Regioselective Synthesis Of Quinoxaline And The Synthetic Process Research Of Anti-HCV Drug Voxilaprevir

(1)Quinoxaline and its derivatives are an important class of nitrogenous heterocyclic blocks of drugs.These blocks have a wide range of pharmacological activities,such as antibacterial,anti-inflammatory,antiviral,anticancer,which can be used as bioisosteres of quinoline and isoquinoline.So they have a broad application in the development of new drugs.There are many synthesis methods of quinoxaline in the literature,but the control of regioselectivity remains a challenge.In this paper,a convenient regioselective synthesis method of quinoxaline derivatives fromα-ketoester and o-phenylenediamine was developed.The regioselectivity of reaction can be regulated by acid and base after the optimizing of reaction conditions.Under acidic conditions,the type and dosage of acids were investigated at first,then solvents were screened as well.The best reaction conditions were found as follows:α-ketoester:o-phenylenediamine=1.2:1,5.0 eq Ac OH as catalyst,Me OH as solvent,at room temperature.This method was compatible with both electron-withdrawing and electron-donating groups substituted o-phenylenediamines,and the 7-substituted quinoxaline derivatives can be selectively obtained as main products.Under basic condition,the type and dosage of bases were examined and the solvents and temperature were investigated as well.The best reaction conditions were found as follows:α-ketoester:o-phenylenediamine=1.2:1,5.0 eq TEA as catalyst,Me OH as solvent,at room temperature.This method is only suitable for the electron-withdrawing groups substituted o-phenylenediamines,and the 6-substituted quinoxaline derivatives can be selectively obtained as main products.（2）Voxilaprevir（GS-9857）,a competitive inhibitor of NS3/4A serine protease,has the structural characteristics of quinoxaline.It has been approved by the FDA for the treatment of genotype 1-6 hepatitis C.However,in the existing synthetic process of Voxilaprevir,there are some shortcomings,such as poor regioselectivity,long reaction time,low yield and high cost.In this paper,some optimizations have been made on the synthetic process of Voxilaprevir.Firstly,the reactivity of starting materials（α-ketoacid andα-ketoester）were investigated.Secondly,the dosage of Cs₂CO₃ and reaction temperature in SN_Ar reaction were investigated.Thirdly,the dosage of Zhan 1B catalyst in RCM reaction was investigated.Then,the concentration and dosage of Li OH and reaction temperature in ester hydrolysis reaction were investigated.Finally,the feeding sequence,temperature and solvent in amidation reaction were investigated.Through the above optimizations,a new process was developed for the synthesis of Voxilaprevir fromα-ketoester and o-phenylenediamine with nine steps including condensation,chlorination,SN_Arreaction,deprotection,amino acid condensation,RCM reaction,hydrogenation,ester hydrolysis and amidation.The total yield is 27%.The regioselectivity of quinoxaline intermediate is as high as 13.5:1 in the new process,avoiding the loss of raw materials and reducing the cost.Meanwhile,the purification of all intermediates can be achieved by crystallization or solidification without column chromatography purification,which is conducive to industrial scale-up production.