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

A technology of glutamine and D-2-, applied in the field of preparing D-2-substituted propionyl-L-glutamine, can solve the problem of unstable product conversion rate, low conversion rate, D-2-substituted propionyl chloride The problem of increasing consumption, etc., achieves the effect of being conducive to large-scale industrial production, stable consumption and conversion rate, and clear consumption trend.

Active Publication Date: 2015-04-22
CHONGQING LUMMY PHARMA
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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

Method used

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

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Embodiment 1

[0030] Add L-glutamine (60g), water (120g) and toluene (120mL) into the reaction flask, cool down to 0±2°C, add dropwise 5mol / L sodium hydroxide solution (102g), dissolve and clarify, add four Butylammonium bromide (3g) and sodium chloride (36g) were stirred evenly. Slowly add D-2-chloropropionyl chloride (62.6g) diluted with toluene (62.6mL) dropwise. After adjusting the pH to 10, start to drop 5mol / L sodium hydroxide solution (150g), and control the temperature at 0±2°C. pH value 9-10, reaction 2h. The layers were allowed to stand, the water layer was taken, concentrated hydrochloric acid (49.7g) was added dropwise to adjust the pH to 2.0, and crystallized. Suction filtration, suction drying, vacuum drying. 94.0 g of white or off-white solid was obtained. The yield is 96.7% (calculated as L-glutamine).

Embodiment 2

[0032] Add L-glutamine (100g), water (250g), petroleum ether (60-90°C, 300mL) into the reaction flask, cool down to 0±3°C, add dropwise 4.5mol / L sodium hydroxide solution (190g ), dissolved and clarified, added tetrabutylammonium chloride (2g), sodium iodide (70g) and stirred evenly. Slowly add D-2-methanesulfonyloxypropionyl chloride (146g) diluted with petroleum ether (60-90°C, 219mL) dropwise, after adjusting the pH to 10, start to drop 5mol / L sodium hydroxide solution (244g), Control the temperature at 0±3°C, pH 9-10, and react for 3 hours. The layers were allowed to stand, and the water layer was taken, and concentrated hydrochloric acid (82.8 g) was added dropwise to adjust the pH value to 1.6, and crystallized. Suction filtration, suction drying, vacuum drying. 197.5 g of white or off-white solid was obtained. The yield is 97.5% (calculated as L-glutamine). 1H-NMR (400MHz, DMSO-d6) 12.63(s, 1H), 8.63(s, 1H), 7.40(s, 1H), 6.90(d, 1H), 5.13(q, 1H), 4.15-4.25(m , 1H),...

Embodiment 3

[0034] Add L-glutamine (80g), water (144g) and ethyl acetate (120mL) into the reaction flask, cool down to 0±3°C, add dropwise 5mol / L sodium hydroxide solution (144g), dissolve and clarify, Add tetrabutylammonium bisulfate (6.4g) and potassium chloride (56g) and stir well. Slowly add D-2-bromopropionyl chloride (108g) diluted with ethyl acetate (108mL) dropwise, adjust the pH to 10, then start to drop 4mol / L sodium hydroxide solution (208g), control the temperature at 0±3°C, pH value 9-10, reaction 4h. The layers were allowed to stand, the water layer was taken, concentrated hydrochloric acid (66.2 g) was added dropwise to adjust the pH to 1.8, and crystallized. Suction filtration, suction drying, vacuum drying. 147.5 g of white or off-white solid was obtained. The yield is 96.2% (calculated as L-glutamine).

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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,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/22C07C231/02
Inventor 周和平黄文峰李胜伟覃培福
Owner CHONGQING LUMMY PHARMA
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