JPH0940603A - Purification of optically active organic polybasic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject polybasic acid almost without consuming auxiliary raw materials, almost without forming waste materials, with an easy operation, having a wide range of variation in the operating conditions and capable of highly purifying the compound easily by purifying through the disproportionation process of an optically active organic polybasic acid hydrogen salt using an organic solvent. SOLUTION: This optically active organic polybasic acid is purified by performing (B) a disproportionation process of the optically active organic polybasic acid hydrogen salt by using (A) an organic solvent. As the component A in the disproportionation process, a solvent not having reactivity with (C) the optically active organic polybasic acid and capable of dissolving >=5wt.% component C at the disproportionation temperature, is preferably used. Further, e.g. concretely, acetone, etc., are used as the component A, and calcium hydrogen L-malate, etc., are preferably treated at 50 deg.C for 1hr under the disproportionation conditions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for purifying optically active organic polybasic acids such as optically active malic acid.

[0002]

The production and purification of optically active malic acid is
It is common to carry out acid decomposition of the normal salt of malic acid.

The method described in JP-A-51-70880 is a method for recovering and purifying L-malic acid produced by fumarase treatment. Under the reaction conditions described, malic acid and fumaric acid are mixed at a ratio of 6: 1. It has become a degree. Therefore, in order to remove fumaric acid, it is once acidified with hydrochloric acid to precipitate fumaric acid to obtain crude L-malic acid. Next, calcium hydroxide is added to crystallize as L-calcium malate, that is, a normal salt of L-malic acid, and sulfuric acid is further added to release L-malic acid. Since calcium sulfate is slightly soluble in water, the recovered L-malic acid is treated with an ion exchange resin to remove calcium sulfate.

As a method for decomposing L-calcium malate, a method of decomposing with a strong acid type cation exchange resin is disclosed in Japanese Patent Laid-Open No.
It is described in JP-A-3-130555. This method is intended to recover L-malic acid from L-calcium malate produced by the action of fumarase, but it is clear that it can be used as one step of producing crude L-malic acid via a calcium normal salt. Is. This method has the advantages that it is easy to operate and does not produce industrial waste of calcium sulfate.

Although not an example of L-malic acid or an optically active organic polybasic acid, JP-A-6-48979 discloses a method for purifying citric acid. In this method, crude citric acid is reacted with calcium citrate to give calcium monohydrogen citrate, and then calcium monohydrogen citrate is disproportionated in an aqueous solution to release citric acid. This method is excellent in that it is easy to operate and does not generate industrial waste.

[0006]

The prior art methods have some problems to be solved when applied to industrial production.

The purification method described in JP-A-51-70880 is (1) complicated in operation, (2) requires a large amount of auxiliary raw material, and (3) has a large amount of calcium sulfate as the auxiliary raw material. There are problems that industrial waste is generated, and (4) L-malic acid is adsorbed on the anion exchange resin, so that the recovery rate is low.

A method proposed to solve the problems of the purification method described in the above publication is disclosed in JP-A-63-13055.
This is the method disclosed in Japanese Patent No. The method described in such publication is L
-It can also be used as a method for purifying malic acid,
It is advantageous in that it does not generate a large amount of calcium sulfate waste and does not adsorb malic acid. A new problem that arises is that a large amount of acidic waste liquid containing calcium salts is generated in the step of regenerating the cation exchange resin.
Therefore, the problem itself that a large amount of waste is generated has not been solved.

With respect to these two prior arts, JP-A-6-
The method described in Japanese Patent No. 48979 is an excellent method since it is difficult in principle to generate salt waste derived from the auxiliary raw material. The problems are (1) the free citric acid is an aqueous solution but the calcium salt is present, and (2) the calcium salt can be reduced by the second treatment, but the operation is complicated. , Can be given.

The present inventor examined the applicability of this method and its similar methods. For example, when sodium salt was used instead of calcium salt, disproportionation did not proceed. Optically active calcium hydrogen malate is also disclosed in JP-A-6-48.
It was not disproportionated by the similar method described in Japanese Patent Publication No. 979. Only exceptionally was it found that DL-calcium hydrogen malate disproportionated under similar conditions. That is, the method described in JP-A-6-48979 or a method similar thereto is effective in limited cases such as citric acid and calcium salt of DL-malic acid, and as an organic acid purification method or an optically active organic acid purification method. It has no generality.

