JPH057395B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing monosodium phosphoenolpyruvate, and more particularly to a method for producing monosodium phosphoenolpyruvate monohydrate.

[Prior Art] Phosphoenolpyruvate (hereinafter abbreviated as PEP) is a high-energy phosphoric acid compound, and is an important compound in biochemistry and oxygen chemistry, particularly in regenerating adenosine triphosphate (ATP). Recently, oxygen-catalyzed organic synthesis reactions [for example, Journal of American Chemical Society (J.
Amer.Chem.SOC.), volume 107, page 7008 and volume 107
p. 7019, 1985] and is also useful as a blood preservative.

Chemical synthesis of PEP and its derivatives has been carried out for a long time, and for example, there is a method using halopyruvate and tolualkyl phosphite. However, the products of these long-known synthetic methods are esters of PEP, and there has been no satisfactory method for producing naturally occurring unesterified PEP on an industrial scale.

Methods for producing non-esterified PEP that have been proposed so far include: (1) a method using a derivative of pyruvic acid and phosphoric acid protected by a trimethylsilyl group (Japanese Patent Application Laid-open No.
56-113789), (2) Hydrolysis of dialkylphosphoenolpyruvate to obtain monopotassium salt with potassium hydroxide (JP-A-59-500515), (3) Hydrogenolysis of monobenzylphosphoenolpyruvate Method [Chem, Ber., vol. 92, p. 952, 1959], (4) PEP cyclohexylamine salt is converted to PEP using an ion exchange resin, and alkali hydroxide is added.
Method for obtaining PEP alkali metal salt aqueous solution [Biochemical Preparation (Biochem.
Prep.), vol. 11, p. 101, 1966] is known.

[Problem to be solved by the invention] However, in the method (1) mentioned above,
It is necessary to protect pyruvic acid with a trimethylsilyl group, which requires the use of expensive trimethylsilyl chloride, and the manufacturing operation is complicated.
The PEP produced is the trisodium salt. Also,
In the method (2) mentioned above, if sodium hydroxide is used instead of potassium hydroxide, it is expected that the sodium salt of PEP will be obtained.
After considering this method, we found that it has good purity.
The monosodium salt of PEP could not be obtained. Furthermore, in the method (3) mentioned above, not only the production yield of the monosodium salt of PEP is low, but also the double bond of the enol is hydrogenated, producing a large amount of by-products and making purification difficult. It becomes complicated. Furthermore, although an aqueous solution of an alkali metal salt of PEP can be obtained by the method (4) described above, the composition of the product obtained by this production method is unknown.

Therefore, the present invention is directed to PEP as described above.
The purpose of this invention is to overcome the problems in the method for producing monosodium and to provide a method for producing PEP monosodium that can be implemented on an industrial scale.

[Means for solving the problem] That is, the present invention has the following formula () [In the formula, R represents an alkyl group, a cycloalkyl group, or an aralkyl group. ] The present invention relates to a method for producing monosodium phosphoenolpyruvate, which comprises hydrolyzing monosubstituted sodium phosphoenolpyruvate represented by the following.

In the present invention, when R is an alkyl group,
The alkyl group is not particularly limited by the number of carbon atoms thereof, and the alkyl group may be a straight-chain alkyl group or a branched alkyl group. Specific examples of such alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec
-butyl group, tert-butyl group, n-amyl group, isoamyl group, sec-amyl group, activated amyl group,
tert-amyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, neohexyl group,
Examples include 2,3-dimethylbutyl group, and preferably methyl group, ethyl group, n-propyl group, and isopropyl group.

Further, when R is a cycloalkyl group, the cycloalkyl group is not particularly limited by the number of carbon atoms thereof, and the cycloalkyl group may be unsubstituted or substituted. Specifically, such alkyl groups include, for example, cyclopropyl group, cyclobutyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, cyclopentyl group, 1-methylcyclobutyl group, 2-methylcyclobutyl group, 1 , 2-dimethylcyclopropyl group, 2,2-dimethylcyclopropyl group, 1-
Ethylcyclopropyl group, 2-ethylcyclopropyl group, cyclohexyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group, 1,2-dimethylcyclobutyl group, 1,3-dimethylcyclo butyl group,
2,2-dimethylcyclobutyl group, 2,3-dimethylcyclobutyl group, 3,3-dimethylcyclobutyl group, 1-ethylcyclobutyl group, 2-ethylcyclobutyl group, 3-ethylcyclobutyl group, 1
-propylcyclopropyl group, 2-propylcyclopropyl group, 1-methyl-2-ethylcyclopropyl group, 1-ethyl-2-methylcyclopropyl group, etc., preferably cyclopentyl group,
Cyclohexyl group, cycloheptyl group, etc. are preferable.

Further, when R is an aralkyl group, the aralkyl group is not particularly limited by the number of carbon atoms, and the aralkyl group may be unsubstituted or substituted. Examples of such aralkyl groups include aralkyl groups in which the aromatic nucleus is unsubstituted such as benzyl, diphenylmethyl, and triphenylmethyl groups, o-chlorobenzyl, p-chlorobenzyl, m-chlorobenzyl, and o-methyl. There are aralkyl groups substituted with an aromatic nucleus such as benzyl group, p-methylbenzyl group, m-methylbenzyl group, and preferably benzyl group.

