Synthesis Process Optimization Of Doravirine And Design,Synthesis And Biological Evaluation Of Its Derivatives

Acquired immune deficiency syndrome(AIDS)mainly caused by human immunodeficiency virus type-1(HIV-1),continues to be a major threat to worldwide human health.Reverse transcriptase(RT)is responsible for reversely transcripting theHIV-1 single-stranded RNA into double-stranded DNA.RT has been perceived as a principal target for anti-HIV drug discovery for its particular and vital role in the virus’s life cycle.HIV-1 non-nucleoside RT inhibitors(NNRTIs)are a mainstay of highly active antiretroviral therapy(HARRT)due to their high activity,high selectivity and relatively low toxicity.Nevertheless,the long-term use of NNRTIs in the clinical leads to the emergence of drug-resistant viruses and potentially severe side effects.Thus,there is an urgent need for novel NNRTIs candidates with improved safety,tolerability and anti-resistance profiles.Doravirine(DOR,also known as MK-1439)is a novel second-generation NNRTI in the phase Ⅲ clinical trial currently possessing high potency,high selectivity,low toxicity,low potential to cause drug-drug interactions.What’s more,the anti-drug resistance profiles are superior to those of the NNRTIs approved by the FDA including efavirenz(EFV),etravirine(ETR),and rilpivirine(RPV),indicating its potential for further development as a new HIV-1 inhibitor.However,the original synthetic route of DOR relied on functional group operations and lacked convergence in the endgame.To simplify manipulations and improve the yield,we made great efforts to establish a new synthetic route of DOR,which was suitable for industrial production with the advantages of short time,simple operation and good yield.The first section of this thesis focused on the optimization of the synthetic route of DOR to find a more productive route.3-Chloro-5-hydroxybenzonitrile rather than 3-bromo-5-chlorophenol was utilized as the raw material.Then through nucleophilic substitution,hydrolysis under the condition of the microwave,3-chloro-5-((2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile (intermediate 18)was obtained.Finally,DOR was prepared from 5-(chloromethyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one(intermediate 5)and intermediate 18 through one more nucleophilic substitution.Ultimately,the reaction time of the hydrolysis step decreased from 48 h to 105 min,and DOR was prepared in a 26.4%overall yield with excellent control of chemical purity in contrast with the 20.6%yield of the original route.In the second part of this thesis,we rationally designed an acetal carbonate prodrug(YP-1)and a phosphonooxymethyl prodrug(YP-2)of DOR aiming at enhancing the solubility of DOR,sequentially improving its oral bioavailability.Then,we tested the solubility and stability of two prodrugs in PBS buffer at both pH 2 and 7.4.The results demonstrated that the solubility threshold of YP-1(43 μg/mL)is comparable to that of DOR(19 μg/mL),while the solubility threshold of YP-2(>4.2 mg/mL)is about 200 times than that of DOR,and YP-2 showed desirable stability(t1/2>24h).In addition,the two compounds displayed moderate affinity to HIV-1 RT.In the third part of this thesis,DOR and NNRTI candidate GW678248 were chosen as lead compounds,and a series of novel acetamide derivates of DOR was rationally designed guided by the principle of molecular hybridization.HIV-1 RT inhibitory assays using commercial kit were performed on all the compounds.Finally,all the compounds displayed moderate affinity to HIV-1 RT.In conclusion,we developed a convergent,high-yielding,less-energy-consuming and robust scalable method toward DOR and key intermediate 18 assisted with microwave reactor.In this novel process,the reaction time was immensely cut down and the overall yield of DOR was increased from 20.6%to 26.4%,with more than 99%chemical purity.In the meantime,two prodrugs of DOR were rationally designed and synthesised using the privileged substituents previously reported.The phosphonooxymethyl prodrug exhibited excellent solubility and desirable stability.Moreover,a series of novel acetamide derivatives of DOR was rationally designed guided by the principle of molecular hybridization.All the compounds displayed moderate affinity to HIV-1 RT.Preliminary structure-activity relationships(SARs)and molecular modeling of the novel acetamide derivatives were discussed in details.