Method for producing hydroxybenzoic acid crystals

Abstract

A method for producing hydroxybenzoic acid crystals with suppressed discoloration is provided. [Solution] A method for producing hydroxybenzoic acid crystals, comprising the step of crystallizing hydroxybenzoic acid from an aqueous solution containing hydroxybenzoic acid and a nonionic surfactant.

Description

Technical Field

[0005] , ,

[0001] The present invention relates to a method for producing hydroxybenzoic acid crystals.

Background Art

[0002] Hydroxybenzoic acid is a kind of aromatic hydroxycarboxylic acid, and is a compound in which a hydroxy group and a carboxy group are each bonded to a benzene ring. There are three isomers of hydroxybenzoic acid due to the difference in the relative positions of the hydroxy group and the carboxy group. Hydroxybenzoic acid is used as a raw material for food preservatives, preservatives, pharmaceuticals, and the like.

[0003] Hydroxybenzoic acid has been industrially produced for many years by an organic chemical synthesis method known as the Kolbe-Schmitt reaction. On the other hand, due to problems such as environmental load and safety, recently, a process for producing hydroxybenzoic acid by a fermentation method using microorganisms has been developed. For example, in Patent Document 1, it has been reported that a culture solution containing hydroxybenzoic acid was obtained by a bioprocess using plant-derived saccharides and microorganisms, and after concentrating the culture solution, hydroxybenzoic acid crystals were recovered from the concentrated solution by a crystallization method.

Prior Art Documents

[0006] The inventors have discovered that crystallizing hydroxybenzoic acid in the presence of a nonionic surfactant yields hydroxybenzoic acid crystals with minimal discoloration and good color.

[0007] In other words, the present invention provides a method for producing hydroxybenzoic acid crystals, comprising the step of crystallizing hydroxybenzoic acid from an aqueous solution containing hydroxybenzoic acid and a nonionic surfactant. [Effects of the Invention]

[0008] According to the present invention, hydroxybenzoic acid crystals with suppressed discoloration can be provided. [Modes for carrying out the invention]

[0009] [Method for producing hydroxybenzoic acid crystals] The present invention provides a method for producing hydroxybenzoic acid crystals, comprising the step of crystallizing hydroxybenzoic acid from an aqueous solution containing hydroxybenzoic acid and a nonionic surfactant. The present invention provides hydroxybenzoic acid crystals with suppressed discoloration. The reason why the discoloration of the hydroxybenzoic acid crystals is suppressed by the present invention is not entirely clear, but it is presumed that one of the factors is that the separation of the crystallization mother liquor and the crystals during filtration after crystallization is improved because crystals with large particle size and few defects are obtained when crystals are precipitated in the presence of a nonionic surfactant.

[0010] In the present invention, the nonionic surfactant only needs to be present during the crystallization of hydroxybenzoic acid. The timing of adding the nonionic surfactant to the aqueous solution containing hydroxybenzoic acid is not particularly limited. Hereinafter, in this specification, "aqueous solution containing hydroxybenzoic acid and a nonionic surfactant" will also be referred to as "the aqueous solution."

[0011] (Hydroxybenzoic acid) Hydroxybenzoic acid exists in three isomers: o-, m-, and p-. These can be denoted as 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, and 4-hydroxybenzoic acid, respectively. In this invention, hydroxybenzoic acid may be any of these isomers, or a mixture of any two or three of the isomers. This invention is more preferably used for the crystallization of p-4-hydroxybenzoic acid.

[0012] Hydroxybenzoic acid is not particularly limited and can be obtained by organic chemical synthesis or fermentation by microorganisms, but from the viewpoint of more easily enjoying the effects of the present invention, it is preferable to obtain it by fermentation by microorganisms. Fermentation production methods for hydroxybenzoic acid using microorganisms are well known and can be achieved by combining known biosynthesis techniques from a carbon source such as glucose, and the starting material may be something other than sugar. For example, International Publication No. 2012 / 081084 describes a method for producing salicylic acid (2-hydroxybenzoic acid) from phthalic acid, Japanese Patent Publication No. Hei 7-184671 describes a method for producing 3-hydroxybenzoic acid from isophthalic acid, and Japanese Patent Publication No. 2004-215586 describes a method for producing 4-hydroxybenzoic acid from toluene or benzoic acid. In the crystallization process of this invention, after obtaining hydroxybenzoic acid, it is possible to use either the hydroxybenzoic acid without extracting it as crystals, or the hydroxybenzoic acid that has been extracted as crystals. The solvent used to dissolve hydroxybenzoic acid is not particularly limited as long as it can dissolve hydroxybenzoic acid, but water is preferably used. The dissolution temperature of hydroxybenzoic acid is preferably 40°C or higher, more preferably 50°C or higher, and even more preferably 60°C or higher, from the viewpoint of completely dissolving hydroxybenzoic acid, and preferably 100°C or lower, more preferably 90°C or lower, from the viewpoint of the stability of hydroxybenzoic acid.

