Method for producing imidazopyrroloquinoline alkali metal salt

Abstract

To provide an easy and convenient method with fewer steps that uses a reaction which can be completed in a shorter time, the method capable of suppressing as much as possible the mixing of the raw material pyrroloquinoline quinone into the product and the formation of impurities causing difficulty in purification, thereby enabling inexpensive mass production of imidazopyrroloquinoline alkali metal salts with higher purity.SOLUTION: A method for producing an imidazopyrroloquinoline alkali metal salt comprises reacting, in an aqueous solution, pyrroloquinoline quinone or a salt thereof at a concentration of 10 to 50 g / L in the presence of glycine or a salt thereof and a basic alkali metal salt so as to precipitate an imidazopyrroloquinoline alkali metal salt represented by the general formula (1) in the figure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a process for preparing alkali metal salts of imidazopyrroloquinolines. [Background technology]

[0002] Imidazopyrroloquinoline (7-oxo-7,10-dihydroimidazo[4,5,1-ij]pyrrolo[2,3-f]quinoline-1,3,9-tricarboxylic acid) (IPQ, as shown below) (hereinafter also referred to as "IPQ") is known as a physiologically active substance, and is an important substance used in pharmaceuticals and functional foods (see, for example, Non-Patent Document 1).

[0003] [ka]

[0004] One proposed method for producing IPQ is to add amino acids to a culture medium obtained from bacteria that produce pyrroloquinoline quinone (PQQ, formula below) (Patent Document 1). However, this method produces IPQ at a very low concentration on the mg / L scale. Therefore, to isolate and obtain it as a solid, a large amount of salt is required to remove the solvent or reduce the solubility and precipitate it. Furthermore, the culture medium contains many impurities and bacterial cells, which has the disadvantage of high impurity content and low concentration of the target product, making it essential to remove the impurities.

[0005] [ka]

[0006] Meanwhile, another method for producing IPQ is known, in which ammonia or formaldehyde is added to a solution containing pyrroloquinoline (Patent Document 2). However, because the ammonia and formaldehyde used in this method are chemical substances harmful to the human body, this method cannot be said to be suitable from the perspective of producing pharmaceuticals or functional foods. Furthermore, because formaldehyde and ammonia react only in this combination, they cannot be said to be suitable reaction substrates for production. Furthermore, in order to obtain highly pure IPQ using this method, many purification steps are required.

[0007] Another known method for producing IPQ is to synthesize IPQ by reacting pyrroloquinoline quinone with glycine and produce IPQ as an alkali metal salt (Patent Document 3). The IPQ alkali metal salt obtained by this method has high solubility and excellent thermal stability. However, because this method is carried out at a high concentration, it is difficult to purify. Furthermore, this method has the disadvantage of requiring multiple purification steps because it generates aromatic impurities with similar structures that are difficult to purify. Furthermore, this method requires the use of large amounts of acid and alkali, which tends to result in a large amount of waste generated during production. Furthermore, to obtain the IPQ alkali metal salt, the free form is first formed and then neutralized to obtain the IPQ alkali metal salt, which requires many steps. Another disadvantage is that the reaction solution solidifies, making it difficult to work with.

[0008] Furthermore, these conventional methods use reactions that are slow, require long reaction times, and have low reaction efficiency.

[0009] For these reasons, efforts have been made to find methods that have fewer steps, methods that use reactions that can be completed in a short time, and methods that can obtain IPQ alkali metal salts with higher purity by minimizing the contamination of the product with the starting material pyrroloquinoline quinone and the formation of impurities that are difficult to purify. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japanese Patent Application Publication No. 09-70296 [Patent Document 2] Japanese Patent Application Publication No. 09-67373 [Patent Document 3] Patent Publication No. 6395101 [Non-patent literature]

[0011] [Non-Patent Document 1] Heliyon. 2020 Jan 29;6(1):e03240. doi: 10.1016 / j.heliyon.2020.e03240. Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide a method for inexpensively and mass-producing a highly pure imidazopyrroloquinoline alkali metal salt by using a reaction that can be completed in a shorter time, with fewer steps, and by minimizing the contamination of the product with the starting material pyrroloquinoline quinone and the production of impurities that are difficult to purify. [Means for solving the problem]

[0013] Means for Solving the Problems of the Invention The present inventors have conducted extensive research to solve the problems of the present invention, and as a result have found a method in which a reaction between glycine and pyrroloquinoline quinone or a salt thereof and an alkali metal salt are simultaneously carried out, and the resulting alkali metal salt is precipitated as a solid, thereby completing the present invention.

