JP4200593B2 - Crystalline L-ascorbic acid-2-phosphate sodium salt and process for producing the same - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel crystalline L-ascorbic acid-2-phosphate sodium salt (hereinafter sometimes abbreviated as “APS”) and a method for producing the same. Crystalline APS is useful as an L-ascorbic acid derivative and is used in cosmetics, pharmaceuticals, food additives, and other various industrial fields.
[0002]
[Prior art]
L-ascorbic acid (vitamin C) has been known to have various physiological actions and pharmacological actions, and has been used in whitening cosmetics because it has an effect of preventing melanin pigmentation. L-ascorbic acid is unstable with respect to oxygen and heat. The L-ascorbic acid is stabilized by phosphoric esterification at the 2-position hydroxyl group of the unstable L-ascorbic acid and used for various applications. In particular, sodium salt, that is, APS, has a feature of high solubility in water and is used for cosmetics.
Since APS powder is hygroscopic in the past, it may cause stability problems depending on the long-term storage state, is likely to be hydrolyzed, and vitamin C, the original raw material, is generated and further decomposed. As a result, this powder gradually changes from white to yellow, which causes problems of discoloration and coloring when used in cosmetics, pharmaceuticals, food additives and the like. Therefore, improvement in hygroscopicity during storage is desired.
About the manufacturing method of APS, a part is introduced in the report regarding L-ascorbic acid-2-phosphate ester (it may abbreviate as {AP} hereafter). For example, Japanese Patent Laid-Open No. 2131494 has a description relating to the manufacture of APS crystals. Methanol was added to the aqueous solution containing APS while heating and refluxing at a temperature of 40 to 80 ° C., and the mixture was further heated to reflux for 2 to 10 hours, and then cooled to room temperature overnight to obtain APS crystals. Have acquired. In this method, the yield is as low as 71 to 85%. In addition, since an aqueous solution containing APS is heated at a temperature of 40 to 80 ° C. for a long time, there is a defect that APS is decomposed to reduce the yield and contaminated vitamin C is decomposed and colored. Furthermore, according to this method, there is a disadvantage that productivity is low, such as continuing heating and refluxing for 2 to 10 hours after completion of addition or cooling to room temperature overnight. Japanese Patent Laid-Open No. 10-17580 describes a method for producing crystalline APS by suspending amorphous APS in an organic solvent and heating. This method also requires a temperature of 40 to 120 ° C., and industrially requires installation of heating equipment and reflux equipment, which is complicated. Furthermore, in this method, it is necessary to obtain solid amorphous APS in advance, and amorphous APS has poor filterability when separating crystallization wet bodies, and is an industrially efficient method. I can't say that.
[0003]
[Problems to be solved by the invention]
Thus, the conventional method for producing crystalline APS capable of improving hygroscopicity is not sufficient in terms of simplicity, yield, coloring and the like.
[0004]
[Means for Solving the Problems]
As a result of intensive studies to improve the above-mentioned drawbacks, the present inventors have found that a novel crystalline APS that has improved hygroscopicity that is easy to produce industrially, with little discoloration and coloring, near room temperature, in a simple and short time. Has been found, and the present invention has been completed.
That is, the present invention relates to the following matters.
(1) Crystalline L-ascorbic acid-2-phosphorus, characterized by crystallizing an organic solvent as a poor solvent from an aqueous solution having a molar ratio of sodium ions to L-ascorbic acid-2-phosphate ions of less than 3 Method for producing acid ester sodium salt.
(2) One or more organic solvents selected from lower aliphatic alcohols having 4 or less carbon atoms, aliphatic saturated ketones having 4 or less carbon atoms, and cyclic ethers having 4 to 6 carbon atoms are used as L-ascorbic acid- Addition to an aqueous solution containing L-ascorbic acid-2-phosphate sodium salt adjusted so that the sodium ion to 2-phosphate ester ion is less than 3 in molar ratio, or L-ascorbic acid-2-phosphate An aqueous solution containing L-ascorbic acid-2-phosphate sodium salt adjusted to have a sodium ion to ester ion molar ratio of less than 3 is added to an organic solvent, and the addition is performed at a temperature of 0 to 40 ° C. In the range, it is dripped over 0.5 to 10 hours so that the density | concentration in the solution of an organic solvent may be 30 to 90% (V / V) Method for producing a crystalline L- ascorbic acid 2-phosphate ester sodium salt.