The object of the present invention is to have generality as a method for purifying an optically active organic polybasic acid, and (1) hardly consume auxiliary materials, (2) hardly generate waste, The present invention provides a method for purifying an optically active organic polybasic acid, which has advantages such as (3) easy operation, (4) wide variable range of operating conditions, and (5) easy purification.

[0012]

The present inventor diligently studied a method for purifying an optically active organic polybasic acid which solves the drawbacks of the prior art. As a result, they found that the optically active organic polybasic acid hydrogen salt is effectively disproportionated in an organic solvent, and it was found that the above objects can be achieved by this, and the present invention was completed based on this finding. Came to.

That is, the above objects can be achieved by (1) a method for purifying an optically active organic polybasic acid via a disproportionation step of an optically active organic polybasic acid hydrogen salt using an organic solvent.

Further, the present invention provides (2) the organic solvent has no reactivity with the optically active organic polybasic acid in the disproportionation step, and at the disproportionation temperature, the organic active polybasic acid is not reacted. The above (1) which dissolves 5% by weight or more
It can also be achieved more suitably by the purification method shown in.

As used herein, the term "disproportionation" refers to the exchange of cations such as hydrogen ions and metal ions between the chemical species existing as (optically active) organic polybasic acid hydrogen salt. The chemical changes to form an (optically active) organic polybasic acid and an (optically active) organic polybasic acid salt are shown. Furthermore, the term organic polybasic acid used in the present invention shall also include organic dibasic acids and organic tribasic acids. Therefore, the term optically active organic polybasic acid also includes optically active organic dibasic acids and optically active organic tribasic acids.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION According to the disproportionation operation of the present invention,
A free optically active organic polybasic acid can be obtained from the optically active organic polybasic acid hydrogen salt. The method for purifying an optically active organic polybasic acid in the present invention comprises a novel step of producing a free optically active organic polybasic acid by disproportionating an optically active organic polybasic acid hydrogen salt in an organic solvent. It includes.

A particularly preferred embodiment of the invention is to treat the solid optically active organic polybasic acid hydrogen salt with an organic solvent. In this respect, it is different from the ordinary extraction method using the partition between the two liquid phases.

This method is different from the method of recovering and purifying an organic acid from a mixture of an organic acid and an organic acid salt. That is, in such a mixture, the organic acid is always present stoichiometrically regardless of the existing state such as solid state or solution state. Recovery and purification of organic acids from such mixtures causes physical changes. This method effectively causes the chemical change of the organic polybasic acid hydrogen salt and is essentially different from the usual separation method.

Embodiments of the present invention will be described below in detail with reference to the drawings.

FIG. 1 is a schematic process diagram showing, as an embodiment of the purification method of the present invention, a flow of a production (purification) process including a preparation step of an optically active organic polybasic acid hydrogen salt which will be described later. is there.

First, the optically active organic polybasic acid hydrogen salt that can be used in the method for purifying the optically active organic polybasic acid of the present invention is not particularly limited and is prepared by a conventionally known method. Is something that can be done. The operation itself of such a preparation method is generally well known, and although it is not particularly novel, it will be briefly described. The optically active organic polybasic acid hydrogen salt necessary for the present invention is obtained by reacting a raw optically active organic polybasic acid as a raw material with an appropriate amount of the optically active organic polybasic acid normal salt as shown in FIG. , Step (I)), or a method of neutralizing the raw optically active organic polybasic acid as a raw material with an appropriate amount of a metal oxide, hydroxide or carbonate.

The crude optically active organic polybasic acid used as a raw material in the above method may be one prepared by any method such as a fermentation method, an enzymatic method, an extraction method and a synthetic method. Among them, the preferable crude optically active organic polybasic acid has the properties that the optically active organic polybasic acid hydrogen salt can be crystallized and that it is difficult to purify in the free acid state.

In the above-mentioned preparation method, the optically active organic polybasic acid hydrogen salt is obtained by crystallizing and precipitating, but it is preferable to further recrystallize it if necessary. Depending on the type of impurities, the optically active organic polybasic acid hydrogen salt can be washed with a suitable organic solvent or the like. By this crystallization (and recrystallization), impurities in the crude optically active organic polybasic acid can be effectively removed, and a highly pure optically active organic polybasic acid hydrogen salt can be prepared.

Next, as a method for purifying the optically active organic polybasic acid according to the present invention, as shown in FIG. 1, an optically active organic polybasic acid hydrogen salt (for example, one obtained by the above-mentioned preparation method) Is disproportionated in an organic solvent to produce an optically active organic polybasic acid and an optically active organic polybasic acid normal salt (formula 1), and these are treated by an appropriate method to finally obtain the optically active organic polybasic acid. The organic polybasic acid is separated and purified (indicated as step (II) in the figure).