[0014] That is, the present invention is as follows. [1] A method for producing an imidazopyrroloquinoline alkali metal salt, comprising reacting pyrroloquinoline quinone or a salt thereof at a concentration of 10 to 50 g / L in an aqueous solution with glycine or a salt thereof and a basic alkali metal salt in the presence of the quinone, to thereby precipitate an imidazopyrroloquinoline alkali metal salt represented by the following general formula (1):

[0015] [ka]

[0016] (In general formula (1), M is an alkali metal.) [2] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the reaction is carried out while blowing an oxygen-containing gas into the aqueous solution. [3] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above item [1], wherein the amount of glycine or a salt thereof used is 0.5 to 2 by weight, assuming that the amount of pyrroloquinoline quinone or a salt thereof used is 1. [4] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the amount of the basic alkali metal salt used is 0.5 to 2 by weight, assuming that the amount of pyrroloquinoline quinone or a salt thereof used is 1. [5] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein M in the general formula (1) is sodium (Na). [6] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the basic alkali metal salt is a basic sodium salt. [7] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the reaction is carried out at a first-stage temperature and then at a second-stage temperature lower than the first-stage temperature. [8] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the purity of the precipitated imidazopyrroloquinoline alkali metal salt as determined by HPLC (high performance liquid chromatography) analysis is 93.0% or more. [9] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the yield of the precipitated imidazopyrroloquinoline alkali metal salt is 50.0% or more.

[10] The method for producing an imidazopyrroloquinoline alkali metal salt according to the above [1], wherein the imidazopyrroloquinoline alkali metal salt is precipitated simultaneously with the reaction of pyrroloquinoline quinone or a salt thereof. [Effects of the Invention]

[0017] The production method of the present invention is an easy and simple method with fewer steps using a reaction that can be completed in a shorter time, and it can minimize contamination of the product with the starting material pyrroloquinoline quinone and the production of impurities that are difficult to purify, thereby making it possible to obtain a high-purity imidazopyrroloquinoline alkali metal salt inexpensively and in large quantities. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention will be described in detail below by showing embodiments thereof. The following embodiments of the present invention are merely examples for explaining the present invention, and are not intended to limit the present invention to the following contents. The present invention can be practiced by appropriately modifying it within the scope of its gist.

[0019] The method for producing an imidazopyrroloquinoline alkali metal salt of the present invention comprises reacting pyrroloquinoline quinone or a salt thereof at a concentration of 10 to 50 g / L in an aqueous solution with glycine or a salt thereof and a basic alkali metal salt to precipitate an imidazopyrroloquinoline alkali metal salt represented by the following general formula (1). The imidazopyrroloquinoline alkali metal salt, which is the target of the production method of the present invention, is a trialkali metal salt of imidazopyrroloquinoline, as represented by the following general formula (1). Hereinafter, the trialkali metal salt of imidazopyrroloquinoline will be simply referred to as an imidazopyrroloquinoline alkali metal salt. Imidazopyrroloquinoline alkali metal salts are known to have high solubility and excellent thermal stability.

[0020] [ka]

[0021] (In general formula (1), M is an alkali metal.)

[0022] The alkali metal represented by M in general formula (1) is preferably any one of sodium (Na), potassium (K), and lithium (Li), more preferably any one of sodium (Na) and potassium (K), and even more preferably sodium (Na). When the alkali metal is any one of sodium (Na) and potassium (K), there is little risk of harmful effects on humans, and when used as an alkaline solution, an amine odor tends to be less likely to be generated.

