JP5935689B2 - Method for producing pyrrolidonecarboxylic acid or a salt thereof - Google Patents

Description

  The present invention relates to a method for producing pyrrolidonecarboxylic acid or a salt thereof.

  Pyrrolidone carboxylic acid (PCA) is a useful compound not only as a cosmetic material but also as a raw material for pharmaceuticals. Pyrrolidone carboxylic acid is synthesized by heating glutamic acid to cause a self-cyclization reaction. As the production method, a solventless direct heating method, a high pressure and high temperature method in the presence of a solvent, a subcritical pressure heating method, and an enzymatic cyclization method are known.

  JP-A-1-132560 (Patent Document 1) describes a solventless direct heating method. The solventless direct heating method is a production method in which a monovalent alkaline earth metal salt of glutamic acid in a solid state is heated to a temperature between 120 ° C. and 250 ° C. until the reaction water for intramolecular condensation is completely discharged. is there. At first glance, the solvent-free direct heating method seems industrially simple and high in production efficiency. However, in the present production method, the melt during the reaction is in the shape of a syrup, and after cooling, it hardens and solidifies on the wall surface of the apparatus. Therefore, it is not always a simple production method in handling the reaction product. Further, it is known that pyroglutamic acid as an impurity is by-produced when the obtained pyrrolidonecarboxylic acid in a solid state is heated (see Japanese Patent Publication No. 41-19431 (Patent Document 2)), From the viewpoint of obtaining pyrrolidone carboxylic acid having high chemical purity, it was not an excellent production method.

  Japanese Examined Patent Publication No. 37-17959 (Patent Document 3) discloses a method in which L-glutamic acid is dissolved by heating at 190 to 200 ° C. to remove water to form pyrrolidonecarboxylic acid, and further a method for obtaining a racemate by heating. Is described. Japanese Patent Application Laid-Open No. 2003-34680 (Patent Document 4) describes a method of reacting glutamic acid with high-temperature and high-pressure water. In these production methods, an autoclave (heating kettle) or the like is used to withstand high temperature and pressure. Therefore, general-purpose chemical purity from the point that it cannot be manufactured with general-purpose equipment without pressure resistance, and the reaction is difficult to control such as when the inside of the container is cooled under reduced pressure. It was not a production method suitable for obtaining pyrrolidonecarboxylic acid with high optical purity.

  JP 10-66566 A (Patent Document 5) discloses an enzymatic cyclization method. A method is described in which pyrrolidone carboxylic acid is obtained from glutamic acid at a high reaction rate at a mild pH and temperature range in water under normal pressure by an enzymatic reaction. However, as described in Example 5 of JP-A-10-66566, in this method, the yield of pyrrolidonecarboxylic acid per 10 ml of the reaction solution is only about 0.4 mg (300 nmol), which is an industrially suitable production method. I couldn't say that.

Japanese Patent Laid-Open No. 1-132560 Japanese Patent Publication No. 41-19431 Japanese Patent Publication No. 37-17959 JP 2003-34680 A JP-A-10-65666

  An object of the present invention is to provide a method for producing pyrrolidone carboxylic acid or a salt thereof having high chemical purity and high optical purity easily and industrially under normal pressure.

  As a result of intensive research, the present inventors have found that the above-mentioned problems can be solved and can be continuously produced by heating and cyclizing glutamic acid under atmospheric pressure in a solution containing pyrrolidone carboxylic acid. The present invention has been completed.

