.2 In the preparation of compound A, the material added in acetic acid containing of Raney nickel was hydrogenated at 45 psi for 3 h. But this method was difficult to operate. We tried the following reactions: first, the compound A was hydrogenized by the reaction of the 70% glacial acetic acid solution with pulvis aci. Second, compound A was hydrogenized by the reaction of the hydrochloric acid with stannous chloride. Finnally, compound B was prepared by the reaction of the harrow with carbo.3 1-(3-Nitrophenyl) piperazine was synthesised by the condensation of the bis(2-chloroethyl) aminehydrochloride.4 We successfully synthesized the new compound 5-[2-[4-(1, 2-dichlorobenzene-3 -y 1)-1 -piperaziny l)ethy l)-6-chloro-1,3 -di hydro-2H-indol-2-one by the condensation of the 6-chloro-5-(2-chloroethyl)-2-oxindole with l-(2,3-Dichloro- phenyl)piperazine.The structure of the compound was confirmed by ¹H-NMR.