[0023] The imidazopyrroloquinoline alkali metal salt obtained by the production method of the present invention may be a hydrate. Examples of the imidazopyrroloquinoline alkali metal salt hydrate include mono- to dodeca-hydrates of imidazopyrroloquinoline alkali metal salts.

[0024] In the production method of the present invention, pyrroloquinoline quinone or a salt thereof is present in an aqueous solution at a concentration of 10 to 50 g / L at the start of the reaction together with glycine or a salt thereof and a basic alkali metal salt. If the concentration of pyrroloquinoline quinone or a salt thereof is lower than this, the precipitate produced by the reaction is small, resulting in a reduced yield. On the other hand, if the concentration is higher than this, the reaction solution solidifies, making it difficult to stir, resulting in a reduced yield.

[0025] In the production method of the present invention, when a salt of pyrroloquinoline quinone is used, the salt of pyrroloquinoline quinone used is, for example, an alkali metal salt, preferably any one of the sodium salt, potassium salt, and lithium salt, more preferably any one of the sodium salt and potassium salt, and even more preferably the sodium salt. A hydrate may also be used as pyrroloquinoline quinone or a salt thereof.

[0026] In the production method of the present invention, the amount of glycine or a salt thereof used is preferably 0.2 to 3, more preferably 0.4 to 2.5, and even more preferably 0.5 to 2, by weight ratio, relative to the amount of pyrroloquinoline quinone or a salt thereof used, taken as 1. If the amount of glycine or a salt thereof used is less than this range, the reaction rate tends to be slower than when the amount is set within the above-mentioned preferred range. On the other hand, if the amount of glycine or a salt thereof used is large, the amount of glycine in the reaction system will be excessive, resulting in higher costs than when the amount is set within the above-mentioned preferred range. Furthermore, the product imidazopyrroloquinoline alkali metal salt will be less likely to precipitate than when the amount is set within the above-mentioned preferred range.

[0027] When a salt of glycine is used in the production method of the present invention, the salt of glycine used is, for example, an alkali metal salt, preferably either the sodium salt or the potassium salt, more preferably the sodium salt. Glycine or a salt thereof may also be used in the form of a hydrate.

[0028] The amount of basic alkali metal salt used in the production method of the present invention is preferably 0.2 to 3, more preferably 0.4 to 2.5, and even more preferably 0.5 to 2, by weight ratio, assuming that the amount of pyrroloquinoline quinone or a salt thereof used is 1. If the amount of basic alkali metal salt is small, the product imidazopyrroloquinoline alkali metal salt is less likely to precipitate than when the amount is set within the above preferred range. Moreover, if the amount of basic alkali metal salt is excessive, the reaction rate tends to be slower than when the amount is set within the above preferred range, and the purity of the product imidazopyrroloquinoline alkali metal salt may decrease.

[0029] Examples of basic alkali metal salts include basic sodium salts such as sodium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; basic potassium salts such as potassium hydroxide, potassium carbonate, potassium bicarbonate, and potassium phosphate; and basic lithium salts such as lithium hydroxide, lithium carbonate, lithium bicarbonate, and lithium phosphate. These can be used alone or in combination. The basic alkali metal salt is preferably basic sodium salts such as sodium hydroxide, sodium carbonate, and sodium bicarbonate; or basic potassium salts such as potassium hydroxide, potassium carbonate, and potassium bicarbonate, and more preferably basic sodium salts such as sodium hydroxide, sodium carbonate, and sodium bicarbonate.

[0030] In the production method of the present invention, the basic alkali metal salt does not necessarily need to be added in its entirety before the reaction. In order to promote precipitation, it may be added after the start of the reaction, or it may be added stepwise in multiple portions, or it may be added gradually.

[0031] The reaction in the production method of the present invention may be carried out in a suspension state. From the viewpoint of further improving the purity of the imidazopyrroloquinoline alkali metal salt, it is preferable to start the reaction in a non-suspended state, and to make the suspension state as the reaction proceeds, thereby precipitating the imidazopyrroloquinoline alkali metal salt.

