Study On The Synthesis Methods Of Clobazam And Its Related Material

Epilepsy is a chronic neurological disease with recurrent,transient,narcolepsy and stereotyped characteristics,brain neurons sudden abnormal discharge of its causes,resulting in transient cerebral dysfunction and very harmful to human health and mental health.The incidence of epilepsy is about1%and 3%of them have a cumulative risk for more than 80 years.Epilepsy is characterized by repeated episodes of long-term,approximately 45%of patients will relapse.Curing epilepsy and improving the quality of life of patients with epilepsy have been the direction of the research efforts of the medical profession.For now,the most widely used classification of epilepsy program is proposed by the International League Against Epilepsy(International League Against Epilepsy,ILAE)in 1981.Based on the symptoms of clinical performance and the characteristics of electroence-phalogram is divided into:generalized seizures,partial seizures and classification of unknown attack.Generalized seizures have six main types:tonic clonic,myoclonic,atonic seizures and absences.These symptoms are related to the loss of consciousness.Typically there is a period of sense recovery after a seizure,which time is generally 3-15 minutes and may last a few hours.The common symptoms include tiredness,headache,speech difficulties,and behavioral abnormalities.Pathogenesis of epilepsy is complex,mainly in three aspects.(1)Abnormal ion channels,which can regulate the nervous system excitability encoding a gene mutation can cause abnormal ion channel,thereby changing the distribution of the electrolyte membrane potential initiator exception,eventually leading to neuronal excited,cause seizures.(2)Abnormal synaptic transmission.Certain neurotransmitters(such as GABA),can inhibit seizures,and some neurotransmitters(such as glutamate)from seizures role in facilitating.GABA receptor binding can inhibit the excitability of the nervous system,decreased GABA levels or receptor abnormalities can cause seizures.The reduction of the levels of glutamate decarboxylase can lead to seizures.(3)Glial cells.Electrolyte balance inside the neurons of the nervous system will maintain normal membrane potential.But abnormal uptaking of potassium ions and other ions can cause electrolyte imbalance,causing seizures,while glial cells can also affect neurotransmitter levels.The reason of epilepsy is not very clear,based on current statistical research results,divided into two categories:congenital and acquired factors.Congenital factors,known as genetic factors,genetic defects can lead to abnormal ion channel structure,causing dysfunction of ion channels,causing epilepsy,as well as congenital abnormalities,neurological abnormalities and other factors are causing seizures.Acquired factors include head trauma,tumors,stroke,nervous system and other internal infection,which can become the reason of inducing seizures.Clobazam,7-chloro-1-methyl-5-phenyl-1,5-Benzodiazepine-2,4(3H)-dio-ne,developed by lundbeck.Its brand name is Onfi,which listed in the United States on October 21,2011,mainly used for treatment of anxiety disorders and intractable epilepsy.The effect of epilepsy complex seizures following systemic onset and Lennox-Gaslaut is better.Objective:The aim is to establish the synthesis methods of Clobazam and its related substances,to optimize the synthetic technologies and to establish the analytic methods.Methods:Using 5-chloro-2-nitro-N-phenylaniline(2)as starting mat-erials,5-chloro-N-phenylbenzene-1,2-diamine(3)was synthesized by the reduction reaction of 5-chloro-2-nitro-N-phenylaniline(2)with hydrogen.The cyclization reaction of intermediate 3 with malonyl chloride gave 8-chloro-1-phenyl-1,5-Benzodiazepine-2,4(1H,3H)-dione(4).The alkylation reaction of intermediate 4 with iodomethane gave 7-chloro-1-methyl-5-p-henyl-1,5-Benzodiazepine-2,4(3H)-dione(1).Changing the feeding amount,the alkylation reaction of intermediate 4 with iodomethane gave 7-chlo-ro-1,3-dimethyl-5-phenyl-1,5-Benzodiazepine-2,4(3H)-dione(5)and 7-chlo-ro-1,3,3-trimethyl-5-phenyl-1,5-Benzodiazepine-2,4-dione(6).Using N-phe-nylbenzene-1,2-diamine(7)as starting materials,1-phenyl-1,5-Benzodiaze-pine-2,4(3H,5H)-d-ione(8)was synthesized by the cyclization reaction of N-phenylbenzene-1,2-diamine(7)and malonyl chloride.The alkylation reaction of intermediate 8 with iodomethane gave 1,3-dimethyl-5-phenyl-1,5-Benzodiazepine-2,4(3H)-dione(9)and 1,3,3-trimethyl-5-phenyl-1,5-B-enzodiazepine-2,4(3H)-dione(10).The structure of intermediates,target products and its related substance were confirmed by melting point,ma-ss spectrum and nuclear magnetic.High performance liquid chromatogra-mphy(HPLC)method was used for the chemical purity of each interm-ediate,the target and its related substance.Results:Clobazam was synthesized successfully,and was confirmed by MS-ESI(m/z)and ~1H-NMR.The chemical purity of intermediates,the target and its related substance was preliminarily determinated by HPLC method.Moreover,some of the synthetic technologies were optimized.Clobazam:white solid,mp.168.5~169.7℃.Conclusion:In this research,using 5-chloro-2-nitro-N-phenylaniline(2)as the starting material,the target product Clobazam was obtained by 3 steps.Some of the synthetic technologies were optimized.The operations of the process were simple,and the generation cycle was short,and the reaction conditions were mild.