That is, the present invention includes the following aspects.
[1] A process for producing pyrrolidone carboxylic acid or a salt thereof, characterized in that glutamic acid is heated and cyclized under normal pressure in an aqueous solution containing pyrrolidone carboxylic acid.
[2] A pyrrolidone carboxylic acid comprising a first step of preparing a pyrrolidone carboxylic acid-containing aqueous solution, a second step of adding glutamic acid and heating and cyclizing under normal pressure, and a third step of extracting a reaction solution containing the generated pyrrolidone carboxylic acid. Or the manufacturing method of the salt.
[3] The first to third steps described in [2] are defined as one cycle, and the remaining reaction solution when the reaction solution is partially extracted in the third step is used in the first step of the next cycle. A continuous production method of an acid or a salt thereof.
[4] The production method according to [2] or [3], wherein the concentration of pyrrolidone carboxylic acid in the pyrrolidone carboxylic acid-containing aqueous solution prepared in the first step is 60 wt% or more and less than 100 wt%.
[5] The production method according to any one of [1] to [4], wherein the heating cyclization temperature is 105 ° C to 150 ° C.
[6] The weight of glutamic acid charged in the second step is 10% to 500% with respect to the weight of pyrrolidone carboxylic acid in the pyrrolidone carboxylic acid-containing aqueous solution. The manufacturing method as described.
[7] The production method according to any one of [1] to [6], wherein a part or all of glutamic acid is glutamate.
[8] The production method according to any one of [1] to [7], wherein a part or all of the pyrrolidone carboxylic acid is pyrrolidone carboxylate.
[9] The ratio (acid molar ratio) of the “acid component (glutamic acid and pyrrolidone carboxylic acid)” to the total number of moles of “glutamic acid and its salt, pyrrolidone carboxylic acid and its salt” during the cyclization reaction is 90% to 10% The production method according to [7] or [8].
[10] The production method according to any one of [2] to [9], wherein a weight ratio (drawing rate) withdrawn as a product is 10% to 100% with respect to a total weight of pyrrolidone carboxylic acid.
[11] The production method according to any one of [1] to [10], wherein an optically active pyrrolidone carboxylic acid or a salt thereof is produced using an optically active pyrrolidone carboxylic acid and an optically active glutamic acid.
[12] A pyrrolidone carboxylic acid or a salt thereof having an optical purity of 100% to 92%, which is obtained by the production method according to [11].
[13] A cosmetic comprising the pyrrolidone carboxylic acid or a salt thereof according to [12].
[14] The production method according to [7], wherein the weight ratio of glutamic acid to glutamate is 50:50 to 0: 100.
[15] The production method according to [8], wherein the weight ratio of pyrrolidone carboxylic acid and pyrrolidone carboxylate is 100: 0 to 50:50.

  According to the present invention, pyrrolidone carboxylic acid having high chemical purity and optical purity can be produced easily and efficiently in an industrially simple manner under normal pressure in a short time.

FIG. 1 is a flowchart showing a continuous manufacturing method. FIG. 2 is a graph showing the relationship between the pyrrolidone carboxylic acid concentration and the boiling temperature (boiling start temperature and stable boiling temperature). FIG. 3 is a graph showing the relationship between the reaction temperature and the reaction time / reaction rate. FIG. 4 is a graph showing the relationship between the acid molar ratio and the reaction time / reaction rate.

  Hereinafter, the present invention will be described in detail.

  The production method of the present invention is a method for producing pyrrolidone carboxylic acid or a salt thereof, characterized in that glutamic acid is heated and cyclized under normal pressure in a pyrrolidone carboxylic acid-containing aqueous solution (hereinafter referred to as “normal pressure production method”). "). In the present invention, the heat cyclization reaction can proceed at normal pressure. In the present specification, “normal pressure” refers to a state in which neither pressure nor pressure reduction is performed, and a state equivalent to atmospheric pressure.

The atmospheric pressure production method of the present invention can continuously produce pyrrolidone carboxylic acid or a salt thereof by reusing part of the produced pyrrolidone carboxylic acid as an aqueous solution containing pyrrolidone carboxylic acid (hereinafter referred to as the present specification). (Referred to as “continuous manufacturing method”).
The continuous production method of the present invention is not particularly limited as long as it is an embodiment in which all or a part of the pyrrolidone carboxylic acid produced by the atmospheric pressure production method is reused. The first step to prepare the first step, the second step in which glutamic acid is added and heated to cyclize under normal pressure, and the third step in which the reaction solution containing the generated pyrrolidone carboxylic acid is withdrawn are defined as one cycle, and the cycle is repeated continuously. I can do it. In FIG. 1, the continuous manufacturing method of the said aspect was shown.

Although the suitable aspect of this invention is demonstrated below, the normal pressure manufacturing method of this invention is not limited to this.
The first step of the present invention will be described. The first step is a step of preparing a pyrrolidone carboxylic acid-containing aqueous solution having a desired concentration and a desired temperature by dissolving pyrrolidone carboxylic acid in water. When carrying out the present invention continuously, after the second cycle, the first step is to adjust the reaction solution containing pyrrolidone carboxylic acid left in the previous step (third step) to a solution having a desired concentration and a desired temperature. It is a process to do. When the pyrrolidone carboxylic acid solution left in the previous step (third step) is used as it is, the first step can be omitted after the second cycle.

  Specific examples of water include city water, industrial water, ion exchange water, and distilled water. From the viewpoint of reducing the coexisting components in the reaction system, ion-exchanged water and distilled water are more preferable.