[0032] The reaction in the production method of the present invention is carried out in an aqueous solution. The aqueous solution may contain an aqueous organic solvent such as ethanol. When the aqueous solution contains an aqueous organic solvent, the content of the aqueous organic solvent is, for example, 50% by mass or less, where the total of water and the aqueous organic solvent is 100% by mass.

[0033] In the production method of the present invention, the reaction is preferably carried out while blowing an oxygen-containing gas into the aqueous solution. The amount of the oxygen-containing gas bubbled into the aqueous solution is preferably 2 to 200 mL / min, more preferably 5 to 50 mL / min, per 25 mL of aqueous solution. The oxygen concentration of the oxygen-containing gas is, for example, 10% by volume or more, and from the viewpoint of cost reduction, it is preferable to use air.

[0034] The reaction temperature in the production method of the present invention is preferably 10°C to 180°C, more preferably 10°C to 120°C, even more preferably 15°C to 90°C, even more preferably 20°C to 70°C, and particularly preferably 20°C to 60°C. Setting the temperature within this range allows the reaction product to be produced within a reasonable time, which is industrially preferable. Furthermore, carrying out the reaction within this temperature range eliminates the need for a pressurized vessel or the like. The reaction temperature may be constant or may be changed stepwise. When changing the reaction temperature stepwise, for example, by carrying out the reaction at a first-stage temperature followed by a second-stage temperature lower than the first-stage temperature, the reaction can be carried out efficiently at the high first-stage temperature, and then the precipitation of the imidazopyrroloquinoline alkali metal salt can be promoted by the lower second-stage temperature, thereby improving the purity of the imidazopyrroloquinoline alkali metal salt. In this case, the temperature in the first stage is preferably set within the above-mentioned preferred reaction temperature range. The temperature in the second stage may be set to a temperature lower than the temperature in the first stage, for example, in the range of 0° C. to 120° C., preferably in the range of 20° C. to 100° C., and more preferably in the range of 20° C. to 50° C. In particular, the temperature in the second stage is preferably 10° C. or more lower, and more preferably 20° C. or more lower, than the temperature in the first stage.

[0035] The reaction time in the production method of the present invention can be set, for example, from 1 hour to 7 days, preferably from 2 hours to 5 days, more preferably from 3 hours to 72 hours, and even more preferably from 6 hours to 48 hours. At high reaction temperatures, the reaction can proceed in a short time. However, at times shorter than 1 hour, the reaction does not proceed sufficiently compared to times set at 1 hour or longer, and the amount of imidazopyrroloquinoline alkali metal salt precipitated may be reduced. On the other hand, when the reaction is continued for longer than 7 days, the production efficiency is not good. For example, when the reaction is carried out at the first-stage and second-stage temperatures described above, it is preferable to maintain each of the first-stage and second-stage temperatures for 0.5 hours or longer.

[0036] In the production method of the present invention, the pH at the end of the reaction is preferably 6 or higher, more preferably 7 or higher, even more preferably 8 or higher, and particularly preferably 9 or higher. If the pH is low, the reaction tends to proceed more slowly than when the pH is set in the above-mentioned preferred range. The upper limit of the pH at the end of the reaction is not particularly limited, but is preferably 14 or lower, and more preferably 10 or lower.

[0037] The progress of the reaction in the production method of the present invention can be monitored by general analytical techniques such as HPLC (high performance liquid chromatography) and paper chromatography.

[0038] In one embodiment, the production method of the present invention can be used to simultaneously precipitate an imidazopyrroloquinoline alkali metal salt with the reaction of pyrroloquinoline quinone or a salt thereof. In this embodiment, both the reaction of pyrroloquinoline quinone or a salt thereof and the precipitation of the imidazopyrroloquinoline alkali metal salt can be carried out in one pot (one reactor), thereby achieving higher production efficiency. In this embodiment, as the reaction of pyrroloquinoline quinone or a salt thereof progresses, the target imidazopyrroloquinoline alkali metal salt, which is the reaction product, can gradually precipitate. In this embodiment, the imidazopyrroloquinoline alkali metal salt can be recovered by filtering or centrifuging the precipitate after completion of the reaction.

