JPS6141332B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing high purity crystals of L-malic acid monopotassium salt and its monohydrate. Potassium salt of L-malic acid is a compound that has excellent medicinal effects as a promoter of cell injection and as a potassium supplement for hypokalemia, but until now there has been no industrially advantageous production method for it. It was unknown. Conventionally, DL-malic acid alkali metal salt is generally
It is known that salts with a 1:2 molar ratio can be obtained by crystallization at pH 7-9 from an aqueous solution containing DL-malic acid and alkali metal ions; however, such dialkali metal salts The crystallization of is accompanied by various difficulties due to its high solubility.
For this reason, for example, a method of crystallization from hydrous alcohol, disclosed in Japanese Patent Application Laid-Open No. 52-3019, has been devised. However, even with the method of JP-A-52-3019, when the alcohol concentration is low, the crystals adhere to each other.
The problem is that it becomes glutinous and difficult to post-process, requiring the use of a large amount of alcohol. It is also known that when equimolar amounts of L-malic acid and a monoacidic basic potassium ion donating substance, such as potassium hydroxide, are mixed in water, L-malic acid monopotassium salt is produced in the solution. Even if crystals are precipitated from the solution by conventional crystallization means such as cooling crystallization and concentration crystallization, highly pure crystals of L-malic acid monopotassium salt cannot be obtained, and L-
Only crystals were obtained in which the molar ratio of malic acid to potassium was about 1:0.6 to 0.8, and the composition was not constant. The formation of such crystals of indeterminate composition means that
It was not observed at all in the case of the monopotassium salt of DL-malic acid and the monosodium salt belonging to the same alkali metal salts of DL-malic acid and L-malic acid;
- This is a unique phenomenon in the case of monopotassium salt of malic acid (see experimental example below). Also, such L
- When a monopotassium malate salt-containing solution is concentrated to dryness, a block-like monopotassium malate salt is obtained, but this block contains impurities in the aqueous solution,
For example, fumaric acid remained as it was, and the crystal water composition was not constant. The present inventors first precipitated crystals from an aqueous solvent solution containing L-malic acid and potassium ions by a commonly used crystallization method under conditions such that the pH of the solution at the end of crystal precipitation was 5.3 or more and less than 6.8. It has been found that by separating this, L-malic acid monopotassium salt monohydrate crystals having a constant composition can be obtained at a good yield. (Special Application No. 52-17511). In particular, this method allows the pH of the solution at the end of crystal precipitation to be 5.3 or higher, even if the pH of the solution at the start of crystal precipitation is 4.7 or lower, and the precipitated crystals present as a liquid crystal have an indeterminate composition. By adjusting the value to less than 6.8, the crystals of indefinite composition are transferred to L-malic acid monopotassium salt monohydrate crystals of constant composition (i.e.,
crystal transfer). Furthermore, as a result of repeated research in search of an industrially advantageous method for producing L-malic acid monopotassium salt monohydrate crystals while avoiding the precipitation of crystals with an indeterminate composition, the present invention has developed When obtaining L-malic acid monopotassium salt monohydrate crystals from an aqueous solvent solution containing potassium ions, the pH of the solution at the start of crystal precipitation is
By adjusting the pH of the solution to 5.0 or higher, continuing crystal precipitation while maintaining the PH of this solution at 5.0 or higher, and adjusting the PH of the solution to 5.0 or higher and lower than 5.3 after the completion of crystal precipitation, the present inventors were able to About 1 more than the method found in
It has been found that L-malic acid monopotassium salt monohydrate crystals having a constant composition can be obtained with a relatively high yield. The method of the present invention is based on such new knowledge, and L-malic acid monopotassium salt monohydrate crystals can be obtained by crystallization from an aqueous solvent solution containing L-malic acid and potassium ions. of the solution of time
It can be produced by precipitating crystals and performing solid-liquid separation under conditions where the pH of the solution is maintained at 5.0 or higher and the pH of the solution at the end of crystal precipitation is 5.0 or higher and lower than 5.3. In addition, when performing solid-liquid separation of the crystals with a constant composition precipitated in this way, monopotassium L-malate can be obtained even if the pH deviates slightly outside this range to the acidic side for a relatively short period of time. salt 1
There is little negative effect on the purity of the hydrate crystals. For example, even if the pH at the time of solid-liquid separation shifts to the acidic side to around 4.8, if the separation operation is completed within about 1 hour, good crystals with no change in purity can be obtained. Rather, shifting the pH of the solution during solid-liquid separation to a slightly acidic side has the advantage of slightly increasing the yield of target crystals. However, the solution pH during solid-liquid separation is
If the temperature drops below 4.7, the precipitated L-malic acid monopotassium salt monohydrate crystals will rapidly transform into crystals with an indeterminate composition, so such conditions should be avoided. By the way, the stability and pH of monopotassium L-malic acid salt monohydrate over time
The results of measuring the relationship between the two are shown in Figure 1. L-malic acid monopotassium salt obtained here