The pyrrolidone carboxylic acid to be used may be either an optically active substance (L-form or D-form) or a racemic form (DL-form). In this specification, “optical activity” means a state in which one amount of L-form and D-form is larger than the other, and means that the L-form and D-form are not racemates in which an equal amount exists. “Optical purity” means, for example, the percentage of L-form to the total of L-form and D-form in the case of L-form.
A commercially available pyrrolidone carboxylic acid can be used. Pyrrolidone carboxylic acid available as a commercial product is L-form, and its optical purity is 100% to 50%. From the viewpoint of obtaining a pyrrolidone carboxylic acid having a high optical purity, the pyrrolidone carboxylic acid to be used is preferably as the L isomer has a higher optical purity, for example, preferably 60% or more, more preferably 70% or more, and more preferably 80% or more. Is more preferable, and 90% or more is particularly preferable.

As the pyrrolidonecarboxylic acid-containing aqueous solution used in the first step after the second cycle, those obtained in the third step of the previous cycle can be used. The higher the optical purity of the pyrrolidone carboxylic acid used in the first step, the more preferable it is as the L form. For example, 100% to 60% is preferable, 100% to 70% is more preferable, 100% to 80% is still more preferable, 90% is even more preferred, 100% to 92% is even more preferred, 100% to 95% is particularly preferred, and 100% to 97% is most preferred.
By using pyrrolidone carboxylic acid with high optical purity in the first step, pyrrolidone carboxylic acid with high optical purity and / or a salt thereof can be obtained in the third step. The optical purity of the pyrrolidone carboxylic acid and / or salt thereof obtained in the third step is, for example, preferably 100% to 60%, more preferably 100% to 70%, still more preferably 100% to 80%, more preferably 100% to 90%. % Is even more preferred, 100% to 92% is even more preferred, 100% to 95% is particularly preferred, and 100% to 97% is most preferred.

  The preparation temperature of the pyrrolidone carboxylic acid-containing aqueous solution is not particularly limited as long as pyrrolidone carboxylic acid can be uniformly dissolved. In terms of rapid dissolution, 105 ° C or higher is preferable, 108 ° C or higher is more preferable, 110 ° C or higher is further preferable, 113 ° C or higher is even more preferable, and 115 ° C or higher is most preferable. In view of the fact that the reaction equipment does not easily deteriorate without requiring a special apparatus, 200 ° C. or lower is preferable, 180 ° C. or lower is more preferable, 150 ° C. or lower is further preferable, 140 ° C. or lower is even more preferable, and 135 ° C. The following are most preferred. The preparation temperature and the cyclization reaction in the second step can be the same temperature.

  “Concentration of pyrrolidone carboxylic acid in pyrrolidone carboxylic acid-containing aqueous solution” means the percentage of the weight of pyrrolidone carboxylic acid with respect to the total weight of pyrrolidone carboxylic acid and water contained in the reaction system, and is obtained from the following formula (1) Can do.

Therefore, for example, even when glutamic acid is added in the second step and glutamic acid is contained in the reaction solution, the weight of glutamic acid is not considered.
Further, the “concentration of pyrrolidone carboxylic acid in the pyrrolidone carboxylic acid-containing aqueous solution” may be just before and immediately after the addition of glutamic acid, and at any time during the start of the thermal cyclization reaction and during the progress of the reaction. May be the concentration.
In order to allow the thermal cyclization reaction to proceed efficiently in a short time, it is preferable to control the reaction immediately before or immediately after the addition of glutamic acid, or by the concentration at the start of the thermal cyclization reaction.

  The concentration of pyrrolidone carboxylic acid in the pyrrolidone carboxylic acid-containing aqueous solution is not particularly limited as long as the cyclization reaction proceeds, but considering the reaction efficiency, a concentration higher than 50 wt% is preferable, and 55 wt% or higher is more preferable. 60 wt% or more, more preferably 65 wt% or more, even more preferably 70 wt% or more, particularly preferably 75 wt% or more, and particularly preferably 80 wt% or more. Moreover, since dissolution requires time if the concentration is too high, it is preferably less than 100 wt%, more preferably 98 wt% or less, still more preferably 95 wt% or less, even more preferably 93 wt% or less, and most preferably 90 wt% or less.