Optically active organic polybasic acid hydrogen salt → optically active organic polybasic acid (Formula 1) As a reaction related to the above Formula 1, in an aqueous solution of the organic polybasic acid hydrogen salt, an organic polybasic acid is converted by an equilibrium reaction. Generating is well known. However, when the organic polybasic acid hydrogen salt aqueous solution is concentrated, the organic polybasic acid hydrogen salt is formed again, and it is usually impossible to obtain a free organic polybasic acid. Therefore, it has been believed difficult to disproportionate an aqueous solution of an organic polybasic hydrogen salt to prepare a free organic polybasic acid. With a lucky exception,
There is a description (Hirokawa Shoten, Kagaku Daijiten) that L-calcium hydrogen malate aqueous solution is disproportionated at 60 ° C (it was difficult to reproduce). Preparation of acid (JP-A-6-4
8979), in connection with these, the present inventor
-It is only seen that it was found to disproportionate when heating the aqueous solution of calcium hydrogen malate.

Purification method according to the present invention (step (I
I)) is characterized in that the organic polybasic acid hydrogen salt is treated in an organic solvent. Disproportionation in this organic solvent is
It enables the general-purpose and effective disproportionation of organic polybasic acid hydrogen salt, which has been considered difficult in the past, and produces an organic polybasic acid in a state where it can be easily separated. This point is qualitatively different from the formation of organic polybasic acid by the equilibrium reaction in an aqueous solution.

The details of the refining method (step (II) in the figure), constituents and the like according to the present invention will be described in detail below.

[Organic Solvent] First, as shown in FIG. 1, an organic solvent is used in the disproportionation step of the step (II).
As this organic solvent, any solvent can be used as long as it dissolves the optically active organic polybasic acid at the temperature of the disproportionation treatment and the deterioration during the disproportionation treatment does not pose a problem.
However, in consideration of the actual operation, an organic solvent capable of dissolving 5% by weight or more, preferably 10% by weight or more of the optically active organic polybasic acid under the temperature condition of the disproportionation treatment is practical. The boiling point of the organic solvent does not directly limit the use range of the organic solvent, but it is preferable that vaporization / condensation is easily caused from the viewpoint of easy recovery and reuse. From this point of view, the boiling point of the organic solvent is preferably 160 ° C. or lower at 1 atm, and more preferably 120 ° C. at 1 atm.
It is the following. Specific examples of the even more preferable organic solvent include ketone-based solvents such as acetone and 2-butanone (MEK),
Tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), ether solvents such as dioxane and ether, alcohol solvents such as methanol, ethanol, butanol and pentanol, acetonitrile (A
N) and other nitrile solvents, ethyl acetate and other ester solvents, dichloromethane and other halogen solvents, and the like.

These organic solvents can also be used as a mixture. It is also possible to add small amounts of substances to promote disproportionation. In particular, it is effective to contain a small amount of water or to add water within a range in which an aqueous phase does not appear under disproportionation conditions. For example, when acetone is used as the organic solvent to disproportionate L-calcium hydrogen malate, it is possible to add 10% or less by volume of water. In this state, an aqueous phase is not formed and solid salts (hydrogen salt and normal salt) are suspended in the organic solvent. When the optically active organic polybasic acid salt has a property of being particularly easily dissolved in water, it is desirable to reduce the amount of water added so that the salt remains in a solid state.

[Disproportionation Temperature and Time] Temperature and time are also important as factors affecting the disproportionation reaction. An example of investigating the effect of temperature on disproportionation is shown in Example 10 (Table 3). For example, when disproportionated at 50 ° C for 1 hour, the disproportionation rate is 8
Although it became 5%, when the mixture was further stirred at 25 ° C. for 24 hours, the disproportionation rate decreased to 18%. The results show that disproportionation is higher at higher temperatures. We also investigated the effect of time. In the same example, the disproportionation rate was examined at 25 ° C., and it was 2% after 1 hour and 14% after 24 hours. As a result, it is shown that the setting of the disproportionation processing time is also important. When the disproportionation treatment time was set to 1 hour, the disproportionation ratio increased remarkably as the temperature increased. In consideration of these examination results, in many examples, the disproportionation treatment condition of 50 ° C. for 1 hour was frequently used. However, the disproportionation treatment conditions are not limited to the temperature and time exemplified in the examples. The disproportionation treatment conditions can be freely set within a range where decomposition of an organic acid is not a problem and a range where disproportionation operation and subsequent separation operation are not difficult. Here, the "disproportionation rate" means the expression 2 below.

