L-cyclic alkylamino acid synthesis method and medicinal composition containing L-cyclic alkylamino acid

Abstract

The invention provides an L-cyclic alkylamino acid synthesis method and a medicinal composition containing L-cyclic alkylamino acid. The synthesis method comprises the following steps: 1, preparing cyclic alkyl ketonic acid or cyclic alkyl ketonate having a structure represented by formula (I) or formula (II); and 2, mixing the cyclic alkyl ketonic acid or cyclic alkyl ketonate with ammonium formate, a leucine dehydrogenase, a formate dehydrogenase and a coenzyme NAD<+>, and carrying out a reduction amination reaction to generate the L-cyclic alkylamino acid, wherein n1 in the formula (I) is not lower than 1, m1 in the formula is not lower than 0, and M1 is H or a univalent cation; n2 in the formula (II) is not lower than 0, m2 in the formula (II) is not lower than 0, and M2 is H or a univalent cation; and the amino acid sequence of the leucine dehydrogenase is represented by SEQ ID No.1. The method utilizes specific leucine dehydrogenase, the formate dehydrogenase and the coenzyme NAD<+> to carry out the reduction amination reaction of the cyclic alkyl ketonic acid or cyclic alkyl ketonate, and has a high raw material conversion rate and a high chiral selectivity.

Description

technical field [0001] The present invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing an L-cyclic alkyl amino acid and a pharmaceutical composition thereof. Background technique [0002] At present, the synthesis of chiral unnatural cyclic alkyl amino acids mainly adopts chemical methods, including the use of noble metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, and the use of chiral reagents to resolve racemization. body, asymmetric synthesis using chiral prosthetic groups, directional synthesis using chiral raw materials, etc. However, these methods have the following disadvantages: [0003] (1) Using precious metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, the disadvantage is that the noble metal asymmetric catalyst is expensive, the reaction requires a large amount of organic solvent, ...

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Problems solved by technology

[0003] (1) Using precious metal asymmetric catalytic hydrogenation to realize the conversion of a single configuration of a key intermediate, the disadvantage is that the noble metal asymmetric catalyst is expensive, the reaction requires a large amount of organic solvent, and there may be heavy metal residues in the product and excessive Reduction by-products, and because the synthetic raw materials contain heterocycles, it often interferes with the combination of noble metals and ligands, resulting in low catalytic efficiency

[0004] (2) Using the traditional chiral resolution method to obtain a required isomer in the racemate will cause waste of the other half of the raw materials

[0005] (3) Asymmetric synthesis using chiral prosthetic groups or chiral raw materials involves expensive chiral raw materials, long synthetic routes and a large amount of organic solvents, and for the synthesis of some cyclic alkyl amino acids, the obtained The optical purity of the product is not high, or the product and impurities are not easily separated

However, due to the special properties of cyclic alkyl amino acids, the prior art has not yet found suitable enzymes and corresponding reaction conditions to synthesize amino acids with chiral cyclic alkyl structures through biotransformation

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