As one embodiment of the present invention, a part or all of pyrrolidone carboxylic acid may be pyrrolidone carboxylate. Possible salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, organic base salts such as zinc salts, ethanolamine salts and diethanolamine salts, lysine salts and arginine salts. And the like, and preferred are alkali metal salts such as sodium salt and potassium salt, and most preferred is sodium salt. These may be one kind or a mixture of two or more kinds. The weight ratio of pyrrolidone carboxylic acid and pyrrolidone carboxylate salt can be 100: 0 to 0: 100, but is preferably 100: 0 to 20:80, more preferably 100: 0 to 35:65, and 100: 0-40: 60 is even more preferred, and 100: 0-50: 50 is most preferred.
The “weight of pyrrolidone carboxylic acid” in the above formula (1) when a part or all of pyrrolidone carboxylic acid is pyrrolidone carboxylate is the total weight of free pyrrolidone carboxylic acid and pyrrolidone carboxylate. “Mole number of pyrrolidone carboxylic acid” in the above formula (2) is the total number of moles of free pyrrolidone carboxylic acid and pyrrolidone carboxylate. The number of moles of polyvalent metal salt such as zinc salt is based on the number of moles of pyrrolidone carboxylate ions.

  The second step of the present invention will be described. The second step is a step in which glutamic acid is added to a pyrrolidonecarboxylic acid-containing aqueous solution and heated and cyclized under normal pressure.

  The input weight of glutamic acid is not particularly limited as long as the fluidity of the system can be maintained, but is 10% to 500% with respect to the weight of pyrrolidone carboxylic acid in the pyrrolidone carboxylic acid-containing aqueous solution. If the weight of glutamic acid is larger than the weight of pyrrolidone carboxylic acid, the fluidity of the system deteriorates and the reaction is delayed, so 300% or less is preferable, and 200% or less is more preferable. If less, the amount of pyrrolidone carboxylic acid obtained decreases, so it is preferably 30% or more, more preferably 50% or more, and most preferably 70% or more. When continuously carried out, the amount of glutamic acid to be added can be adjusted by quantifying the content of unreacted glutamic acid in the previous cycle by HPLC or the like.

  The glutamic acid to be used may be L-form or D-form optically active glutamic acid, DL-form racemic glutamic acid, or any of these. The higher the optical purity of glutamic acid as L-form, the more preferable, for example, 100% to 60% is preferable, 100% to 70% is more preferable, 100% to 80% is still more preferable, 100% to 90% is still more preferable, 100% to 92% is particularly preferable, 100% to 95% is particularly preferable, and 100% to 97% is most preferable.

As one embodiment of the present invention, part or all of glutamic acid can be converted to glutamate. Possible salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, organic base salts such as ethanolamine salts and diethanolamine salts, bases such as lysine salts and arginine salts. Amino acid salts and the like, preferably alkali metal salts such as sodium salts and potassium salts, and most preferably sodium salts. These may be one kind or a mixture of two or more kinds. The weight ratio of glutamic acid and glutamate can be 100: 0 to 0: 100, preferably 80:20 to 0: 100, more preferably 65:35 to 0: 100, and 60:40 to 0: 100 is even more preferable, and 50:50 to 0: 100 is most preferable.
“Mole number of glutamic acid” in the following formula (2) when a part or all of glutamic acid is glutamate is the total number of moles of free glutamic acid and glutamic acid.

  The progress of the thermal cyclization reaction is affected by the acid molar ratio. In this specification, the acid molar ratio is the number of moles of “acid component (glutamic acid and pyrrolidone carboxylic acid)” relative to the total number of moles of “glutamic acid and its salt, pyrrolidone carboxylic acid and its salt” present during the cyclization reaction. It means ratio.

  The acid molar ratio can be obtained from the following formula (2).

Although the reaction proceeds even when the acid molar ratio is 100%, the acid molar ratio is preferably 90% or less, more preferably 80% or less, and even more preferably 75% or less, from the viewpoint that the reaction proceeds more quickly. 70% or less is still more preferred, 65% or less is particularly preferred, and 60% or less is particularly preferred. Further, from the viewpoint of reaction operability, it is preferably 10% or more, more preferably 20 or more, further preferably 25% or more, still more preferably 30% or more, particularly preferably 35% or more, and particularly preferably 40% or more.
In the first cycle of the normal pressure production method or continuous production method, heating is performed by appropriately adjusting the amount of pyrrolidone carboxylic acid or its salt used in the first step and / or the amount of glutamic acid or its salt used in the second step. The acid molar ratio during the cyclization reaction can be adjusted. For example, (1) an embodiment in which free pyrrolidone carboxylic acid is used in the first step and glutamic acid and / or a salt thereof are added in the second step, (2) pyrrolidone carboxylic acid and / or a salt thereof is added in the first step Any mode of using only the free glutamic acid in the second step and (3) using the pyrrolidone carboxylic acid and / or salt thereof in the first step and adding glutamic acid and / or salt thereof in the second step It may be.
In the second and subsequent cycles of the continuous production method, pyrrolidone carboxylic acid and / or a salt thereof, and / or an acid molar ratio in consideration of the acid molar ratio of the reaction solution obtained in the third step of the previous cycle, and / or Alternatively, glutamic acid and / or a salt thereof may be used. For example, when the acid molar ratio of the reaction solution obtained in the third step of the previous cycle is too high, free pyrrolidonecarboxylic acid and / or glutamic acid may be used more than its salt, and the reaction obtained in the third step When the acid molar ratio of the solution is too low, the pyrrolidone carboxylic acid and / or glutamic acid salt may be used more than the free form. Furthermore, in order to maintain the acid molar ratio during the reaction in an appropriate range, a free form of pyrrolidonecarboxylic acid and / or glutamic acid and / or a salt thereof may be added during the reaction.