[0031]

[Equation 1]

It is a value represented by

The amount of hydrogen ions in the formula (2) can be measured by neutralizing titration with sodium hydroxide using an optically active organic polybasic acid hydrogen salt or an optically active organic polybasic acid as an aqueous solution. In order to reduce the titration error, the hydrogen ion concentration (pH) is measured with a pH meter, and the hydrogen ion amount is determined with the time point at which the pH change per added sodium hydroxide is the maximum as the neutralization point. The pH of the neutralization point in this process are those generally 2-3 higher than the acid dissociation constant of the formula 3 (pKa _n), titration error is 0.2% or less.

[0034]

Embedded image

[Optically Active Organic Polybasic Acid Hydrogen Salt] This disproportionation method is generally applicable to organic polybasic acid hydrogen salts, and is applicable to various optically active organic polybasic acid hydrogen salts. Therefore, this disproportionation method is also applicable to an optically active organic polybasic acid hydrogen salt obtained by using a preparation method other than the above-mentioned preparation method (step (I) in the figure). . However, if the optically active organic polybasic acid is volatile, it will be difficult to separate it from the organic solvent, and the highly volatile optically active organic polybasic acid will be easily purified by the distillation method, so it will go through the disproportionation process. It is considered that the significance of applying the present purification method is small. Therefore, a hydrogen salt of an optically active organic polybasic acid that cannot be practically distilled is a target of application of this disproportionation method. In the examples, hydrogen salts of optically active malic acid, citramalic acid, tartaric acid, methylsuccinic acid, isocitric acid, etc. were exemplified, but the object of the present invention is not limited to these optically active organic polybasic acid hydrogen salts.

Various cations can be used as the cation in the optically active organic polybasic acid hydrogen salt used in the disproportionation step in the purification method (step (II) shown in FIG. 1) according to the present invention. For example, alkali metal ions such as ammonium ions, lithium ions, sodium ions, and potassium ions, alkaline earth metals such as magnesium ions, calcium ions, strontium ions, and barium ions, and various metal ions such as zinc can be used. The type of these cations greatly affects the disproportionation rate. Practically, it is desirable to easily realize a high disproportionation rate, and in this respect, it is preferable to use lithium ion, magnesium ion, calcium ion, strontium ion, barium ion, or zinc ion. In particular, it is preferable to use calcium ion as a cation in the optically active organic polybasic acid hydrogen salt, which generally gives a high disproportionation rate.

The optically active organic polybasic acid hydrogen salt used in the disproportionation step in the purification method (step (II) shown in FIG. 1) according to the present invention is not limited to the anhydrous salt. That is, the present disproportionation method can be applied even if the optically active organic polybasic acid hydrogen salt contains crystal water, adsorbed water, or adhering water. When various kinds of water are contained in the optically active organic polybasic acid hydrogen salt, it is desirable to increase or decrease the water content in the organic solvent according to the content of water.

[Particle Size of Optically Active Organic Polybasic Acid Hydrogen Salt and Stirring During Disproportionation Operation] Under the conditions that this disproportionation method can be effectively applied, the optically active organic polybasic acid hydrogen salt is dissolved in an organic solvent. Particles are suspended. A small particle size is advantageous because the disproportionation proceeds faster. However, since it is seen that the particles disintegrate as the disproportionation reaction progresses, the disproportionation process can be performed even for large particles by prolonging the treatment time and stirring strongly. It is also effective to perform disproportionation treatment twice for large particles. Example 11 (2) described later is
It is a disproportionation of optically active calcium hydrogen malate of a slightly large particle. In the first disproportionation, the disproportionation rate was a little low at 78%, but the particles disintegrated and became fine particles. As a result, the second disproportionation proceeded effectively and was almost completely disproportionated.

[Mixing Ratio of Optically Active Organic Polybasic Acid Hydrogen Salt and Organic Solvent] The mixing ratio of the optically active organic polybasic acid hydrogen salt and the organic solvent is the number of moles of hydrogen ions in the optically active organic polybasic acid hydrogen salt. Based on the above, it is practical that the organic solvent is 0.1 to 50 ml per 1 mmol of hydrogen ion. Preferably, the organic solvent is 0.5 to 10 ml per 1 mmol of hydrogen ion of the optically active organic polybasic acid hydrogen salt.

