Preparation

In the past more than a century, the production and preparation methods of amino acids have always been one of the research hotspots. At present, the research on the production method of L-phenylalanine has been relatively mature, mainly including the direct fermentation method, enzymatic method, and chemical synthesis method. However, D-phenylalanine is an unnatural amino acid that is difficult to obtain from natural products, nor can it be prepared by direct fermentation. The chemical synthesis production process is complicated and requires high equipment and is difficult to produce on a large scale. With the continuous expansion of the application of D-phenylalanine in light industry, medicine, pesticides, food, and other fields, the market demand will also continue to increase. Therefore, we are looking for D-phenylalanine with a simple process and cheap raw materials. The preparation method of acid has become one of the research directions of chemists. The current methods for preparing D-phenylalanine mainly include resolution, biological, and asymmetric chemical synthesis. Among them, asymmetric synthesis, especially asymmetric catalytic hydrogenation, has shown broad prospects.
1) Split method
Racemic phenylalanine is a compound composed of L-phenylalanine and D-phenylalanine mixed in equal amounts. Their physical and chemical properties are the same, but the optical rotation is opposite to each other. Therefore, it is difficult to separate the racemate into a single configuration of phenylalanine with general physical methods, and special methods must be used to separate it. Using 35-dinitrobenzene substituted β-cyclodextrin as the stationary phase, the D and L-amino acids were resolved by chiral thin-layer chromatography. The experiment found that phenylalanine was due to the presence of the benzene ring structure. It has a strong effect on the chiral stationary phase, which makes the racemic phenylalanine appear with different physical properties, thus obtaining a better resolution effect. However, the splitting agent used in this method is expensive, consumes a lot, and splits the efficiency is not high, so it is difficult to prepare for large-scale production use. The penicillin acylase was immobilized, and then the racemic phenylalanine derivatives N-phenyl acetyl-D and L-phenylalanine were resolved to obtain crude N-phenyl acetyl-D-phenylalanine. After removing the protective group, the cation resin exchange desalting process is used to obtain D-phenylalanine with an optical purity of 91.4% and a yield of 67%. This method also has disadvantages such as low efficiency, high energy consumption, low yield, and low product optical purity. There are also related literature reports that the resolution of racemic phenylalanine with chemical reagents dioxaphosphine compounds, but the resolution rate is less than 36%.
2) Biological Law
The biological method has been widely concerned and highly valued in the field of amino acid production due to its relatively mild reaction conditions and high stereoselectivity. There are also many literature reports on the use of biological methods to produce D-phenylalanine. The D-configuration amino acid acylase is induced by two special bacteria. This enzyme can convert N-acetyl-D-phenylalanine into D-phenylalanine, and the highest yield can reach 83.1%. The optical purity of the product has not been reported. Although this method is feasible, it is limited to laboratory research and does not yet have the conditions for industrial production. According to related reports, Japan Zhongsheng Chemical Company recombined D-hydantoins and N-carbamylamino acid into Escherichia coli using genetic engineering and successfully expressed it, and extracted the crude enzyme for immobilization to produce D-phenylalanine. Good experimental results have been achieved. At present, Japanese companies such as Zhongshenghua have improved the strains through genetic engineering methods, but there are still disadvantages in the production of D-phenylalanine, such as low substrate concentration, long conversion time, and low conversion rate.
3) Asymmetric synthesis method
Asymmetric synthesis generally refers to a type of reaction that uses special chemical reagents, solvents, catalysts, or physical factors to convert latent units into chiral units to produce unequal amounts of stereoisomeric products. The asymmetric synthesis reaction has developed rapidly in recent years and has achieved remarkable results. It has become one of the most active research fields in organic chemistry. There are many reports on the use of this method to synthesize phenylalanine. In 1988, it was reported that D-camphor one imine condensed with D-camphor and glycine butyl vinegar was used as a chiral synthon. D-phenylalanine was synthesized enantioselectively through asymmetric synthesis. The optical purity of the product was The ee value reaches 95%, and the yield reaches 92.7%. However, this method requires more stringent reaction conditions, high energy consumption, and high cost, and is only suitable for small-scale synthesis research in the laboratory. Another effective method for the asymmetric synthesis of α-amino acids is to use rhodium-catalyzed tandem 1,4-addition protonation (Michael type addition reaction) to catalyze α, β-dehydroamino acids. The organic metal reagent is used to react the amido acrylate in the presence of a rhodium catalyst and a chiral phosphine ligand to obtain the corresponding α-chiral amino acid derivative. The ee value of the phenylalanine derivative is 89.5% and is in the L configuration. The method is simple to operate, but the reaction uses too many rhodium catalysts and chiral phosphine ligands, the cost is too high and the optical purity of the product is not high, and it only stays in the laboratory research stage, and there is no production report using this method.