  Glutamic acid can be added in several batches as needed to ensure the fluidity of the system. The number of times of charging is preferably 1 to 10 times, more preferably 1 to 5 times, and particularly preferably 1 to 3 times. Of course, it is also possible to add continuously as the reaction proceeds.

  The reaction temperature in the second step is not particularly limited as long as the reaction can proceed. In terms of reducing the reaction time, 105 ° C. or higher is preferable, 108 ° C. or higher is more preferable, 110 ° C. or higher is further preferable, 113 ° C. or higher is even more preferable, and 115 ° C. or higher is most preferable. In view of the fact that the reaction equipment does not easily deteriorate without requiring a special apparatus, 200 ° C. or lower is preferable, 180 ° C. or lower is more preferable, 150 ° C. or lower is further preferable, 140 ° C. or lower is even more preferable, and 135 ° C. The following are most preferred. From the viewpoint of good thermal efficiency, it is preferable to carry out the reaction by controlling the temperature (at the highest temperature reached) while maintaining the boiling state of the system.

  The reaction time is 10 minutes to 40 hours. The reaction time depends on the reaction temperature and the selection of the acid molar ratio, but is preferably 30 minutes or more, more preferably 1 hour or more, still more preferably 2 hours or more, and even more preferably 6 hours or more. On the other hand, from the viewpoint of suppressing racemization as a side reaction, it is preferably within 20 hours, more preferably within 14 hours, further preferably within 12 hours, particularly preferably within 10 hours, and most preferably within 8 hours.

The third step of the present invention will be described. The third step is a step in which a specific amount of the obtained reaction solution containing pyrrolidone carboxylic acid is taken out and used as a product, and the rest is used as a solution in the first step of the next cycle. When not using the continuous production method, all of the reaction solution containing pyrrolidonecarboxylic acid may be taken out.
The ratio of the weight withdrawn as a product to the total weight of pyrrolidone carboxylic acid present in the system (hereinafter referred to as “drawing rate”) can be appropriately calculated from the amount of glutamic acid to be added and the reaction rate. The more pyrrolidone carboxylic acid to be extracted, the greater the yield per cycle. Therefore, the higher the value, the more preferably 100%. On the other hand, in order to leave a necessary amount for a continuous cycle, the drawing rate is preferably 90% or less, more preferably 80% or less, and further preferably 70% or less.
The drawing method is not particularly limited, and it may be appropriately drawn according to the reaction apparatus to be used. For example, in the case of a device having a drain at the bottom of the reaction vessel, the drain may be opened and a specific amount may be withdrawn from the vessel, or may be withdrawn from the open portion at the top of the reaction device using a pump.

The product taken out in the third step can be appropriately purified according to a conventional method using an ion exchange resin or recrystallization. Moreover, it can mix | blend with cosmetics etc. as it is, without carrying out additional refinement | purification.
In the third step, when pyrrolidone carboxylic acid is obtained in a free form, it may be converted into a pyrrolidone carboxylic acid salt according to a conventional method. When a pyrrolidone carboxylic acid salt is obtained, pyrrolidone carboxylic acid is obtained according to a conventional method. You may convert into the free body of an acid. When a mixture of a free form of pyrrolidone carboxylic acid and a salt is obtained, all may be converted to a free form or salt of pyrrolidone carboxylic acid according to a conventional method.
In the case of obtaining a salt of pyrrolidone carboxylic acid, examples of the salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic salts such as zinc salt, ethanolamine salt and diethanolamine salt. Examples include basic amino acid salts such as base salts, lysine salts, and arginine salts.

  As one embodiment of the present invention, it can be optionally concentrated under reduced pressure after or before the third step. Although there is no restriction | limiting in particular about the temperature to concentrate under reduced pressure, It is 40 to 100 degreeC. Since it takes time to concentrate at a low temperature, it is preferably 50 ° C. or higher, more preferably 60 ° C. or higher, from the viewpoint that it can be concentrated under reduced pressure in a short time. The degree of vacuum is not particularly limited as long as water can be distilled off, and is preferably 50 kpa or less. On the other hand, 5 kpa or more is preferable, 10 kpa or more is more preferable, and 30 kpa or more is more preferable as a condition for ensuring a reduced pressure without using special equipment.

