Method for preparing D-2-substituted propionyl-L-glutamine

Abstract

The invention relates to the technical field of pharmaceutical chemistry, and discloses a method for preparing D-2-substituted propionyl-L-glutamine. According to the method for preparing the D-2-substituted propionyl-L-glutamine disclosed by the invention, a phase transfer catalyst and inorganic salt are added in the process of preparing the D-2-substituted propionyl-L-glutamine. Therefore, the relative rate of L-glutamine to OH<-> in an organic phase is greatly improved; the concentration of the OH<-> in the organic phase is reduced; the relative rate of the L-glutamine to the OH<-> in the organic phase is finally improved; fuller and more complete reaction is facilitated; the side reaction such as hydrolysis of the compound shown in the formula I is also greatly reduced; and the conversion rate of the reaction is improved. The preparation method disclosed by the invention does not need to prolong the subsequent reaction time and has substantial timeliness compared with the prior art. Meanwhile, the controllability of the reaction is strengthened; and the production cost is greatly reduced, and large-scale industrial production is further facilitated.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing D-2-substituted propionyl-L-glutamine. Background technique [0002] N(2)-L-alanyl-L-glutamine is a derivative of amino acid, which plays an extremely important role in maintaining intestinal function, promoting immune function, maintaining alkali balance in the body and improving the body's adaptation to stress. It is an ideal substitute for the most abundant amino acid glutamine (GLN) in the human body. At present, N(2)-L-alanyl-L-glutamyl has become a relatively popular amino acid dipeptide product at home and abroad, and the demand for its raw materials is quite huge, close to 1,000 tons per year. D-2-substituted propionyl-L-glutamine is a key intermediate for the preparation of N(2)-L-alanyl-L-glutamine, and its structural formula is as follows: [0003] [0004] Wherein, X=Cl, Br, I, OMs or OTs. [0005] Patents US5380934, EP0595345,...

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Problems solved by technology

[0006] However, because D-2-substituted propionyl-L-glutamine is dissolved in sodium hydroxide solution to form a sodium salt, it is only soluble in water and insoluble in aprotic solvents such as toluene, while D-2-substituted propionyl chloride is only soluble in Aprotic solvents such as toluene are insoluble in water, so prepare D-2-substituted propionyl-L-glutamine according to the above method, when D-2-substituted propionyl chloride is added dropwise under alkaline conditions for reaction, the reaction is only Can be carried out under heterogeneous conditions, resulting in incomplete reaction conversion and low conversion rate

Moreover, the rate of the microscopic reaction itself of the heterogeneous condensation reaction is very fast, and the diffusion of the reactant between the two phases is the rate-limiting step of the macroscopic reaction. In the reaction process, there is an obvious competition trend between L-glutamine and OH-, The conversion rate of the product is unstable, and the difficulty of controlling the reaction process increases

[0007] In order to ensure that the fully reacted L-glutamine and D-2-substituted propionyl chloride, some preparation methods prolong the reaction time after the addition of the feed, which nearly doubles the entire process time, but still cannot substantially improve the L- The reaction competitiveness of glutamine alleviates the occurrence of hydrolysis reaction, and causes the dosage of D-2-substituted propionyl chloride to increase and the reaction time to prolong

Since D-2-substituted propionyl chloride is an optical isomer, the price is expensive, which greatly increases the production cost

Therefore, the existing D-2-substituted propionyl-L-glutamine preparation method is difficult to reduce costs and improve production efficiency to meet the growing demand for medication

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