[Treatment after Disproportionation Operation] In the purification method according to the present invention, after the disproportionation reaction, as shown in step (II) of FIG. 1, solid-state optically active organic polybasic acid salts and Solid-liquid separation is performed with an organic solvent solution of an optically active organic polybasic acid.
Separation of both of them can be carried out by a commonly used separation method such as a filtration method, a centrifugal separation method or a decantation method.
Since the disproportionation rate changes when the temperature is changed and left after the disproportionation treatment, it is desirable to rapidly separate the optically active organic polybasic acid salts and the organic solvent solution of the optically active organic polybasic acid. Further, as shown in step (II) of FIG. 1, in the purification method according to the present invention, the optically active organic polybasic acid salt is separated and recovered. The recovered optically active organic polybasic acid salt can be disproportionated again to release the optically active organic polybasic acid hydrogen salt from the remaining optically active organic polybasic acid hydrogen salt. By repeating disproportionation treatment of the recovered optically active organic polybasic acid salts, it is possible to finally disproportionate all the optically active organic polybasic acid hydrogen salts to obtain optically active organic polybasic acid normal salts. It is possible if necessary.

Subsequently, the separated organic solvent solution of the optically active organic polybasic acid is subjected to a treatment of distilling or evaporating the organic solvent as shown in step (II) of FIG. Separate and collect each basic acid. This separation and recovery method is a general method. The organic solvent recovered here can be reused in the disproportionation step. In this disproportionation step, by controlling the disproportionation conditions, it is possible to recover a highly pure optically active organic polybasic acid.

As shown in step (II) of FIG. 1, when the above-described disproportionation step is one step of the method for purifying an optically active organic polybasic acid, the disproportionation treatment may be performed once or more. The recovered optically active organic polybasic acid salt is used as it is or as a raw material for producing an optically active organic polybasic hydrogen acid salt by removing the remaining organic solvent by washing or evaporation. By this operation, the base component derived from the auxiliary material used first can be recovered and reused. As a result, it is possible to purify the optically active organic acid with almost no consumption of auxiliary raw materials, and thus with almost no generation of waste materials derived from the auxiliary raw materials.

[0043]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 (Disproportionation of L-magnesium hydrogen malate) L-magnesium hydrogen malate sample 544 containing water of crystallization
3 mg of an organic solvent was added to mg (436 mg, containing 1.50 mmol of L-magnesium hydrogen malate) at 50 ° C.
For 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. The organic solvents used and the results are summarized in Table 1.

Example 2 (Disproportionation of strontium hydrogen malate) L-strontium hydrogen malate sample 64 containing water of crystallization
To 2 mg (531 mg, containing 1.50 mmol L-strontium hydrogen malate), 3 ml of an organic solvent was added, and 5
Stirred at 0 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. The organic solvents used and the results are summarized in Table 1.

Example 3 (Disproportionation of L-barium hydrogen malate) 640 mg of L-barium hydrogen malate sample containing water of crystallization
3 ml of an organic solvent was added to (containing 605 mg, 1.50 mmol of L-barium hydrogen malate) and stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is the organic solvent 1
Washed twice with each ml. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. Table 1 shows the organic solvents used and the results.
Summarized in

Example 4 (Disproportionation of L-Lithium hydrogen malate) 485 mg of L-lithium hydrogen malate sample containing water of crystallization
3 ml of an organic solvent was added to (containing 420 mg, 3.00 mmol of lithium hydrogen malate) and stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is the organic solvent 1
Washed twice with each ml. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. Table 1 shows the organic solvents used and the results.
Summarized in

Example 5 (Disproportionation of L-sodium hydrogen malate) L-sodium hydrogen malate sample 524m containing water of crystallization
3 g of an organic solvent was added to g (468 mg, containing 3.00 mmol of L-sodium hydrogen malate), and the mixture was added at 50 ° C. for 1 hour.
Stir for hours. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. The organic solvents used and the results are summarized in Table 1.

Example 6 (Disproportionation of L-potassium hydrogen malate) 525 mg of L-potassium hydrogen malate sample containing water of crystallization
3 ml of an organic solvent was added to (517 mg, containing 3.00 mmol of L-potassium hydrogen malate) and stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is the organic solvent 1
Washed twice with each ml. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. Table 1 shows the organic solvents used and the results.
Summarized in

Example 7 (Disproportionation of ammonium hydrogen L-malate) To 345 mg (3.00 mmol) of ammonium hydrogen L-malate was added 3 ml of an organic solvent, and the mixture was stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is 1 ml of an organic solvent.
Washed twice with each. The organic phase and washing solution are combined and concentrated, and L
-Get malic acid. The organic solvents used and the results are summarized in Table 1.