(3) The manufacturing method as described in (1) or (2) whose sodium ion with respect to L-ascorbic acid-2-phosphate ester ion is 2.70-2.99 by molar ratio.
[0005]
(4) The production method according to any one of (1) to (3), wherein the concentration of L-ascorbic acid-2-phosphate sodium salt is 1 to 15 (wt / V) in the solution.
(5) The production method according to any one of (1) to (4), wherein the organic solvent is methanol and / or acetone.
(6) Powder X-ray diffraction using CuKα rays, with interplanar spacing d () and relative intensity [expressed in% in (). ] Within the range of experimental error 10.35 (61), 8.45 (100), 7.09 (27), 6.43 (8), 5.76 (9), 5.16 ( 89), 4.96 (30), 4.57 (10), 4.37 (28), 4.20 (47), 4.13 (18) 4.01 (14), 3.59 (47) 3.47 (39), 3.37 (10), 3.29 (17), 3.11 (57), 3.07 (49), 3.03 (30), 2.99 (25), 2.95 (21), 2.90 (11), 2.81 (17), 2.74 (23), 2.67 (40), 2.57 (60), 2.43 (19), 2 .35 (34), 2.28 (13), 2.23 (10), 2.06 (19), 1.94 (12), 1.85 (10), 1.76 (12) crystals Quality L-Asco Bin 2-phosphate ester sodium salt.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be specifically described below.
[0007]
The novel crystalline APS according to the present invention exhibits the following physicochemical properties.
(1) X-ray diffraction spectrum: X-ray diffraction results obtained by measurement under the conditions of CuKα ray, 40 kV, and 40 mA are expressed in terms of interplanar spacing d () and relative intensity [(). ] Is as follows. However, the X-ray diffraction result is changed within a generally allowable range depending on measurement conditions.
10.345 (61), 8.450 (100), 7.087 (27) 6.430 (8), 5.764 (9), 5.157 (89), 4.957 (30), 4. 572 (10), 4.367 (28), 4.203 (47), 4.134 (18) 4.005 (14), 3.593 (47), 3.466 (39), 3.368 ( 10), 3.288 (17), 3.114 (57), 3.074 (49), 3.025 (30), 2.988 (25), 2.947 (21), 2.899 (11) ), 2.812 (17), 2.743 (23), 2.673 (40), 2.573 (60), 2.434 (19), 2.352 (34), 2.278 (13) 2.230 (10), 2.064 (19), 1.940 (12), 1.847 (10), 1.762 12).
(2) Infrared absorption spectrum: FIG. 1 shows an infrared absorption spectrum measured by the KBr tablet method.
(3) Solubility is soluble in water (solubility at 25 ° C. is 38% (wt / V) and insoluble in organic solvents (alcohols, ketones, chloroform, etc.).
(4) Hygroscopicity shows a comparison of the rate of weight increase due to moisture absorption with amorphous APS in FIG.
[0008]
According to the method for producing crystalline APS of the present invention, a solution containing APS adjusted so that sodium ion to AP ion is less than 3 in molar ratio is used.
When an organic solvent is dropped into a solution containing APS adjusted so that the sodium ion to AP ion exceeds 3 in molar ratio, the deposited APS is partially in a bowl shape even under a temperature condition of 0 to 40 ° C. Becomes agar-like and difficult to separate. When a solution containing APS adjusted so that the sodium ion to AP ion exceeds 3 in molar ratio is dropped into an organic solvent, either amorphous APS or crystalline APS described in JP-A-2-131494 is produced. Although produced, the filterability by separation after crystallization is deteriorated, separation becomes difficult, and the purity is lowered due to poor solid-liquid separation.
