Method for preparing adrenaline

Abstract

The invention relates to a method for preparing adrenaline. According to the method, a substrate undergoes reduction reaction in the presence of a ketoreductase, a coenzyme and a coenzyme regeneration system so as to produce adrenaline, wherein the coenzyme regeneration system comprises glucose and glucose dehydrogenase, the reduction reaction is carried out in a buffer solution with the pH value of 5-7, and the reaction temperature is 0-15 DEG C. According to the method, adrenaline is prepared from the ortho-position dihydroxyl-protected substrate by using a ketoreductase one pot-method, thus, efficient asymmetric enzyme reduction is realized, and then, the pH value is adjusted so as to remove protecting groups through hydrolysis; compared with the existing chemical resolution methods or chemical metal asymmetric synthesis methods, the yield and optical purity are higher, and the cost is lower.

Description

technical field [0001] The invention belongs to the technical field of biological pharmacy and biochemical industry, and in particular relates to a preparation method of epinephrine. Background technique [0002] Adrenaline (adrenaline or epinephrine) is mainly used to treat cardiac arrest, bronchial asthma, and anaphylactic shock, and can also treat urticaria, hay fever, and nasal mucosa or gum bleeding. Its structure is as follows: . [0003] Adrenaline contains a chiral hydroxyl center, and its preparation methods mainly include asymmetric synthesis and resolution. The asymmetric synthesis uses a chiral metal catalyst for hydrogenation reduction to obtain a chiral hydroxyl center, such as figure 1 , the current method requires the use of expensive transition-state metal catalysts and chiral ligands, and uses a large amount of organic reagents, which is costly and environmentally friendly (such as Yao Jinshui, etc., Chemical Journal of Chinese Universities, 2002, 23 (1...

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Problems solved by technology

[0003]Epinephrine contains a chiral hydroxyl center, and its preparation methods mainly include asymmetric synthesis and resolution. The asymmetric synthesis uses a chiral metal catalyst for hydrogenation reduction to obtain Chiral hydroxyl centers, such as Figure 1, the current method Need to use expensive transition state metal catalysts and chiral ligands, and use a large amount of organic reagents, the cost is high, and the environmental friendliness is not high (such as Yao Jinshui et al., Chemical Journal of Chinese Universities, 2002, 23 (1), 68-70 ), there is no industrialization report yet

The resolution method is widely used, and tartaric acid is usually used for resolution, such as WO 2009 / 004593, etc., but there is a problem that the theoretical yield is lower than 50%, and the raw material cost is high (such as Figure 2)

[0004]It is undoubtedly an ideal method to directly reduce substrate precursors containing carbonyl groups to chiral alcohols. Ketoreductase catalyzes this type of reaction, which is environmentally friendly and efficient, but At present, no biocatalyst capable of efficiently catalyzing this reaction has been found, which may be due to the strong repulsion between the structure of the ortho-dihydroxyl group on the benzene ring of the substrate and the structure near the catalytic site of the enzyme.

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