Example 8 (Disproportionation of zinc L-malate malate) A sample of zinc L-malate malate containing water of crystallization 573 mg (4
97 mg and 1.50 mmol of L-zinc hydrogen malate (containing) were mixed with 3 ml of an organic solvent and stirred at 50 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution are combined and concentrated, and L-
I got malic acid. The organic solvents used and the results are summarized in Table 1.

[0052]

[Table 1]

Example 9 (Disproportionation of L-calcium hydrogen malate) L-calcium hydrogen malate sample 609m containing water of crystallization
3 g of an organic solvent was added to g (459 mg, containing 1.50 mmol of L-calcium hydrogen malate), and the mixture was added at 50 ° C. to 1
Stir for hours. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain L-malic acid. The organic solvents used and the results are summarized in Table 2.

As the organic solvent, acetone, MEK,
When ether, THF and dioxane were used, 501 mg of L-calcium hydrogen malate sample (well dried,
403 mg, containing 1.32 mmol L-calcium hydrogen malate). These results are also shown in Table 2.

[0055]

[Table 2]

Example 10 (Disproportionation of L-calcium hydrogen malate) L-calcium hydrogen malate sample 536m containing water of crystallization
g (403 mg, containing 1.32 mmol of L-calcium hydrogen malate) in water-containing acetone (acetone: water = 1)
2: 1) 3 ml was added and the mixture was stirred under the disproportionation conditions shown in Table 3. The organic phase was separated by filtration, and the residue was washed twice with 1 ml of water-containing acetone at the same temperature as the disproportionation condition (boiling point in the case of 60 ° C.). The organic phase and the washing solution are combined and concentrated, and L-
I got malic acid. The results are summarized in Table 3 together with the disproportionation conditions.

[0057]

[Table 3]

Example 11 (Purification of L-malic acid) (1a) Preparation of L-calcium hydrogen malate 43.0 g (0.25 mol) of L-malate and 33.5 g (0.25 mol) L-malic acid at 50 ° C
It was dissolved in 603 ml of warm water. The solution was cooled to 0 ° C. to precipitate L-calcium hydrogen malate crystals.
The obtained crystals were almost hexahydrate, and the amount that could be recovered was 9
It was 0.8 g (89% of the theoretical recovery).

(1b) L prepared from crude L-malic acid
-Preparation of calcium hydrogen malate 7.8 g of crude L-malic acid containing 6.7 g (0.05 mol) of L-malic acid and 1.1 g of fumaric acid was added to 120 ml of water and insoluble at 25 ° C. Was filtered off.
8.6 g (0.05 mol) of L-calcium malate was added and heated to 50 ° C. to dissolve. Cool the solution to 0 ° C., L
-Precipitated crystals of calcium hydrogen malate. The precipitated crystals were washed twice with 5 ml of cold water. The obtained crystals were almost hexahydrate, and the amount that could be recovered was 17.1 g (recovery rate 85% based on the theoretical value). Fumaric acid in this crystal was 0.4%.

(2) Disproportionation of L-calcium hydrogen malate 10.7 g (8.06 g, 26.3 mmol of L-apple) of the L-calcium hydrogen malate sample containing the water of crystallization obtained in (1a) above. 50 ml of water-containing acetone (acetone: water = 12: 1) was added to calcium hydrogenate) and the mixture was heated at 50 ° C. for 2 hours.
Stir for hours. The organic phase was separated by filtration, and the residue was washed twice with 11 ml each of water-containing acetone (acetone: water = 12: 1). The organic phase and the washing solution were combined and concentrated to obtain 2.77 g (20.7 mmol) of L-malic acid. The L-malate salt residue was recovered. 25 ml of water-containing acetone (acetone: water = 12: 1) was added to the L-malate salt residue, and the mixture was stirred again at 50 ° C. for 2 hours. Filter to separate the organic phase,
6 ml of water-containing acetone (acetone: water = 12: 1)
Washed twice with each. The organic phase and washing solution are combined and concentrated, and L
0.82 g (6.1 mmol) of malic acid was obtained. This result showed that the L-calcium hydrogen malate can be almost completely disproportionated by performing two disproportionation operations. The L-malic acid obtained here had high purity and the amount of calcium as an impurity was 0.022%.