[0013] In the present invention, the aqueous solution containing hydroxybenzoic acid is preferably an aqueous solution derived from a microbial culture medium, from the viewpoint of more easily enjoying the effects of the present invention and from the viewpoint of industrial productivity. The microorganism may be a wild-type strain, a mutant strain, or a mutant strain in which mutations such as insertion, substitution, or deletion of the base sequence have occurred through various genetic manipulations. It may also be a microorganism to which the ability to produce hydroxybenzoic acid has been conferred by known artificial modifications. For example, microorganisms capable of producing hydroxybenzoic acid include the genera Escherichia, Rhodococcus, Acinetobacter, Bradyrhizobium, Corynebacterium, Pseudomonas, Rhodopseudomonas, Sinorhizobium, and Brevibacterium. Examples of microorganisms include those belonging to the genera *m*, *Novosphingobium*, *Ralstonia*, *Nocardioidaceae*, *Microbacterium*, *Streptomyces*, *Amycolatopsis*, *Kineococcus*, *Pantoea*, *Klebsiella*, and *Arthrobacter*.

[0014] The culture medium used for culturing microorganisms capable of producing hydroxybenzoic acid preferably contains, as culture materials, a carbon source, an inorganic nitrogen source, or an organic nitrogen source, as well as other necessary organic trace nutrients that the microorganisms can utilize. Examples of carbon sources include sugars (glucose, sucrose, maltose, etc.), organic acids, dextran, soluble starch, methanol, and the like. Examples of inorganic or organic nitrogen sources include ammonium salts, nitrates, various amino acids, corn steep liquor, tryptone, peptone, casein, yeast extract, meat extract, soybean meal, potato extract, and the like. It may also contain inorganic salts (such as sodium chloride, calcium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, magnesium chloride, magnesium sulfate, and manganese sulfate), vitamins, and antibiotics (such as tetracycline, neomycin, kanamycin, spectinomycin, and erythromycin).

[0015] The cultivation of microorganisms can be carried out using general methods, provided that the conditions allow the microorganisms to grow and produce hydroxybenzoic acid. The culture temperature is preferably 20°C or higher, more preferably 30°C or higher, and also preferably 40°C or lower, more preferably 37°C or lower. The pH of the culture medium during cultivation is preferably pH 4 or higher, more preferably pH 5 or higher, and also preferably pH 9 or lower, more preferably pH 8 or lower. The inoculation amount of microorganisms into the culture medium is preferably 0.01% (v / v) or more, more preferably 0.1% (v / v) or more, even more preferably 0.5% (v / v) or more, and also preferably 40% (v / v) or less, more preferably 30% (v / v) or less, and even more preferably 20% (v / v) or less. The culture period for microorganisms can be set appropriately according to the growth of the microorganisms, but is preferably 0.1 days or more, more preferably 0.2 days or more, even more preferably 0.3 days or more, and also preferably 20 days or less, more preferably 10 days or less, and even more preferably 8 days or less, based on a 24-hour day. Conventional culture vessels can be used for cultivation as appropriate. For example, aerated and agitated culture vessels, bubble tower culture vessels, and fluidized bed culture vessels can be used, and the process can be carried out in batch, semi-batch, or continuous configurations.

[0016] Through such culturing, a microbial culture solution containing hydroxybenzoic acid can be obtained. Since the culture solution contains, in addition to hydroxybenzoic acid, contaminants, microbial cells, and unused culture raw materials, it is preferable to perform separation operations such as centrifugation, membrane separation, and adsorption separation to obtain an aqueous solution containing hydroxybenzoic acid. In the present invention, an aqueous solution containing hydroxybenzoic acid is obtained by removing mainly microbial cells from the microbial culture solution containing hydroxybenzoic acid by the separation operation.