By drying the monohydrate crystal until it loses crystal water, it can be made into a highly pure anhydrous L-malic acid monopotassium salt crystal. An aqueous solvent solution containing L-malic acid and potassium ions can be prepared by, for example, dissolving L-malic acid in an aqueous solvent, and adding a basic potassium ion donating substance (in terms of potassium ion amount in a molar ratio of 1.0 to 1.9, particularly preferably 1.1 to 1.4). It is convenient to prepare by adding a molar ratio) and further adjusting the pH of the solution at the start of crystal precipitation to be 5.0 or more, more preferably 5.0 or more and less than 5.3. As the basic potassium ion donating substance, for example, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, etc. can be used. Examples of the aqueous solvent include water and a mixed solvent of water and a hydrophilic organic solvent such as methanol, ethanol, acetone, and ethyl acetate. The temperature at which L-malic acid and the basic potassium ion donor are dissolved is usually cold or heated;
Preferably, 30 to 80°C is appropriate. When L-malic acid and a monoacidic basic potassium ion donating substance are mixed in an equimolar ratio, the liquid property is usually about
It becomes 4.1. In such a case, it is necessary to further adjust the liquid properties to the specified range and then precipitate crystals by a commonly used crystallization means. At this time, it is convenient to use the same alkaline substance as the basic potassium ion donating substance, but sodium hydroxide or ammonia may also be used. Furthermore, as the crystal precipitation progresses, the PH of the solution shifts to the neutral side, so it is also necessary to adjust the PH of the solution to the above-mentioned specific range at the end of crystal precipitation. Acetic acid, hydrochloric acid, etc. can also be used as the acidic substance used at this time, but
Preference is given to using L-malic acid. Note that these acidic substances can also be suitably used when lowering the pH of the solution to 4.8 during solid-liquid separation. As a drying method for producing anhydrous L-malic acid monopotassium salt crystals by removing crystal water from the L-malic acid monopotassium salt monohydrate crystals obtained in this way, for example, a hot air temperature of 50°C is used. When drying in a room, it is appropriate to keep the relative humidity at 31% or less. The L-malic acid monopotassium salt and its monohydrate crystals obtained as described above not only have high purity but also have the advantage of being easy to handle without hygroscopicity or other disadvantages. Example 1 68.1 g (0.508 mol) of L-malic acid is dissolved in 200 ml of water and 34.2 g (0.61 mol) of potassium hydroxide is added. Concentrate this solution under reduced pressure to reduce the remaining liquid volume to approximately 120ml.
After that, it is cooled to about 10°C to precipitate crystals.
The pH of the solution at the start of crystal precipitation was 5.0, and after 3 hours the pH rose to 5.5, so 14.8g of an aqueous L-malic acid solution (containing 34.07W/W% L-malic acid) was added to adjust the pH of the solution. is set to 5.0, and crystal precipitation is continued. After completion of crystal precipitation (PH of the solution is 5.1), solid-liquid separation is performed to obtain 73.0 g of L-malic acid monopotassium salt monohydrate crystals. Yield 75.6% (Preparation L-
Malic acid standard) mp.: 184-185℃ (decomposed) [α] _D -5.6゜ (C=4, water) Elemental analysis value: K・C ₄ H ₅ O ₅・H ₂ O Calculated value: C, 25.26 ; H, 3.72; K, 20.56 Actual value: C, 25.21; H, 3.69; K, 20.55 (However, potassium content is determined by neutralization titration after treatment with anion exchange resin) This product was analyzed for water using the Karl-Fitscher method. As a result, the crystal water content was 9.43% (theoretical value: 9.46%). If this product is dried with hot air for 24 hours at 60℃ (relative humidity 20%), L-malic acid monopotassium salt crystals without crystal water can be formed (however, the Karl-Fitscher method According to water analysis, the moisture content is 0.12%). mp.184-185℃ [α] ²² _D -6.1゜ (C=4, water) Example 2 L-malic acid 68.1g and potassium hydroxide 34.2g
is dissolved in 180 ml of water and the solution is concentrated to about 110 ml. The resulting concentrated solution is cooled, 0.1 g of L-malic acid monopotassium salt monohydrate crystals are added as seed crystals, and the mixture is stirred at 10° C. for 3 hours for crystallization. In addition,
The pH of the solution at the start of crystal precipitation is 5.1. During this time, in order to maintain the pH of this solution at 5.0 or more and less than 5.3, adjust the pH by adding hydrochloric acid from time to time. After solid-liquid separation and washing the resulting crystals with water-containing methanol, store at 30°C.
Let it air dry overnight. 73.8 g of L-malic acid monopotassium salt monohydrate crystals were obtained. Yield 76.4%. The physicochemical properties of this product were consistent with those of the specimen obtained in Example 1. Example 3 L-malic acid 134.1g and potassium hydroxide 65.6g
g in 400 ml of water and concentrate the solution to about 240 ml. The obtained concentrated solution is cooled, 0.1 g of seed crystals of L-malic acid monopotassium salt monohydrate is added, and crystallization is performed by stirring at 10° C. for 4 hours. During this time, in order to maintain the solution pH of the crystallization system at 5.0 to 5.2,
Adjust the pH by adding 35% hydrochloric acid as needed. Note that the pH of the solution at the start of crystal precipitation is 5.1. Next, the solution pH of the crystallization system is adjusted to 4.8 with 35% hydrochloric acid, solid-liquid separation is performed after 1 hour, and the obtained crystals are washed with cold aqueous methanol and then dried. 155.0 g of L-malic acid monopotassium salt monohydrate crystals were obtained. Yield 81.5%. The physicochemical properties of this product were consistent with those of the specimen obtained in Example 1. Experimental example What composition of crystals can be obtained when crystals are crystallized from an aqueous solution containing equimolar amounts of DL- or L-malic acid and sodium or potassium ions without pH adjustment? is described below as a reference example. (1) In the case of sodium salt: Dissolve 26.8 g (0.2 mol) of L-malic acid and 8.0 g (0.2 mol) of sodium hydroxide in 200 ml of water (PH 4.1), then reduce the remaining liquid amount to 60 g under reduced pressure. Concentrate the solution until it becomes pure, and perform crystallization by stirring for 4 hours while cooling to 10°C. Filter the precipitated crystals (pH of mother liquor
4.1), after washing with 80% aqueous methanol, at 35℃ for 16
Air dry for an hour. The crystal weight is 23.2g. When 1 g of this crystal is dissolved in 10 ml of water, the liquid has a pH of 4.1. Further, the chemical analysis values of this crystal are as shown in Table 1, indicating that this crystal is a monopotassium L-malic acid salt dihydrate crystal.

