| Daclatasvir dihydrochloride which is developed by Bristol-Myers Squibb Company is a group of highly selective hepatitis C virus (HCV) NS5A inhibitor.It is not only a small molecule drugs with direct antiviral effect but also a first HCV NS5A replication complex inhibitor for clinical trial. In the phase II clinical trial of Daclatasvir dihydrochloride, it can found that when this small molecule drug combination with pegylated interferon-a and ribavirin were used to treat the refractory genes I type chronic hepatitis C patients, its sustained virological response rate was92%after discontinuation of12weeks. Daclatasvir dihydrochloride is currently being evaluated in further phase III clinical trials. Therefore, study on the synthesis of Imidapril is of great importance.This paper describes the status of hepatitis C and significance of synthesizing Daclatasvir dihydrochloride. Advantages and disadvantages of its synthetic routes were summarized and the optimal synthetic method was screened out. The compound1was obtained via Friedel-Crafts acylation reaction of biphenyl and bromoacetyl bromide which was catalyzed by AlC13. The compound1reaction with Boc-L-proline and catalyzed by acid tied triethylamine to give compound2, and then with ammonium acetate to give compound3via cyclization reaction,followed by acidic conditions to deprotection to form compound4. In the presence of triethylamine, DCC and HBOt, through a nucleophilic substitution reaction of compound4and N-methoxycarbonyl-L-valine (compound5), the final product (compound6) was obtained. Compound5was composed of L-valine methyl chloroformate and sodium carbonate via a nucleophilic substitution reaction under basic conditions.Influences of temperature, reaction time and material ratio were investigated, and best conditions were screened out. Product was characterized by1H nuclear magnetic resonance (HNMR), mass (MS), infrared spectroscopy (IR). Results showed that the synthesis rout was feasible. |
PDF Full Text Request