[0039] A feature of the production method of the present invention is that it contains few impurities with similar structures containing aromatic carboxylic acids. The precipitated imidazopyrroloquinoline alkali metal salt can be easily recovered using common methods such as washing and drying. When the purity is high, purification is not necessary. Furthermore, the reduced purification burden allows for production at lower cost. The purity of the imidazopyrroloquinoline alkali metal salt can be measured and calculated by HPLC analysis. The purity of the imidazopyrroloquinoline alkali metal salt determined by HPLC analysis (hereinafter referred to as "HPLC purity") can be calculated as the ratio (%) of the peak area to the total area when the absorbance is measured using a UV detector (ultraviolet absorbance detector) at a specific wavelength, for example, between 220 and 400 nm, particularly between 240 and 280 nm (e.g., a wavelength corresponding to the maximum absorption wavelength in the ultraviolet absorption spectrum). Specifically, the conditions described in the following examples can be used. The purity of the imidazopyrroloquinoline alkali metal salt precipitated in the production method of the present invention as determined by HPLC analysis can be increased to, for example, 85.0% or more, 90.0% or more by optimization, 93.0% or more by further optimization, and 95.0% or more by further optimization.

[0040] The solids precipitated from the aqueous solution may contain impurities detectable by HPLC, as well as the raw material glycine, alkali metal salts, and water. These non-aromatic impurities have significantly different physical properties from the target imidazopyrroloquinoline alkali metal salt, and can be easily separated. Specifically, this is done by washing and drying. In particular, even if impurities are present, most of the impurities are water, so high purity can be achieved by drying alone.

[0041] In the production method of the present invention, the precipitated target imidazopyrroloquinoline alkali metal salt can be further purified by a known method. For example, the purity of the imidazopyrroloquinoline alkali metal salt can be further increased by purifying it by recrystallization or various types of chromatography.

[0042] The yield of the imidazopyrroloquinoline alkali metal salt precipitated in the production method of the present invention is preferably 30.0% or more, more preferably 40.0% or more, and even more preferably 50.0% or more.

[0043] The imidazopyrroloquinoline alkali metal salt obtained by the production method of the present invention can be used in foods, cosmetics, supplements, pharmaceuticals, and veterinary drugs.

[0044] The imidazopyrroloquinoline alkali metal salt obtained by the production method of the present invention can be provided in the form of a hard capsule, a soft capsule, or a tablet, and may be mixed with other additives.

[0045] The imidazopyrroloquinoline alkali metal salt obtained by the production method of the present invention can be used as a pharmaceutical, cosmetic, food, and feed, taking advantage of its high solubility in water, and can also be used as an infusion solution, an injection solution, and a beverage. For example, the imidazopyrroloquinoline alkali metal salt can be easily mixed with an emulsion and incorporated into cosmetic creams and cakes. Furthermore, the imidazopyrroloquinoline alkali metal salt can be easily mixed with rice or wheat flour, and can also be used in foods using such flour. [Example]

[0046] The present invention will be specifically described below with reference to examples. However, the present invention is not limited to these examples. In the following description, unless a temperature is specified, the temperature condition is room temperature (23±3°C), and unless a pressure is specified, the pressure condition is atmospheric pressure (1 atm). In the examples and comparative examples shown below, unless otherwise specified, reagents manufactured by Wako Pure Chemical Industries, Ltd. were used. Pyrroloquinoline quinone dinatrium (NaPQQ) was used as "BioPQQ" (product name) manufactured by Mitsubishi Gas Chemical Company, Inc.

[0047] [Example 1] In a 50 mL glass container, 0.50 g of glycine and 0.50 g of sodium carbonate (Na2CO3) were added to 25 mL of water. Air was bubbled through the solution at 25 mL per minute using a Teflon tube (inner diameter 2 mm). The mixture was stirred at 300 rpm using a magnetic stirrer. 0.50 g of pyrroloquinoline quinone dinatrium (Na2PQQ) was added to the solution. Initially, the solution was homogeneous. After 20 hours at room temperature (23 ± 3°C), the stirring and air bubbling were stopped. The reaction mixture contained a yellow precipitate. The pH of the reaction mixture was 9.3.