[Table] (2) For potassium salts (a) DL-malic acid 26.8 g (0.2 mol) of DL-malic acid and 13.8 g (0.1 mol) of potassium carbonate are dissolved in 200 ml of water (PH4.1), and then Concentrate under reduced pressure until the remaining liquid amount is 60 g. Cool this to 10℃ and
Crystallization was performed by stirring for hours, the precipitated crystals were collected by filtration (filtrate pH4.1), and after washing with aqueous methanol,
Dry with air at ℃ for 16 hours. Crystal weight is 26.4g
It is. The liquid property of the 10% aqueous solution of this product is PH4.1. The chemical analysis values of this crystal are as shown in Table 2, indicating that this crystal is a DL-malic acid monopotassium salt monohydrate crystal.

[Table] (b) L-malic acid 26.8 g (0.2 mol) of L-malic acid and 13.8 g (0.1 mol) of potassium carbonate were dissolved in 200 ml of water (PH4.1), and then the remaining liquid was reduced under reduced pressure. Concentrate to 60g. Cool this to 10℃ and
Crystallization was performed by stirring for hours, the precipitated crystals were collected by filtration (filtrate pH 5.1), and after washing with aqueous methanol,
Dry with air at ℃ for 16 hours. Crystal weight is 23.4g
It is. mp.174-177℃ [α] ²⁴ _D -4.7゜ (C=4, water) The chemical analysis values of this crystal are as shown in Table 3, and the calculation of L-malic acid monopotassium salt (anhydrous salt) The relative content of potassium is significantly insufficient compared to the value.

