CN101250198A - A kind of synthetic method of phosphoenol pyruvate potassium salt - Google Patents

Abstract

The invention discloses a method for synthesizing potassium salt of phosphoenolpyruvate, which comprises the steps of using pyruvic acid as a starting material and undergoing a bromination reaction with bromine to generate a liquid intermediate crude bromopyruvate; The crude product is directly phosphorylated with trialkyl phosphite solution to generate dialkyl phosphoenolpyruvate; the reaction mixture of dialkyl phosphoenolpyruvate is directly hydrolyzed with water to generate phosphoric acid Enol-pyruvate; the aqueous solution of phosphoenol-pyruvate synthesized by the bromination, phosphorylation, and hydrolysis three-step reaction in one pot, remove the insoluble residue by filtration, and then adjust its pH value to 2 with potassium hydroxide ~5, after treatment with absolute ethanol, the crystalline solid powder of potassium salt of phosphoenolpyruvate can be obtained. The invention has the advantages of low cost, high yield, environmentally friendly synthesis method and simple process flow.

Description

A kind of synthetic method of phosphoenol pyruvate potassium salt

【Technical field】

The invention relates to the fields of fine chemical industry and biochemical industry, in particular to a method for synthesizing phosphorylation reagent potassium phosphoenolpyruvate which is widely used in biochemical reaction process.

【Background technique】

Potassium phosphoenolpyruvate (PEPK for short) is a widely used phosphorylation reagent in biochemical reactions. Compared with other phosphorylation reagents, potassium phosphoenolpyruvate is stable from It has certain advantages in terms of safety and side reaction control, but its disadvantage is that it is expensive. Quotations for potassium phosphoenolpyruvate products from major chemical companies in the world show that the product price of Sigma-Aldrich, the world's number one chemical reagent manufacturer, has reached a high price of 207.6 US dollars per gram (2005-2006 catalogue) , see Table 1 for details. The supply of this product in my country is basically dependent on imports. In the 1980s, Dr. Whitesides, a famous scientist in the United States, took the lead in developing the synthesis of molar-scale phosphoenolpyruvate potassium salt, and applied it to the preparation of some biochemical reagents with higher added value in the pharmaceutical and chemical fields such as glucose 6-phosphate. .

Table 1 Quotation of PEPK products in major chemical companies in the world

The existing synthetic method of phosphoenol pyruvate potassium salt is three-step reaction and six processing steps with pyruvate as initial raw material: (1) generate bromopyruvate through bromination reaction; (2) use a large amount of petroleum hydrocarbon After the solvent-like treatment, high-purity bromopyruvate is obtained; (3) bromopyruvate after purification is phosphorylated with trialkyl phosphite to generate dialkyl phosphoenolpyruvate; (4) The dialkyl ester of phosphoenolpyruvate is dissolved in water after distilling off the solvent; (5) the dialkylester of phosphoenolpyruvate is hydrolyzed to generate phosphoenolpyruvate (PEPA for short); (6) ) is finally treated with alkali KOH/absolute ethanol to obtain potassium salt of phosphoenol pyruvate. Its shortcoming is, (1) prior art needs to use a large amount of organic solvents to purify intermediate bromopyruvate, causes the high cost of solvent recycling, discharge process operation, and the waste water and waste gas containing solvent of discharge can cause environmental pollution; (2) The prior art requires many steps, the technological process is loaded down with trivial details, and the cost is high. Due to the expensive price of potassium phosphoenolpyruvate, at present, the efficient and environmentally friendly synthesis method to reduce its production cost is the direction and focus of its research.

【Content of invention】

The purpose of the present invention is to overcome the deficiencies of the existing synthesis methods, and provide a synthesis method of potassium phosphoenolpyruvate to reduce production costs and simultaneously solve the problem of environmental pollution caused by organic solvents.

To achieve the above object, the present invention is achieved through the following technical solutions:

(1) Adopt cheap domestic pyruvic acid, its mass fraction is more than 95%, as starting material, through the bromination reaction with bromine, the molar ratio of bromine and pyruvic acid is 0.9: 1～1.5: 1, generates liquid Intermediate bromopyruvate, wherein the intermediate bromopyruvate does not require solvent purification;

(2) The crude product of the intermediate bromopyruvate is directly phosphorylated with trialkyl phosphite solution, and the molar ratio of trialkyl phosphite to pyruvic acid is 0.8:1 to 2.5:1 to generate phosphoenol Dialkyl ester solution of formula pyruvic acid, wherein, the dialkyl ester of phosphoenol pyruvic acid does not need to be purified;

(3) After the dialkyl ester reaction solution of phosphoenolpyruvate is evaporated by the solvent, it directly reacts with water for hydrolysis to generate an aqueous solution of phosphoenolpyruvate;

(4) The phosphoenolpyruvate aqueous solution synthesized by the above-mentioned three-step reaction of bromination, phosphorylation and hydrolysis in one pot, removes the insoluble residue by filtration, and then uses solid potassium hydroxide or high-concentration potassium hydroxide The solution adjusts the pH value of the phosphoenolpyruvate aqueous solution to 2-5, and then treats it with absolute ethanol to obtain phosphoenolpyruvate potassium salt crystal solid.

