Preparation method of (R)-alpha-thioctic acid

Abstract

The invention relates to a preparation method of (R)-alpha-thioctic acid, and belongs to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: introducing Candida parapsilosis to a fermentation medium, carrying out multiplication culture, and centrifuging; introducing above obtained reductase catalyst to a system composed of 6-carbonyl-8-chloroctanoic acid, glucose dehydrogenase, glucose, nicotinamide adenine dinucleotide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and water, and carrying out a chiral reduction reaction; adding above obtained (S)-6-hydroxy-8-chloroctanoic acid to a system composed of a chlorination reagent, a catalyst and a solvent, and carrying out a chlorination reaction; and adding obtained (R)-6,8-dichloroctanoic acid to a system composed of sulfur, sodium sulfide, a phase transfer catalyst and water, and carrying out a cyclization reaction to obtain the finished product. The method has the advantages of mild technologic conditions, low cost, realization of high purity, high yield and high optical purity of the product, easy obtaining of reagents used in the above technologic route, and reasonable and environmentally-friendly technical scheme.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of (R)-alpha-lipoic acid. Background technique [0002] α-lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble. Universal antioxidant drug. Alpha-lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumor, and nervous system degeneration. For example, it can assist in the treatment of type 2 diabetes, improve the glucose metabolism of islet function, protect nerve cells, and prevent cataracts. Prevents muscle damage and more. [0003] Studies have shown that the two enantiomers of lipoic acid show different biological activities, among which the biological activity of the R-type is much higher than that of the S-type, and the S-type is basically inactive, but has ...

AI Technical Summary

Problems solved by technology

Because in the chlorination step, (R)-6-hydroxy-8-chlorooctanoic acid ethyl ester (or methyl ester) will produce part of the configuration inversion, so that the product will produce part of the S-type product, reducing the (R)- The optical purity of α-lipoic acid has seriously affected the popularization and application of industrial production

[0005] Invention Patent Publication No. CN103451124A discloses "a strain of Rhodococcus and its use for preparing optically pure (R)-6-hydroxy-8-chlorooctanoate and other optically active chiral alcohols", which teaches the use of culture fermentation The prepared carbonyl reductase produces intermediates such as (R)-6-hydroxy-8-chlorooctanoate, but in each step of the reaction to prepare (R)-α-lipoic acid, the chlorination reaction is the key In the first step, there is a competition probability of configuration maintenance and configuration inversion, which is not conducive to obtaining the desired single configuration, reduces optical purity, and is not conducive to scale-up production and industrialization

However, because the enzyme reduction reaction is mainly an aqueous solution system, 6-carbonyl-8-chlorooctanoic acid ethyl ester is selected as the substrate raw material, its solubility is low, the reaction conditions are harsh, and it is easy to fluctuate, and the controllability is poor. Conducive to cost control and industrial production applications