[0048] The reaction mixture was centrifuged at 300 rpm for 15 minutes to recover the solids, and the supernatant was discarded. 5 mL of 70% ethanol was added and mixed thoroughly. Centrifuged and the supernatant was discarded. 5 mL of ethanol was added, shaken thoroughly, and centrifuged. The supernatant was discarded, and the mixture was dried under reduced pressure at 60°C for 2 hours to obtain 0.38 g of a yellow solid. The HPLC purity and yield of the target product, imidazopyrroloquinoline quinone trisodium (Na3IPQ), obtained as a solid, were calculated using HPLC analysis under the analytical conditions shown below. The HPLC purity and yield were 98.2% and 62.0%, respectively. The reaction and precipitation were carried out in a single reactor, enabling the production of highly pure imidazopyrroloquinoline quinone trisodium (Na3IPQ).

[0049] (Analysis conditions) Measurement was carried out under the following analytical conditions, and the HPLC purity was calculated from the peak area. UV-Vis detector (ultraviolet-visible absorbance detector): Shimadzu Corporation "UV1800" (product name) HPLC (High Performance Liquid Chromatography): Shimadzu Corporation "LC-2010" (product name) Measurement wavelength: 259nm Measurement temperature: 40℃ Column: YMC-Pack ODS-A 150mm, 4.6mm Mobile phase: 30 mM acetic acid - 70 mM ammonium acetate Flow rate: 1.5mL / min

[0050] [Example 2] A solid was obtained in the same manner as in Example 1, except that the reaction time was changed from 20 hours to 3 hours. The pH of the reaction solution was 9.3. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 96.2% and the yield was 71.5%.

[0051] [Example 3] A solid was obtained in the same manner as in Example 1, except that the reaction was first carried out at 50°C for 2 hours, and then at room temperature (23±3°C) for 1 hour. The pH of the reaction solution was 9.3. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 99.7% and the yield was 74.7%.

[0052] [Example 4] A solid was obtained in the same manner as in Example 1, except that 0.50 g of sodium bicarbonate (NaHCO3) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 9.1. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 98.7% and the yield was 90.0%.

[0053] [Example 5] A solid was obtained in the same manner as in Example 1, except that 0.50 g of sodium hydroxide (NaOH) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 9.5. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 98.2% and the yield was 63.5%.

[0054] [Example 6] A solid was obtained in the same manner as in Example 1, except that the amount of pyrroloquinoline quinone dinatrium (NaPQQ) used was changed from 0.50 g to 1.00 g and 0.50 g of sodium bicarbonate (NaHCO) was used instead of sodium carbonate. The pH of the reaction solution was 8.8. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 94.5% and the yield was 57.8%.

[0055] [Example 7] A solid was obtained in the same manner as in Example 1, except that 1.00 g of sodium bicarbonate (NaHCO3) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 9.3. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 95.4% and the yield was 59.6%.

[0056] [Example 8] A solid was obtained in the same manner as in Example 1, except that the amount of glycine used was changed from 0.50 g to 1.00 g, the amount of pyrroloquinoline quinone dinatrium (NaPQQ) used was changed from 0.50 g to 1.00 g, and 1.00 g of sodium bicarbonate (NaHCO) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 9.3. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 94.3% and the yield was 67.3%.

[0057] [Comparative Example 1] A solid was obtained in the same manner as in Example 1, except that 0.50 g of sodium carbonate was not used. The pH of the reaction solution was 5.1. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 76.4% and the yield was 0.7%.

[0058] Comparative Example 2 A solid was obtained in the same manner as in Example 1, except that 0.50 g of sodium chloride (NaCl) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 5.8. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 81.4% and the yield was 18.2%.

[0059] Comparative Example 3 A solid was obtained in the same manner as in Example 1, except that the amount of pyrroloquinoline quinone dinatrium (NaPQQ) used was changed from 0.50 g to 0.05 g and 0.50 g of sodium bicarbonate (NaHCO) was used instead of 0.50 g of sodium carbonate. The pH of the reaction solution was 9.3. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 99.6% and the yield was 0.6%.