The synthetic method route of the present invention is:

The positive effect of the synthetic method of a kind of phosphoenol pyruvate potassium salt of the present invention is:

(1) the present invention overcomes the deficiency that multi-step reaction carries out separately in the original synthetic method;

(2) The present invention does not use any solvents such as petroleum hydrocarbons to carry out the purification of the intermediate product bromopyruvate, which overcomes the deficiency of using petroleum hydrocarbon solvents in large quantities in the prior art;

(3) the present invention completely avoids the use of a large amount of organic solvents to the purification intermediate bromopyruvate, and the defect of the solvent recovery process brought thereby, reduces production costs, and substantially eliminates the environmental pollution problem caused by organic solvents;

(4) The present invention is a three-step reaction one-pot French synthesis method, all of its reactions can be carried out in the same reaction vessel, so its synthesis process flow and equipment can be greatly simplified, and the product yield is close to the existing method, about Between 40% and 50%, the production cost is correspondingly greatly reduced.

【Detailed ways】

The specific implementation of the synthesis method of a potassium phosphoenolpyruvate salt of the present invention is provided below, but the present invention is not limited to the provided examples.

Millimolar synthesis of embodiment 1 phosphoenol pyruvate potassium salt (PEPK)

Pyruvate (purity 98.5%, 103.4mmol), 1 drop of concentrated sulfuric acid, and 15ml CH2Cl2 were added to a three-necked flask equipped with a magnetic stirrer, dropping funnel and a reflux condenser equipped with acid absorption. Bromine water (103.4 mmol) was added with stirring. After the dropwise addition was completed, the mixture was stirred overnight at room temperature. Evaporation of the solvent afforded brown crude bromopyruvate. Dissolve the prepared bromopyruvate in 20 ml of anhydrous ether, and add it dropwise into a solution of trimethyl phosphite (108.0 mmol) in 50 ml of anhydrous ether with stirring, so that the reaction system is in a reflux state. The reaction was held at reflux for 3.5 hours. Then the reaction mixture was stirred at room temperature for 1.0 hour, and the solvent was removed by rotary evaporation to obtain a brown viscous oil. The oil was dissolved in 30ml of water and stirred at room temperature for 24 hours. Then 6.05g of KOH solid and 200ml of absolute ethanol were added, and the precipitated white precipitate was filtered and washed with absolute ethanol to obtain 10.2g of white solid PEPK (based on pyruvic acid, yield 48%), melting point 166-167°C.

Mole-scale synthesis of embodiment 2 phosphoenol pyruvate potassium salt

Add 0.70 mol of pyruvic acid, 60 ml of CH ₂ Cl ₂ , and 3-4 drops of concentrated sulfuric acid into a three-neck flask equipped with a magnetic stirring bar, a dropping funnel, and a reflux condenser equipped with acid absorption. Bromine water 0.70mol was added under stirring. After the dropwise addition was completed for 2 hours, the mixture was stirred for another 1 hour. After the solvent was evaporated, pour 220ml of anhydrous ether into the prepared crude bromopyruvate, stir and drop into 20ml of anhydrous ether solution of 0.95mol of trimethyl phosphite, so that the reaction system was in a reflux state. After the dropwise addition was complete for 2 hours, the reaction was kept at reflux for another 1 hour. After the solvent was distilled off, 120 ml of distilled water was added to the reaction mixture, followed by stirring overnight at normal temperature. The hydrolyzate was filtered to obtain a clear aqueous solution of phosphoenolpyruvate, and then 43.5 g of potassium hydroxide solid was added to adjust the pH value to about 3. Pour 250ml of absolute ethanol, and filter the settled white precipitate, wash with absolute ethanol to obtain 70.0g of white solid PEPK (based on pyruvic acid, yield 47%), melting point 160-161°C.

Claims (1)

1. a synthetic method of phosphoenolpyruvate potassium salt, is characterized in that, it is carried out according to the following reaction equation,

The specific steps are, (1) adopt pyruvic acid, as starting raw material, through the bromination reaction with bromine, the mol ratio of bromine and pyruvic acid is 0.9: 1～1.5: 1, generates liquid intermediate bromopyruvic acid crude product; (2) The intermediate bromopyruvate crude product is directly phosphorylated with trialkyl phosphite solution, and the molar ratio of trialkyl phosphite to pyruvic acid is 0.8:1 to 2.5:1 to generate phosphoenol formula Dialkyl esters of pyruvate; (3) After the reaction solution of dialkyl phosphoenolpyruvate is evaporated to remove the solvent, its reaction mixture directly reacts with water for hydrolysis to generate an aqueous solution of phosphoenolpyruvate; (4) The phosphoenolpyruvate aqueous solution synthesized by the above-mentioned three-step reaction of bromination, phosphorylation, and hydrolysis in one pot, which is then filtered to remove insoluble residue, and then solid potassium hydroxide or potassium hydroxide solution The pH value of the aqueous solution of phosphoenolpyruvate is adjusted to 2-5, and then treated with absolute ethanol to obtain phosphoenolpyruvate potassium salt crystal solid.