  The amount of water after concentration is not particularly limited as long as the system has fluidity, but is 1 wt% to 30 wt%. When the water content is low, the fluidity tends to be difficult to ensure, so the content is preferably 4 wt% or more, more preferably 6 wt% or more, and still more preferably 8 wt% or more.

  The reaction solution remaining in the third step can be used as the pyrrolidone carboxylic acid-containing aqueous solution in the first step. At this time, addition of pyrrolidone carboxylic acid, addition of water, or concentration under reduced pressure may be performed as necessary so that the pyrrolidone carboxylic acid has the appropriate concentration described above. The method of concentration under reduced pressure is the same as described above.

  By repeating the cycle from the first to third steps, it is possible to obtain pyrrolidone carboxylic acid or a salt thereof having high chemical purity and high optical purity continuously at normal pressure under industrial pressure. it can.

  In the production method of the present invention, a coexisting component can be added to water as long as the cyclization reaction is not inhibited. The coexisting component is not particularly limited as long as it does not react with the substrate under the reaction conditions, and specifically includes alcohols such as methanol, ethanol, t-butanol and propylene glycol; ketones such as acetone and methyl ethyl ketone. You may use these 1 type or in mixture of 2 or more types.

  The pyrrolidone carboxylic acid or salt thereof obtained in the present invention is a facial cleanser, soap, cleansing foam, lotion, milky lotion, beauty essence, beauty cream, shampoo, hair rinse, hair conditioner, enamel, foundation, lipstick, funny, powder , Packs, perfumes, cologne, toothpaste and other cosmetics.

  Commonly used ingredients generally used in cosmetics or external preparations for skin can be used as additives. Ingredients commonly used in cosmetics or topical skin preparations include antioxidants, anti-inflammatory agents, UV absorbers, whitening agents, hair restorers, cell activators, moisturizers, metal chelators, oily ingredients, and surface active agents Agent, solvent, polymer substance, powder substance, pigments, fragrance, transdermal absorption enhancer, antiseptic, anti-fading agent, buffer, acne agent, anti-dandruff / itch agent, antiperspirant deodorant, burn Drugs, anti-ticks / lices, keratin softeners, xeroderma, antivirals, hormones, vitamins, amino acids / peptides, proteins, astringents, refreshing / irritant, animal and plant derived ingredients, antibiotics And antifungal agents.

  EXAMPLES Hereinafter, although this invention is demonstrated in more detail using an Example, these examples do not limit this invention.

[Quantitative and optical purity analysis method]
Pyrrolidone carboxylic acid and glutamic acid are quantified by high performance liquid chromatography (chiral column: “Sumichiral OA-5500” manufactured by Sumitomo Chemical Analysis Center, column temperature: 25 ° C., eluent: 2 mmol copper (II) sulfate aqueous solution, flow rate: 1 ml / min. , Detection: UV254 nm). Standard solutions of L-glutamic acid (manufactured by Wako Pure Chemical Industries) and pyrrolidone carboxylic acid (manufactured by Ajinomoto Co., Inc.) were prepared, and the content was calculated from the relative area. Moreover, the optical purity analysis of pyrrolidone carboxylic acid made L / L + D ratio with the detected area ratio.

Experimental example 1
[Relationship between pyrrolidone carboxylic acid concentration and system temperature]
Pyrrolidonecarboxylic acid and water were placed in a 20 ml test tube to prepare 50, 60, 80, 88, 90, and 95 wt% aqueous solutions. Put a small magnetic stirrer bar in the test tube, insert a digital thermometer so that it does not touch the bottom or side of the test tube, heat it using an oil bath, and start boiling temperature (temperature at which gas begins to be released from the system) , And a stable boiling temperature (a temperature at which the boiling state is stably maintained) was measured. The results are shown in FIG.

  From the results of FIG. 2, it has been clarified that the boiling point exceeds 105 ° C. when the pyrrolidone carboxylic acid concentration in the pyrrolidone carboxylic acid-containing aqueous solution is 60 wt% or more, and the boiling point exceeds 110 ° C. when it is 80 wt% or more.