[0009]
However, when a solution containing APS adjusted so that the sodium ion to AP ion is less than 3 in molar ratio is used, an organic solvent is preferably added dropwise to the solution containing APS, or a solution containing APS is added. Crystalline APS can be obtained in any case where it is preferably added dropwise to an organic solvent, and the filterability of separation after crystallization is very good.
[0010]
In this way, crystallization is performed with a solution containing APS adjusted so that the sodium ion to AP ion is less than 3 in a molar ratio near room temperature, particularly 0 to 40 ° C., thereby obtaining crystalline APS. By doing so, it is possible to produce a crystalline APS with good quality and efficiency in a short time.
The solution containing APS used in the present invention may be a solution containing AP, but an aqueous solution is preferable. It can be prepared from an AP solution, an alkali metal salt solution of AP, or an alkaline earth metal salt solution. Examples thereof include AP-containing solutions obtained by directly phosphorylating ascorbic acid (Japanese Patent Publication No. 43-9219, Japanese Patent Publication No. 45-23746, Japanese Patent Laid-Open No. 6-345786, etc.). Further, AP-containing solutions obtained by phosphorylating 5,6-O-isopropylidene-L-ascorbic acid (Japanese Patent Publication No. 43-9219, Japanese Patent Publication No. 45-4497, Japanese Patent Publication No. 45-30328), Japanese Examined Patent Publication No. 59-4438 can also be suitably used. Furthermore, an AP-containing solution (Japanese Patent Laid-Open No. 2-42996, etc.) produced from L-ascorbic acid and a phosphate donor by the action of an enzyme or a microorganism can also be used. Examples of the metal salt include potassium salt and sodium salt, and examples of the alkaline earth metal salt include magnesium salt and calcium salt.
[0011]
When AP is in the form of a salt, or when the AP-containing solution contains an alkali metal or alkaline earth metal, it is desirable to decationize the aqueous solution by treating it with an appropriate ion exchange resin. AP is adsorbed on an ion exchange resin and eluted with 0.1 to 2N dilute hydrochloric acid, and then the amount of sodium is adjusted with sodium hydroxide.
Adjustment of the amount of sodium with sodium hydroxide is usually performed with a 10 to 48% sodium hydroxide aqueous solution. The range of sodium to be adjusted is that sodium ions with respect to AP ions are less than 3 in terms of molar ratio, but from the viewpoint of recovery, the range is particularly preferably 2.70 to 2.99.
The concentration of APS in the solution after sodium adjustment is 1 to 15% (wt / V), preferably 5 to 10% (wt / V). If necessary, dilute with water, or heat, decompress, reverse It is concentrated by an osmotic membrane or the like.
[0012]
Then, under stirring, the organic solvent shown below is used within the range of the organic solvent concentration in the solution after the addition is 30 to 90% (V / V), and the solution containing APS is preferably added to the organic solvent. Dripping. If the amount of the organic solvent used at this time is too small, the recovery rate of APS is lowered. On the other hand, even if it is too much, there is almost no change in the recovery rate of APS. Therefore, the range of 50 to 80% (V / V) is particularly preferable, although it varies somewhat depending on the type of organic solvent used.
[0013]
The organic solvent used in the present invention includes lower aliphatic alcohols having 4 or less carbon atoms such as methanol, ethanol and isopropyl alcohol, aliphatic saturated ketones having 4 or less carbon atoms such as acetone and methyl ethyl ketone, and tetrahydrofuran, 1, 4 -C4-C6 cyclic ethers, such as a dioxane, are mentioned. These solvents can be used alone or in combination. Since these organic solvents are recovered from the water-organic solvent-based mother liquor by an operation such as distillation after isolating APS as a solid, low-boiling and inexpensive solvents having no azeotropic point are preferred. Therefore, methanol, acetone or a mixed solvent thereof is particularly preferable.