[0060] Comparative Example 4 2 g of glycine, 1.00 g of pyrroloquinoline quinone dinatrium (NaPQQ), and 5 mL of water were mixed. After 1 hour at room temperature (23±3°C), the reaction mixture solidified. The reaction was continued for another 3 days at 70°C, after which 10 mL of 10% aqueous sodium chloride solution was added and the mixture was filtered. The solid obtained by filtration was analyzed by HPLC. The HPLC purity and yield were calculated in the same manner as in Example 1, and the HPLC purity was 76.3% and the yield was 24.6%.

[0061] The amounts of each component used, reaction conditions, and the HPLC purity and yield of the target product, imidazopyrroloquinoline quinone trisodium (Na3IPQ), in the examples and comparative examples are summarized in the table below.

[0062] [Table 1]

[0063] The results of Examples 1 to 8 show that imidazopyrroloquinoline alkali metal salts can be precipitated with high HPLC purity and high yield by reacting pyrroloquinoline quinone or its salt at a concentration of 10 to 50 g / L in an aqueous solution with glycine or its salt and a basic alkali metal salt. In particular, in Example 3, in which the imidazopyrroloquinoline alkali metal salt was precipitated by reacting at a first-stage temperature and then at a second-stage temperature lower than the first-stage temperature, a very high HPLC purity was obtained.

[0064] On the other hand, in Comparative Example 1, in which a basic alkali metal salt was not added, the yield was extremely low and the HPLC purity was also low. In Comparative Example 2, in which a neutral alkali metal salt was used instead of a basic alkali metal salt, the HPLC purity was low and the yield was also low. In Comparative Example 3, in which the pyrroloquinoline quinone feed concentration was reduced to 2 g / L, the yield was extremely low. In Comparative Example 4, the reaction mixture solidified and was difficult to handle, and the reaction did not proceed smoothly. Even when the reaction was carried out at high temperature for a long period of time, the yield was low and the purity was also low, requiring further purification.

[0065] The production method of the present invention makes it possible to efficiently produce imidazopyrroloquinoline alkali metal salts that have high solubility and excellent thermal stability. [Industrial Applicability]

[0066] The imidazopyrroloquinoline alkali metal salts produced by the production method of the present invention are useful in various fields such as pharmaceuticals, cosmetics, foods (particularly functional foods), and feeds.

Claims

1. A method for producing an imidazopyrroloquinoline alkali metal salt, comprising reacting pyrroloquinoline quinone or a salt thereof at a concentration of 10 to 50 g / L in an aqueous solution with glycine or a salt thereof and a basic alkali metal salt, to precipitate an imidazopyrroloquinoline alkali metal salt represented by the following general formula (1): 【Chemical 1】 (In general formula (1), M is an alkali metal.)

2. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the reaction is carried out while blowing an oxygen-containing gas into the aqueous solution.

3. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the amount of glycine or a salt thereof used is 0.5 to 2 by weight, relative to the amount of pyrroloquinoline quinone or a salt thereof used, which is taken as 1.

4. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the amount of the basic alkali metal salt used is 0.5 to 2 by weight, relative to the amount of the pyrroloquinoline quinone or a salt thereof used, which is taken as 1.

5. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein M in general formula (1) is sodium (Na).

6. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the basic alkali metal salt is a basic sodium salt.

7. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the reaction is carried out at a temperature in the first stage and then at a temperature in the second stage which is lower than the temperature in the first stage.

8. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the purity of the precipitated imidazopyrroloquinoline alkali metal salt as determined by HPLC (high performance liquid chromatography) analysis is 93.0% or more.

9. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the yield of the imidazopyrroloquinoline alkali metal salt is 50.0% or more.

10. 2. The method for producing an imidazopyrroloquinoline alkali metal salt according to claim 1, wherein the imidazopyrroloquinoline alkali metal salt is precipitated simultaneously with the reaction of pyrroloquinoline quinone or a salt thereof.

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