Experimental example 2
[Relationship between reaction temperature, reaction time and reaction rate]
The change with time of the reaction rate from L-glutamic acid to L-pyrrolidonecarboxylic acid at each reaction temperature was examined. 50 g of pyrrolidone carboxylic acid was dissolved in 7 g of water, 50 g of L-glutamic acid was added, and the reaction was carried out using a reflux apparatus under normal pressure. The temperature of the oil bath was adjusted to 120 to 145 ° C., and the temperature in the test tube was controlled to be 100, 110, 115, 120, and 136 ° C., respectively. In addition, the reaction rate was made into the ratio of the L-pyrrolidone carboxylic acid obtained by reaction with respect to the added L-glutamic acid. The results are shown in FIG.

  As is clear from FIG. 3, it was confirmed that the reaction rate was dramatically improved as the reaction temperature increased, and the reaction time was greatly shortened.

Experimental example 3
[Evaluation of reaction operability, reaction efficiency, and optical purity]
0 to 70 g of pyrrolidonecarboxylic acid was added to 7 g of water and dissolved by heating. After dissolution, L-glutamic acid was added, and the reaction was carried out under normal pressure using a reflux apparatus while maintaining the boiling state. In addition, the reaction rate was made into the ratio of the L-pyrrolidone carboxylic acid obtained by reaction with respect to the added L-glutamic acid.

Judgment criteria for reaction operability are as follows.
◎: During the reaction, the entire system is fluid at all times. ○: During the reaction, fluidity is obtained almost throughout the system. However, there is local fluidity immediately after the raw material is divided and added. △: During the reaction, almost throughout the system. Although fluidity can be obtained, there may be only local agitation fluidity temporarily after dividing the raw material. ×: The system cannot be agitated without fluidity.

Regarding the reaction efficiency, the time required to reach a reaction rate of 90% was measured and evaluated as follows.
◎: Less than 5 hours ○: 5 hours or more and less than 8 hours Δ: 8 hours or more and less than 10 hours ×: 10 hours or more

The optical purity was evaluated as follows.
◎: L-form existence ratio is 95% or more ○: L-form existence ratio is 92% or more and less than 95% △: L-form existence ratio is 89% or more and less than 92% ×: L-form existence ratio is less than 89%

  In Examples 1 to 5, pyrrolidone carboxylic acid having high optical purity and high chemical purity could be obtained with excellent reaction operability and reaction efficiency under normal pressure. In Comparative Examples 1 and 2, the fluidity was poor and the reaction could not proceed.

Experimental Example 4
[Relationship between the ratio of pyrrolidone carboxylic acid and pyrrolidone carboxylate and system temperature]
A predetermined amount of pyrrolidone carboxylic acid, sodium pyrrolidone carboxylate and water were placed in a 20 ml test tube to prepare a 90 wt% aqueous solution. A small magnetic stirrer bar was placed in the test tube, a digital thermometer was inserted so as not to contact the bottom and side surfaces of the test tube, heated using an oil bath, and the temperature at the time of stable boiling was measured. The results are shown in Table 2.

  From the results in Table 2, it was shown that even when pyrrolidone carboxylic acid was replaced with sodium pyrrolidone carboxylate, it boiled stably at almost the same temperature.

Experimental Example 5
[Relationship between acid molar ratio and reaction operability, reaction efficiency and optical purity]
The amount of pyrrolidone carboxylic acid, L-glutamic acid and its salt was varied, and the relationship between reaction time and reaction rate was examined. Specifically, an aqueous solution of pyrrolidone carboxylic acid was prepared according to Table 3. Next, according to Table 3, L-glutamic acid and / or L-glutamic acid monosodium salt monohydrate was added and reacted at 120 ° C. using a reflux apparatus under normal pressure. The transition of the reaction rate under each condition was followed. In addition, the reaction rate was made into the ratio of the L-pyrrolidone carboxylic acid obtained by reaction with respect to the added L-glutamic acid or its salt. FIG. 4 shows the change over time in the reaction rate.
Reaction operability, reaction efficiency, and optical purity were evaluated according to the same criteria as in Experimental Example 3.

  In Examples 6 to 11, pyrrolidonecarboxylic acid or a salt thereof having high optical purity and high chemical purity could be produced with excellent reaction operability and reaction efficiency under normal pressure. It was confirmed that the reaction proceeded the earliest at 53% of the evaluated acid molar ratio.