[0014]
The temperature at which the solution containing APS is added to the organic solvent is suitably around room temperature, particularly 0 to 40 ° C. When a solution containing APS and an organic solvent are mixed, a heat of dilution is generated when they are mixed. Therefore, the solution containing the organic solvent or APS is cooled to 10 to 20 ° C. in advance, and the solution containing APS to be added or It is preferable to cool the organic solvent to 10 to 20 ° C. in advance. If the temperature during the addition is 40 ° C. or higher, APS decomposition or contaminating VC decomposition occurs, resulting in coloration. Moreover, although there is no problem regarding the recovery rate or coloring of APS at a temperature of 0 ° C. or lower, it is economically disadvantageous because the capacity of a cooling facility such as a refrigerator must be increased. It is particularly preferable to continue cooling during the addition and to keep the addition at 10 to 30 ° C.
[0015]
The time required to add the solution containing APS is 0.5 to 10 hours. If the dripping time is too fast, the particle size of the precipitated APS will be fine, causing leakage during separation and acquisition with a centrifuge, resulting in a low recovery rate. When the dropping time is slow, there is no problem in the recovery rate and coloring, but it is economically disadvantageous because it occupies the plant meaninglessly. Therefore, it is particularly preferable to add in 1 to 6 hours.
[0016]
After dropping a solution containing APS in an organic solvent, aging is performed at a temperature of 0 to 40 ° C. for 0.25 to 1 hour, and using a device such as a centrifuge, the solid of APS is isolated, and the organic solvent After sufficiently washing with, a white powdery crystalline APS is obtained with high purity and high yield by treatment such as vacuum drying.
[0017]
In the crystalline APS production method of the present invention, the crystalline APS according to the present invention is added as a seed crystal in advance to an organic solvent, and an APS having a sodium ion to AP ion molar ratio of less than 3 is added to the organic solvent. The crystalline APS according to the present invention can be produced by adding the aqueous solution contained therein.
[0018]
The crystalline APS obtained by the production method of the present invention has low hygroscopicity and excellent stability. For example, pharmaceuticals (eg, oral medicine, eye drops, bath preparations, etc.), cosmetics (eg, lotion, emulsion) , Cream, pack, etc.), food (eg, bread, etc.) and the like.
[0019]
【Example】
EXAMPLES Next, although an Example demonstrates this invention in more detail, this invention is not limited to these Examples.
[0020]
Example 1
Under a nitrogen atmosphere, 1210 mL of pure water, 303 g of pyridine, and 150 g of 5,6-isopropylidene-L-ascorbic acid are mixed and dissolved. After cooling to 0 to 10 ° C., a 50% aqueous potassium hydroxide solution is added to adjust the pH to about 13 Adjusted. To this solution, 150 g of phosphorus oxychloride and a 50% aqueous potassium hydroxide solution were added dropwise, and the reaction was carried out while maintaining a pH of 13 to 0 to 10 ° C. After completion of the dropwise addition, pyridine was distilled off under reduced pressure, and 35% hydrochloric acid was added to adjust the pH to 4.
The pH adjustment solution was diluted by adding 6500 mL of pure water, and then passed through a column packed with 2000 mL of a medium basic anion exchange resin (Amberlite IRA-68 Organo). Subsequently, it developed with 23.5 L of 0.05 N hydrochloric acid. Furthermore, it developed by 0.2L-hydrochloric acid 11L, and the fraction division containing only AP was obtained.
A 48% aqueous sodium hydroxide solution was added to the solution in this fractionation section, and the ratio of the molar amount of sodium ions to the molar amount of 2-AP ions was adjusted to 2.85. Under reduced pressure, a concentration operation was performed until the concentration of APS was 9% (wt / V) to obtain a solution containing APS.
Under a nitrogen atmosphere, 750 mL of 95% methanol was stirred at a speed of 400 rpm and cooled to 10 to 15 ° C. 250 mL of a solution containing APS that had been cooled to 10 to 15 ° C. in advance was added dropwise over 4 hours while continuing cooling so that the temperature of the solution was in the range of 10 to 25 ° C. After completion of the dropwise addition, the mixture was further stirred for 1 hour and aged.
[0021]
Using a centrifuge, the precipitated APS solid was collected by filtration, and the solid was thoroughly washed with 100 mL of 95% methanol.
It was dried at 40 ° C. under vacuum to obtain 20.0 g (yield 89%) of crystalline APS.
