Hydrolase Catalysis Synthesis Of 1,4-Dihydropyridine Antihypertensive Drug And Its Derivatives

With the continuous improvement of drug synthesis technology,medical researchers hope to find a more efficient,convenient and green synthetic route to prepare drugs.Due to its unique advantages,enzyme-catalyzed promiscuity has attracted the attention of more and more chemical researchers and has been successfully applied in many organic synthesis reactions.However,research on enzyme-catalyzed promiscuity in drug synthesis is still rare.Therefore,discovering and studying the new catalytic function of enzymes has become a promising topic and has opened a new path for the synthesis of green catalytic drugs.The domino reaction refers to an organic synthesis method in which a plurality of reactions having similar or identical reaction conditions are combined together,and the advantage is that the new functional group obtained in the previous step is directly used for the next synthesis step without extracting intermediate and a series of complicated purification steps are omitted.Based on the enzymatic synthesis of C-C bonds,the Knoevenagel condensation/Michael addition tandem reaction and the Hantzsch reaction system involving aromatic aldehydes were studied in order to develop a highly efficient green organic synthesis method under enzyme catalysis conditions.Specific research includes the following:In this paper,the new functions of Knoevenagel condensation/Michael addition tandem reaction catalyzed by hydrolase were studied.The conditions of enzyme source,enzyme amount and solvent were optimized to obtain the optimal reaction conditions.Under the optimal conditions,the antihypertensive drugs felodipine,nifedipine,nitrendipine and nemadipine and 19 other derivatives were synthesized by enzyme catalysis,which extended the range of substrates.It provides a simple,rapid,efficient and environmental friendly synthesis method for the preparation of 1,4-dihydropyridine derivatives.The catalysis of the active center of the enzyme was verified by BSA and inactivated Papain.In this paper,the Hantzsch reaction of enzymatic synthesis of symmetric 1,4-dihydropyridine in organic solvent was studied.The conditions of enzyme source,reaction medium,enzyme amount and substrate structure were investigated.The results showed that PPL had the most catalytic effect in DMSO.Well,finally,ten symmetrical 1,4-dihydropyridine derivatives were synthesized.In conclusion,this paper successfully used the enzyme-catalyzed promiscuity to prepare a series of 1,4-dihydropyridine antihypertensive drugs and their derivatives which broadened the application range of enzyme-catalyzed promiscuity technology in organic synthesis and drug synthesis reactions.