Example 12 (Disproportionation of L-calcium hydrogen tartrate) 607 mg of L-calcium hydrogen tartrate sample containing water of crystallization
3 ml of an organic solvent was added to (containing 507 mg, 1.50 mmol of L-calcium hydrogen tartrate) and stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is the organic solvent 1
Washed twice with each ml. The organic phase and the washing liquid were combined and concentrated to obtain L-tartaric acid. The organic solvent used and the results are summarized in Table 4.

[0062]

[Table 4]

Example 13 (Disproportionation of L-calcium hydrogen citramalate) L-calcium hydrogen citramalate sample 17 containing water of crystallization
3 ml of an organic solvent was added to 0 mg (167 mg, containing 0.50 mmol of L-calcium hydrogen citramalate), and 5
Stirred at 0 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing liquid were combined and concentrated to obtain L-citramalic acid. The organic solvents used and the results are summarized in Table 5.

Example 14 (Disproportionation of L-sodium hydrogen citramalate) L-Sodium hydrogen citramalate sample 18 containing water of crystallization
3 mg of an organic solvent was added to 6 mg (170 mg, containing 1.00 mmol of sodium hydrogen citramalate) 5
Stirred at 0 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing liquid were combined and concentrated to obtain L-citramalic acid. The organic solvents used and the results are summarized in Table 5.

[0065]

[Table 5]

Example 15 (Disproportionation of calcium hydrogen (-)-methylsuccinate) 310 mg (302 mg, 1.00 mmol (-) of calcium hydrogen (-)-methylsuccinate sample containing water of crystallization
-Containing calcium hydrogen succinate) and organic solvent 3
ml was added and the mixture was stirred at 50 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain (-)-methylsuccinic acid. The organic solvents used and the results are summarized in Table 6.

Example 16 (Disproportionation of sodium hydrogen (-)-methylsuccinate) A sample of sodium hydrogen (-)-methylsuccinate (310 mg) containing water of crystallization (308 mg, 2.00 mmol (-)).
-Containing sodium hydrogen succinate) and organic solvent 3
ml was added and the mixture was stirred at 50 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain (-)-methylsuccinic acid. The organic solvents used and the results are summarized in Table 6.

Example 17 (Disproportionation of ammonium hydrogen (-)-methylsuccinate) A sample of ammonium hydrogen (-)-methylsuccinate containing water of crystallization 299 mg (298 mg, 2.00 mmol of ammonium hydrogen (-)-methylsuccinate). 3 ml) of an organic solvent was added to (containing) and the mixture was stirred at 50 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain (-)-methylsuccinic acid. The organic solvents used and the results are summarized in Table 6.

[0069]

[Table 6]

Example 18 (Disproportionation of calcium monohydrogen (-)-isocitrate) An aqueous solution of (-)-isocitrate (192 m in 10 ml).
g (containing 1 mmol of (−)-isocitric acid) and 74 mg (1 mmol) of calcium hydroxide were reacted and dried under vacuum to obtain 230 mg (1.00 mmol of calcium monohydrogen (-)-isocitrate). 5 ml of water-containing acetone (acetone: water = 20: 1) was added to hydrogen ion (including 1.00 milliequivalent), and the mixture was stirred at 50 ° C. for 10 minutes. The organic phase was separated by filtration and the residue was washed twice with 2 ml each of organic solvent. The organic phase and the washing solution were combined and concentrated to obtain (-)-isocitric acid. The (-)-isocitric acid obtained was 0.8.
9 mg (0.0046 mmol, hydrogen ion 0.01
4 meq) and the disproportionation rate based on the amount of hydrogen ions was 1.4%.

Example 19 (Disproportionation of calcium dihydrogen (-)-isocitrate) An aqueous solution of (-)-isocitrate (192 m in 10 ml).
g (containing 1 mmol of (−)-isocitrate) and 37 mg (0.5 mmol) of calcium hydroxide were reacted and dried under vacuum to obtain 211 mg (0.50) of calcium dihydrogen (-)-isocitrate. Millimol, hydrogen ion 2.0
5 ml of water-containing acetone (acetone: water = 20: 1) was added to 0 milliequivalent, and the mixture was stirred at 50 ° C. for 6 minutes. The organic phase is separated by filtration and the residue is washed with 2 ml of organic solvent.
Washed times. The organic phase and the washing solution were combined and concentrated to obtain (-)-isocitric acid. The (-)-isocitric acid obtained was 8
9.2 mg (0.464 mmol, hydrogen ion 1.39)
And the disproportionation rate based on the amount of hydrogen ions is 7
It was 0%.