[0022]
Example 2
A solution containing APS was prepared in the same manner as in Example 1.
In a nitrogen atmosphere, 500 mL of 98% acetone was stirred at a speed of 400 rpm and cooled to 10 to 15 ° C. 250 mL of a starting solution containing APS that had been cooled to 10 to 15 ° C. in advance was added dropwise over 4 hours while continuing cooling so that the temperature of the solution was in the range of 10 to 25 ° C. After completion of the dropwise addition, the mixture was further aged by continuing stirring for 0.5 hour.
The precipitated APS solid was collected by filtration using a centrifuge, and the solid was thoroughly washed with 80 mL of 98% acetone.
It was dried at 40 ° C. under vacuum to obtain 20.5 g (yield 91%) of crystalline APS.
[0023]
Example 3
A solution containing APS was prepared in the same manner as in Example 1.
Under a nitrogen atmosphere, 750 mL of 98% tetrahydrofuran was stirred at a speed of 400 rpm and cooled to 10 to 15 ° C. 250 mL of a starting solution containing APS that had been cooled to 10 to 15 ° C. in advance was added dropwise over 2 hours while continuing cooling so that the temperature of the solution was in the range of 10 to 25 ° C. After completion of the dropwise addition, the mixture was further aged by continuing stirring for 1 hour.
The precipitated APS solid was collected by filtration using a centrifuge, and the solid was thoroughly washed with 120 mL of 98% tetrahydrofuran.
It dried under vacuum at 40 degreeC and obtained 19.6g (yield 87%) of crystalline APS.
[0024]
Example 4
A solution containing APS was prepared in the same manner as in Example 1, but the molar ratio of sodium ions to the molar amount of AP ions at this time was adjusted to 2.55.
Under a nitrogen atmosphere, 750 mL of 95% methanol was stirred at a speed of 400 rpm and cooled to 10 to 15 ° C. 250 mL of a starting solution containing APS that had been cooled to 10 to 15 ° C. in advance was added dropwise over 6 hours while continuing cooling so that the temperature of the solution was in the range of 10 to 25 ° C. After completion of the dropwise addition, the mixture was further aged by continuing stirring for 0.5 hour.
Using a centrifuge, the precipitated APS solid was collected by filtration, and the solid was thoroughly washed with 100 mL of 95% methanol.
It dried under vacuum at 40 degreeC and obtained 15.8g (yield 70%) of crystalline APS.
[0025]
Example 5
32 g of L-ascorbic acid-2-phosphate magnesium salt was dissolved in 368 g of pure water. This solution was passed through a column packed with 2000 mL of a strongly acidic cation exchange resin (Amberlite IR-120B Organo). Furthermore, 1600 mL of a solution containing only AP was obtained through pure water 1200. The magnesium ion contained in this solution was 3 ppm or less.
A 48% aqueous sodium hydroxide solution was added to this solution, and the molar ratio of sodium ions to AP ions was adjusted to 2.85. Concentration operation was added under reduced pressure until the concentration of APS was 9% (wt / V) to obtain a starting solution.
Under a nitrogen atmosphere, 750 mL of 95% methanol was stirred at a speed of 400 rpm and cooled to 10 to 15 ° C. 250 mL of a starting solution containing APS that had been cooled to 10 to 15 ° C. in advance was added dropwise over 2 hours while continuing cooling so that the temperature of the solution was in the range of 10 to 25 ° C. After completion of the dropwise addition, stirring was continued for 0.25 hours, followed by aging.
Using a centrifuge, the precipitated APS solid was collected by filtration, and the solid was thoroughly washed with 100 mL of 95% methanol.
It was dried at 40 ° C. under vacuum to obtain 20.7 g (yield 92%) of crystalline APS.
[0026]
Example 6
A starting solution containing APS was prepared in the same manner as in Example 1.