[Table] Furthermore, the IR spectrum of this product is completely different from that of the L-malic acid monopotassium salt crystal (anhydrous salt) produced by the method of the present invention in Example 1. Comparative Experimental Example (Experimental Method) 13.4 g of L-malic acid was dissolved in 100 ml of water, and potassium hydroxide was added to adjust the pH to a predetermined value. This solution was concentrated under reduced pressure until the remaining amount was about 30 g, and after further adjusting the pH as necessary, it was cooled to 10°C. The precipitated crystals were collected by filtration, washed with aqueous methanol, and then dried with air at 30°C overnight. (Results) The composition and yield of the obtained crystals are shown in the table below.

【table】 [Brief explanation of the drawing]

FIG. 1 shows the stability of L-malic acid monopotassium salt monohydrate crystals as a liquid base with respect to the pH of the mixed solution. The vertical axis represents the molar ratio (composition ratio) of the amount of potassium to the amount of L-malic acid in the liquid bottom body (solid phase), and the horizontal axis represents the time course of the mixed liquid. Straight line a indicates the pH of the mixture is 5.0 or more and less than 5.3, and curve b indicates the pH of the mixture.
Curve C, whose pH is 4.8, shows the composition of the liquid bottom body when the pH of the mixture is 4.7. The temperature at the time of measurement was 10°C.

Claims (1)

[Claims] 1. From an aqueous solvent solution containing L-malic acid and potassium ions, the pH of the solution at the time of crystal precipitation is
L-malic acid monopotassium salt characterized in that crystals are precipitated and solid-liquid separated under conditions in which the pH of the solution at the end of crystal precipitation is maintained at 5.0 or more and 5.5 or less and 5.0 or more and less than 5.3.・Production method of monohydrate crystals. 2. The method for producing L-malic acid monopotassium salt monohydrate crystals according to claim 1, wherein purified crystals of L-malic acid monopotassium salt monohydrate are used as seed crystals for crystal precipitation. 3 In claim 1 or 2,
A method for producing L-malic acid monopotassium salt monohydrate crystals having a pH of 4.8 or more and less than 5.3 during solid-liquid separation. 4 From an aqueous solvent solution containing L-malic acid and potassium ions, determine the pH of the solution at the time of crystal precipitation.
Under conditions where the pH of the solution is maintained at 5.0 or more and 5.5 or less, and the pH of the solution at the end of crystal precipitation is 5.0 or more and less than 5.3, crystals are precipitated and solid-liquid separated to obtain L-malic acid monopotassium salt monohydrate. 1. A method for producing anhydrous monopotassium L-malic acid salt crystals, which comprises obtaining crystals of L-malic acid and then drying the crystals until they lose crystal water.