[Continuous production example 1]
The first cycle of the continuous reaction was performed as follows.
As a first step, 40 g of pyrrolidone carboxylic acid (L-form content 97.7%) and 5.6 g of water were added to a 200 mL four-necked flask and dissolved by heating at 120 ° C. As a second step, 45.6 g of L-glutamic acid as a raw material was added and heated at 120 ° C. for 8 hours. As a third step, the reaction solution was depressurized at a temperature of 100 to 115 ° C. and the system was kept at 120 ° C. for 1 hour to remove about 6.1 g of water, and 81 g of pyrrolidonecarboxylic acid aqueous solution was obtained. At this time, the pyrrolidonecarboxylic acid content was 98.1%, the optical purity was 96.3%, and the unreacted glutamic acid content was 1.9%. 40 g of the obtained pyrrolidonecarboxylic acid-containing aqueous solution was used as the first step solution in the second cycle of the continuous reaction.
The second cycle of the continuous reaction was performed as follows.
As a first step, 40.1 g of the pyrrolidone carboxylic acid aqueous solution obtained in the first cycle was placed in a 200 mL four-necked flask and heated and dissolved at 120 ° C. As a second step, 38.5 g of L-glutamic acid as a raw material and 2 g of water were added to adjust the system concentration. Then, it heated at 120 degreeC for 9 hours. The reaction solution was depressurized at a temperature of 100 to 115 ° C. and maintained at 120 ° C. for 3 hours to remove about 5.7 g of water, and then 71.7 g of a pyrrolidonecarboxylic acid-containing aqueous solution was obtained. At the end of the reaction, the reaction rate to pyrrolidonecarboxylic acid in the system was 99.2%, the optical purity was 94.7%, and the glutamic acid content was 0.8%. The contents of continuous production example 1 are summarized in Table 4.
From these results, it was found that pyrrolidone carboxylic acid having high chemical purity and high optical purity can be obtained industrially easily and under normal pressure by continuously carrying out the same reaction cycle.

Formulation Example 1 Cream

Formulation Example 2 Liquid Hand Soap

  It was possible to provide a method for efficiently obtaining pyrrolidonecarboxylic acid or a salt thereof having high chemical purity and optical purity in an industrially simple manner under normal pressure in a short time.

  This application is based on Japanese Patent Application No. 2010-031056 filed in Japan, the contents of which are incorporated in full herein.

Claims (11)

  An optical activity characterized by heat-cyclizing optically active glutamic acid at 115 ° C. to 140 ° C. under normal pressure in an optically active pyrrolidone carboxylic acid-containing aqueous solution having a concentration of optically active pyrrolidone carboxylic acid of 80 wt% or more and less than 93 wt%. A method for producing pyrrolidonecarboxylic acid or a salt thereof.   First step of preparing an optically active pyrrolidone carboxylic acid-containing aqueous solution having an optically active pyrrolidone carboxylic acid concentration of 80 wt% or more and less than 93 wt%, an optically active glutamic acid is added, and heat cyclization is carried out at 115 to 140 ° C under normal pressure. A process for producing an optically active pyrrolidone carboxylic acid or a salt thereof, comprising a third step of extracting a reaction solution containing the produced optically active pyrrolidone carboxylic acid in two steps.   An optically active pyrrolidone carboxylic acid, wherein the first step to the third step according to claim 2 are defined as one cycle, and the remaining reaction solution when the reaction solution is partially extracted in the third step is used in the first step of the next cycle. Or the continuous manufacturing method of the salt.   The production method according to claim 2 or 3, wherein the weight of the optically active glutamic acid added in the second step is 10% to 500% with respect to the weight of the optically active pyrrolidonecarboxylic acid in the optically active pyrrolidonecarboxylic acid-containing aqueous solution. .   The production method according to any one of claims 1 to 4, wherein a part or all of the optically active glutamic acid is converted to an optically active glutamate.   The production method according to any one of claims 2 to 5, wherein in the first step, part or all of the optically active pyrrolidone carboxylic acid is converted to an optically active pyrrolidone carboxylate.   The ratio (acid molar ratio) of the “acid component (optically active glutamic acid and optically active pyrrolidonecarboxylic acid)” to the total number of moles of “optically active glutamic acid and its salt, optically active pyrrolidonecarboxylic acid and its salt” during the cyclization reaction is It is 90%-10%, The manufacturing method of Claim 5 or 6.   The production method according to claim 2, wherein the ratio of the weight withdrawn as a product (drawing rate) is 10% to 100% with respect to the total weight of the optically active pyrrolidone carboxylic acid.   The manufacturing method as described in any one of Claims 1-8 whose optical purity of the optically active pyrrolidone carboxylic acid or its salt obtained is 100%-92%.   The production method according to claim 5, wherein the weight ratio of the optically active glutamic acid to the optically active glutamate is 50:50 to 0: 100. The production method according to claim 2 , wherein the weight ratio of the optically active pyrrolidone carboxylic acid to the optically active pyrrolidone carboxylate is 100: 0 to 40:60.

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