The substituted phosphoenolpyruvate represented by the formula () is, for example, represented by the following formula () [In the formula, R and R' may be the same or different, and represent an alkyl group, a cycloalkyl group, or an aralkyl group as defined for R above. ] It can be obtained by reacting the substituted phosphoenolpyruvic acid represented by the following with sodium iodide.

These compounds represented by the above formula () include, for example, halopyruvic acid and the following formula () [In the formula, R, R', and R'' may be the same or different, and represent an alkyl group, a cycloalkyl group, or an aralkyl group as defined for R and R' above.] [Chem.
Rev.), vol. 61, p. 607, 1961].

The reaction formula shows the method for producing sodium monosubstituted phosphoenolpyruvate, which is a raw material represented by the formula () described above. becomes.

In the present invention, sodium monosubstituted phosphoenolpyruvate represented by the formula () obtained by the production method described above is hydrolyzed in water or an aqueous solution. Examples of the aqueous solution include a water-alcohol mixed solution such as a water-methanol mixed solution, a water-ethanol mixed solution, and a water-based organic solvent such as a water-acetone mixed solution or a water-tetrahydrofuran mixed solution. Mixed solvents can be used. In this case, the amount of water used should be changed as appropriate depending on the type of substituent in the monosubstituted sodium phosphoenolpyruvate, but it is usually 1.5 to 10 times the weight of the monosubstituted sodium phosphoenolpyruvate. It is preferable to do so. The reaction temperature is also preferably varied depending on the type of substituent, but is usually 5 to 50°C, preferably 20 to 40°C. The reaction time depends on the type of substituent, amount of water, reaction temperature, etc., but usually 5
~72 hours is recommended.

To precipitate monosodium pyruvate as a monohydrate from water or an aqueous solution after hydrolysis,
A water-soluble organic solvent such as acetone, methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane, etc. may be added to the hydrolysis solution. The amount of organic solvent used at this time is preferably 2 to 10 times the volume of water used during hydrolysis. The precipitated crystals were isolated using conventional methods,
For example, it is dried by air drying. The crystals obtained in this way are analyzed by NMR spectroscopy (solvent: heavy water, internal standard: hydroquinone) and high performance liquid chromatography (column: TSK gel QSA).
-2SW, eluent: 0.15 mol KC aqueous solution, detector: UV210 nm, internal standard: maleic acid) and atomic absorption spectrometry, it was found to be monosodium phosphoenolpyruvate monohydrate.

[Example] Hereinafter, the present invention will be explained in more detail based on Reference Examples and Examples.

Reference Example A solution of 8.4 g of bromopyruvic acid in 20 ml of anhydrous ether was added dropwise to a solution of 6.8 g of trimethyl phosphite in 40 ml of anhydrous ether with stirring at such a rate that the ether slowly refluxed. After the dropwise addition was completed, the reaction was continued for an additional hour, and then the reaction solution was concentrated under reduced pressure to obtain a viscous liquid. Add this liquid to 60ml of methyl ethyl ketone.
Add 7.5g of sodium iodide dissolved in
The mixture was stirred for 6 hours. The precipitated crystals were separated, washed with a small amount of methyl ethyl ketone, and dried under reduced pressure to obtain 9.8 g of monomethylphosphoenolpyruvate monosodium salt.

Example 1 9.8 g of monosodium monomethylphosphoenolpyruvate was dissolved in 19.6 ml of water and stirred at 25° C. for 30 hours. After the reaction is complete, add 98ml of acetone,
Cooled to 0°C. The precipitated crystals were separated and dried under reduced pressure. This crystal was analyzed by melting point, NMR spectrum, IR spectrum, and elemental analysis, and was confirmed to be phosphoenolpyruvate monosodium salt monohydrate. yield
7.2g. Melting point: 120℃ (decomposition).

Purity determined by high performance liquid chromatography
It was 99.3%.

Analytical value of Na: 11.03% (calculated value: 11.05%) Example 2 The same operation as in Example 1 was performed except that the solvent for crystallization was changed from acetone to ethanol.

Yield 6.9g. Melting point 120℃ (decomposition).

Purity 99.0% determined by high performance liquid chromatography.
Na analysis 11.10%.

Example 3 The same operation as in Example 1 was performed except that monobenzylphosphoenolpyruvate monosodium salt obtained in the same manner as in Reference Example was used.

Yield 6.8g. Melting point 120℃ (decomposition).

Purity 98.9%. Na analysis 11.12%.

[Effects of the Invention] According to the production method of the present invention, highly purified sodium phosphoenolpyruvate can be obtained,
Furthermore, since the production method of the present invention is easy to operate, sodium phosphoenolpyruvate can be produced on an industrial scale.

Claims (1)

[Claims] Linear formula () [In the formula, R represents an alkyl group, a cycloalkyl group, or an aralkyl group. ] A method for producing monosodium phosphoenolpyruvate, which comprises hydrolyzing monosubstituted sodium phosphoenolpyruvate represented by the following. 2 carrying out the hydrolysis in water or an aqueous solution;
A water-soluble organic solvent is added to the resulting solution of monosodium phosphoenolpyruvate to precipitate crystals, which are then dried and isolated as monosodium phosphoenolpyruvate monohydrate. A method for producing monosodium phosphoenolpyruvate according to item 1.