Diltiazem, as an important cardiovascular drug, is widely used in the long-term treatment of angina pectoris and hypertension. The drug has two chiral centers. Traditional chemical synthesis methods use lysine as a resolving agent to carry out chiral resolution of synthetic intermediates. The process is complex and cumbersome, the route is lengthy, the resolution yield is low, and the optical purity of the product is poor. Compared with chemical resolution methods, the chemical-enzymatic process for synthesizing the chiral precursor of diltiazem has significant advantages. Extracellular lipase derived from Serratia is used to efficiently catalyze the chiral resolution of the precursor epoxy ester. The substrate concentration is as high as 200 g/L, and an optically pure single-configuration bidirectional central intermediate can be obtained in one step of catalysis, and then (2S)-cis hydroxyllactam can be synthesized in one step through chemical methods. It greatly simplifies the synthetic process route of diltiazem precursor (2S)-cis-hydroxylactam, and reduces the synthesis steps from 7 steps in the original chemical method to 3 steps. The process is simple, the product has good optical purity, high yield, and waste emissions are less. Based on the previous screening and obtaining of wild-type Serratia lipase (China invention authorization patent ZL200410067046.1), this achievement has made major improvements. Molecular modification and homologous recombination expression of the enzyme have been carried out. The activity of the enzyme has been increased by 4 times and the expression level has been increased by 50 times. Compared with the wild-type lipase preparation, the activity of the second-generation lipase liquid preparation increased by 200 times. Compared with the original enzymatic reaction process, using a new generation of lipase preparations to catalyze the resolution of diltiazem synthesis precursors, the amount of catalyst is greatly reduced, the emulsification of the reaction liquid is slight, the product separation and extraction are simple, and the product yield is higher. The corresponding emission of fermentation waste liquid and reaction waste are significantly reduced, saving energy and emission reduction, and making it greener and more environmentally friendly. This achievement has been applied for for a China invention patent, application number 201610379653.4.  

With the improvement of people's living standards, the number of patients with hypertension has increased year by year, and blood-pressure drugs have a broad pharmaceutical market. Developing a green and environmentally friendly new production process for lowering blood pressure drugs and reducing drug production costs has significant economic and social benefits. With an annual output of 400 tons of diltiazem synthetic intermediate, the annual output value is expected to reach 100 million yuan, with profits and taxes of 30 million yuan.