Under a nitrogen atmosphere, 250 mL of the starting solution containing APS was stirred at a speed of 300 rpm and cooled to 10 to 15 ° C. 750 mL of 95% methanol that had been cooled to 10 to 15 ° C. in advance was added dropwise over 4 hours while continuing cooling so that the temperature of the liquid was in the range of 10 to 25 ° C. After completion of the dropwise addition, stirring was continued for another 0.5 hours to ripen.
Using a centrifuge, the precipitated APS solid was collected by filtration, and the solid was thoroughly washed with 100 mL of 95% methanol.
It was dried at 40 ° C. under vacuum to obtain 20.3 g (yield 90%) of crystalline APS.
[0027]
【The invention's effect】
The production method of the present invention provides crystalline L-ascorbic acid-2-phosphate sodium salt in a simple and high yield. In addition, the present invention provides a novel crystalline L-ascorbic acid-2-phosphate sodium salt that has low hygroscopicity and excellent stability.
[0028]
[Brief description of the drawings]
FIG. 1 is an infrared absorption spectrum of crystalline L-ascorbic acid-2-phosphate sodium salt obtained in the present invention.
FIG. 2 shows moisture absorption of crystalline L-ascorbic acid-2-phosphate sodium salt and amorphous L-ascorbic acid-2-phosphate sodium salt (conditions: relative humidity 75 ± 5%, temperature 25 ° C.). It is the comparison data of the weight increase rate by. The vertical axis indicates the rate of increase when compared with the original weight, and the horizontal axis indicates time.
[0029]
[Explanation of symbols]
1 Hygroscopic increase curve of crystalline L-ascorbic acid-2-phosphate sodium salt 2 Hygroscopic increase curve of amorphous L-ascorbic acid-2-phosphate sodium salt

Claims (6)

Crystalline L-ascorbic acid-2-phosphate sodium salt characterized by crystallizing an organic solvent as a poor solvent from an aqueous solution having a molar ratio of sodium ion to L-ascorbic acid-2-phosphate ion of less than 3 Method for producing salt. One or more organic solvents selected from lower aliphatic alcohols having 4 or less carbon atoms, aliphatic saturated ketones having 4 or less carbon atoms and cyclic ethers having 4 to 6 carbon atoms are used as L-ascorbic acid-2-phosphorus Added to an aqueous solution containing L-ascorbic acid-2-phosphate sodium salt adjusted so that the sodium ion relative to the acid ester ion is less than 3 in terms of molar ratio, or to the L-ascorbic acid-2-phosphate ion An aqueous solution containing L-ascorbic acid-2-phosphate sodium salt adjusted to have a sodium ion molar ratio of less than 3 is added to an organic solvent, and such addition is performed at a temperature range of 0 to 40 ° C. Crystalline material added over 0.5 to 10 hours so that the concentration of the organic solvent in the solution is 30 to 90% (V / V) - method for producing ascorbic acid-2-phosphate sodium salt. The production method according to claim 1 or 2, wherein the sodium ion to L-ascorbic acid-2-phosphate ion is 2.70 to 2.99 in molar ratio. The manufacturing method according to any one of claims 1 to 3, wherein the concentration of L-ascorbic acid-2-phosphate sodium salt is 1 to 15 (wt / V) in the solution. The production method according to any one of claims 1 to 4, wherein the organic solvent is methanol and / or acetone. In powder X-ray diffraction using CuKα rays, the interplanar spacing d () and relative intensity [expressed in% within (). ] Within the range of experimental error 10.35 (61), 8.45 (100), 7.09 (27), 6.43 (8), 5.76 (9), 5.16 ( 89), 4.96 (30), 4.57 (10), 4.37 (28), 4.20 (47), 4.13 (18) 4.01 (14), 3.59 (47) 3.47 (39), 3.37 (10), 3.29 (17), 3.11 (57), 3.07 (49), 3.03 (30), 2.99 (25), 2.95 (21), 2.90 (11), 2.81 (17), 2.74 (23), 2.67 (40), 2.57 (60), 2.43 (19), 2 .35 (34), 2.28 (13), 2.23 (10), 2.06 (19), 1.94 (12), 1.85 (10), 1.76 (12) crystals Quality L-Asco Bin 2-phosphate ester sodium salt.

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