Example 20 (Disproportionation of L-magnesium hydrogen malate) Sample 544 of L-magnesium hydrogen malate containing water of crystallization
mg (containing 436 mg, 1.50 mmol L-magnesium hydrogen malate) containing water DME (DME: water = 1)
2: 1) 3 ml was added and stirred at 80 ° C. for 1 hour. The organic phase was separated by filtration, and the residue was washed twice with 1 ml each of water-containing DME. The organic phase and the washing liquid were combined and concentrated, and 162 ml of L-malic acid (1.21 mmol, disproportionation rate 80.3%)
I got

Example 21 (Disproportionation of L-calcium hydrogen tartrate) 405 mg of L-calcium hydrogen tartrate sample containing water of crystallization
(338 mg, containing 1.00 mmol of L-calcium hydrogen tartrate) in water-containing dioxane (dioxane: water = 1)
2: 1) 3 ml was added and stirred at 80 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of hydrous dioxane. The organic phase and the washings were combined and concentrated to obtain 141 ml of L-tartaric acid (0.94 mmol, disproportionation rate 94%).

Example 22 (Disproportionation of L-strontium hydrogen tartrate) L-strontium hydrogen tartrate sample 421 containing water of crystallization
3 mg of hydrous dioxane (dioxane: water = 12: 1) was added to mg (386 mg, containing 1.00 mmol of strontium hydrogen tartrate) and stirred at 50 ° C. for 1 hour. The organic phase is separated by filtration and the residue is hydrous dioxane 1
Washed twice with each ml. The organic phase and the washing liquid were combined and concentrated to obtain 80 ml of L-tartaric acid (0.54 mmol, disproportionate ratio 54%).

Example 23 (Disproportionation of L-strontium hydrogen tartrate) L-strontium hydrogen tartrate sample 421 containing water of crystallization
3 mg of hydrous dioxane (dioxane: water = 12: 1) was added to mg (386 mg, containing 1.00 mmol of strontium hydrogen tartrate) and stirred at 80 ° C. for 1 hour. The organic phase is separated by filtration and the residue is hydrous dioxane 1
Washed twice with each ml. The organic phase and the washing solution were combined and concentrated to obtain 146 ml (0.97 mmol, disproportionation rate 97%) of L-tartaric acid.

Example 24 (Disproportionation of L-strontium hydrogen tartrate) L-strontium hydrogen tartrate sample 421 containing water of crystallization
3 mg of methanol was added to mg (386 mg, containing 1.00 mmol of strontium hydrogen tartrate) 50
The mixture was stirred at 0 ° C for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of methanol. The organic phase and the washing solution were combined and concentrated to obtain 74 ml of L-tartaric acid (0.49 mmol, disproportionation ratio 49%).

Example 25 (Disproportionation of L-calcium hydrogen malate) L-calcium hydrogen malate sample 609m containing water of crystallization
g (459 mg, containing 1.50 mmol L-calcium hydrogen malate) in water containing DME (DME: water = 12:
1) 3 ml was added and stirred at 80 ° C. for 1 hour. The organic phase was separated by filtration and the residue was washed twice with 1 ml each of water-containing DME. The organic phase and the washing solution are combined and concentrated to give L-malic acid 196.
mg (1.46 mmol, disproportionation rate 97.3%) was obtained. In this example, formation of a paste-like liquid phase was confirmed during the treatment, but in this case as well, it was also confirmed that a solid salt was formed again at the final point of the treatment.

[0078]

EFFECT OF THE INVENTION The method for purifying an optically active organic polybasic acid according to the present invention goes through a disproportionation step of an optically active organic polybasic acid hydrogen salt, and (1) hardly consumes an auxiliary material, (2) Generates almost no waste, (3) Easy operation,
It has the advantages that (4) the variable range of operating conditions is wide and (5) it is easy to achieve high purity.

[Brief description of drawings]

FIG. 1 is a process drawing showing one embodiment of a purification method according to the present invention.

Claims (2)

[Claims] 1. A method for purifying an optically active organic polybasic acid via a disproportionation step of an optically active organic polybasic hydrogen salt using an organic solvent. 2. A solvent in which the organic solvent has no reactivity with the optically active organic polybasic acid in the disproportionation step and dissolves 5% by weight or more of the optically active organic polybasic acid at the disproportionation temperature. The purification method according to claim 1, wherein