The enzyme process efficiently synthesizes (R)-sulfuric acid

The rapid customization of biocatalysts and the key technology projects of high-efficiency synthetic hand chemicals
the rapid customization of biocatalysts and the key technology projects of high-efficiency synthetic hand chemicals completed by Xu Jian and the teaching team of East China University of Technology, using enzyme process synthesis (R)-sulfuric acid, the reaction steps are reduced by half compared to traditional chemical synthesis, and the product yield is more than doubled, and the economic and environmental benefits are significantly improved. The technology won the first prize of the Technology Invention Award at the Shanghai 2018 Science and Technology Awards Conference held recently.
proposed innovative solutions
(R)-sulfuric acid is a vitamin-like, all-in-one, high-efficiency antioxidant that is widely used in the prevention and treatment of heart disease, diabetes, and Alzheimer'

. However, the chemical synthesis conditions of its key intermediate hand chlorol are very harsh, and the safety and environmental protection pressure of the production enterprises is huge, which has been the bottleneck that restricts the marketing application. In order to solve this problem, Xu Jian and led the research and development team to focus on the niobium-based reductase catalyst, hoping to use biosynthetic method instead of traditional chemical synthesis method, improve yield, reduce "three waste" emissions.
" niobium-based reductase is an important tool for catalyzing high-end chemicals such as synthetic hand alcohols, which have unique advantages in the field of drug synthesis, with mild reaction conditions and strong three-dimensional selectivity. However, there are many technical problems in its industrial application, including the difficulty of enzymatic creation in industrial catalysis, the low success rate, the ineration of enzymes in industrial production, and the difficulty of connecting enzyme-promoting reaction with chemical conversion process. Xu Jian and introduced.
In 1996, East China University of Technology set up the earliest bio-catalytic research laboratory in China, and put forward innovative solutions: First, the establishment of a pilot enzyme library for reconnaissance to narrow the search scope of the target enzyme;
technical difficulties one by one to overcome the
natural enzyme gene number is huge, moving millions, from which to screen out an efficient and stable industrial bio-catalytic enzyme, is the same as looking for a needle in a haystack.By combing the generalization gene evolution tree, clustering about simple, selecting a representative from every 3,000 similar genes, and using conventional molecular cloning and fermentation techniques, the
project team produced 1,214 pilot enzymes representing more than 3 million unknown genes, reducing the search range of target enzyme genes by 3 orders of magnitude and improving the efficiency and success rate of industrial enzyme customization.
Xu Jianhe explained: "The pilot enzyme molecule is like a front-line 'reconnaissance' lurking in the vast gene 'Linhai', once with the target substrate to be tested on the 'dark', can guide the gene search engine to target the direction of the evolutionary tree active pilot enzyme adjacent gene community, and then through high-volume screening methods, quickly target, improve the target biocatalyst design and development of the targeted and hit rate." In the past, enzyme catalysts were developed over a period of 1 to 2 years, but now we only need 1 to 2 weeks. On this basis, in view of the low vitality and poor stability of wild enzyme catalysts, we analyze the structure and structure of enzymes, invent multi-target parallel enzyme molecular transformation technology, the catalytic efficiency of wild enzymes increased by 960 times, stability increased by 1940 times. In
obtained an efficient niobium-based reductase, and the problem of enzyme ineration was put before the task force. Local overacid or over-alkali in large reactors can easily cause enzyme infestion, and researchers have developed enzyme stabilization techniques by regulating pH, designing special lye cloths and spray devices. The project team also aimed at the unstable reaction substrate in the water phase, frequent change of working medium caused a lot of waste and sewage, in the enzyme-promoting reduction reaction to introduce the next step of the common solvent, formed a toluene-water two-phase enzyme catalytic media system, inhibited the spontaneous hydrolysis of the substrate ketone, realized the enzyme reaction and subsequent chemical transformation between seamless docking, reduce solvent loss, improve product yield.
more than ten years of hard work, the research and development team finally cracked a series of difficult problems, the realization of (R)-sulfuric acid enzyme method industrial production.
economic and environmental benefits are obvious
innovation brings about a significant increase in technical performance, economic indicators and environmental protection benefits. Xu Jianhe gave a set of data: the use of enzyme-chemical coupled method of the new process, (R)-sulfuric acid synthesis steps from 6 steps to 3 steps, the substrate upload capacity of up to 330g/L, space-time yield of 530g/L/d, the optical purity of the product in more than 99%. Compared with traditional chemical synthesis technology, the yield of new process products increased from 25% to 55%, the unit energy cost decreased from 85 yuan to 45 yuan, solvent consumption decreased from 6 kg to 4 kg, the comprehensive cost decreased from 1100 yuan per kg to 800 yuan, and the environmental load decreased from 27 kg to 15 kg.
excellent technical and economic indicators attracted many domestic pharmaceutical companies to seek cooperation. At present, the new process of niobium-based reductase asymmetric synthetic hand alcohol has been in Suzhou Fujilai Pharmaceutical Co., Ltd., Jiangxi Keyuan Biopharmaceutical Co., Ltd., Xiamen Omek Biotech Co., Ltd. and more than 10 other enterprises to promote the application. Among them, Suzhou Fujilai built a 10-ton reactor-scale industrial production line, can produce an annual output of (R)-sulfuric acid 50 tons, (R)-sulphate aminotin triol 20 tons; The cumulative output value of these two enterprises in the past three years totaled 979 million yuan and profits of 182 million yuan.
" chemical industry is facing an increasingly severe market environment, the synthesis of high-end chemicals and many neck problems. Enzyme is the core 'chip' of the biological manufacturing industry, and it is also a sharp weapon for the transformation and upgrading of the traditional chemical industry. Our team will adhere to the source of innovation on the basis of the combination of machine deep learning and other intelligent computing methods, continue to work deep, to support China's chemical and pharmaceutical industry to the high end. Xu Jian and said.