[0017] (Content of hydroxybenzoic acid in the aqueous solution) In the present invention, the content of hydroxybenzoic acid in the aqueous solution containing hydroxybenzoic acid may be below the saturated solubility of hydroxybenzoic acid. From the viewpoint of productivity, it is preferably 1% by mass or more, more preferably 2% by mass or more, still more preferably 2.5% by mass or more. Also, from the viewpoint of improving the yield during the cell separation operation, it is preferably 20% by mass or less, more preferably 15% by mass or less, still more preferably 12% by mass or less. The content of hydroxybenzoic acid in the aqueous solution is preferably 1 to 20% by mass, more preferably 2 to 15% by mass, still more preferably 2.5 to 12% by mass.

[0018] (pH adjustment of the aqueous solution containing hydroxybenzoic acid) In the present invention, after the separation operation, a step of contacting an adsorbent with the aqueous solution containing hydroxybenzoic acid can be included. The pH of the aqueous solution is not particularly limited, but from the viewpoint of suppressing crystal coloring, it is preferable to perform the treatment of contacting the adsorbent after adjusting the pH of the aqueous solution containing hydroxybenzoic acid. The pH of the aqueous solution containing hydroxybenzoic acid to be contacted with the adsorbent is preferably 1.0 or more, more preferably 2.0 or more, still more preferably 2.5 or more, even more preferably 3.0 or more, preferably 7.0 or less, more preferably 6.5 or less, still more preferably 6.0 or less, even more preferably 5.0 or less, or preferably 1.0 to 7.0, more preferably 2.0 to 6.5, still more preferably 2.5 to 6.0, even more preferably 3.0 to 5.0. The acid used for pH adjustment can be used without particular limitation as long as its pKa is smaller than that of hydroxybenzoic acid, and inorganic acids are particularly preferred. Examples of inorganic acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, etc. Sulfuric acid and hydrochloric acid are preferred. The pH was measured using the pH measuring device described in the examples, and calibration was performed at 25 °C with a three-point calibration using pH standard solutions (pH 1.68, 6.86, 9.18). When the sample temperature was other than 25 °C, the pH was calculated using the automatic temperature compensation function of the pH meter.

[0019] (Treatment of contacting the adsorbent) As the adsorbent, a porous adsorbent is preferred, and examples include activated carbon, silicon dioxide, and solid acid adsorbents. Examples of solid acid adsorbents include acid clay, activated clay, activated alumina, silica gel, silica-alumina, aluminum silicate, etc. These can be used alone or in combination of two or more. Among them, activated carbon is preferred from the viewpoint of suppressing crystal coloring. The raw material from which the activated carbon is derived is not particularly limited, and examples include sawdust, coal, coconut shells, etc. Further, activated carbon activated by a gas such as steam or a chemical is preferably used. The shape of the activated carbon is not particularly limited, and examples include powdery, granular, and fibrous. As the activated carbon, commercially available products such as Shirasagi P (Osaka Gas Chemical Co., Ltd.) and Kuraray Coal GW (Kuraray Co., Ltd.) can be used.

[0020] In this treatment, from the viewpoint of fast filtration speed and good productivity, perlite, silicon dioxide, diatomaceous earth, etc. may be appropriately added as a filter aid.

[0021] From the viewpoint of suppressing discoloration of crystals, the amount of adsorbent used is preferably 0.1% by mass or more, more preferably 0.3% by mass or more, and even more preferably 0.5% by mass or more, relative to the aqueous solution containing hydroxybenzoic acid. Furthermore, from the viewpoint of industrial productivity, it is preferably 10% by mass or less, more preferably 6% by mass or less, and even more preferably 3% by mass or less. The amount of adsorbent used is preferably 0.1 to 10% by mass, more preferably 0.3 to 6% by mass, and even more preferably 0.5 to 3% by mass, relative to the aqueous solution containing hydroxybenzoic acid.

[0022] Methods for contacting an aqueous solution containing hydroxybenzoic acid with an adsorbent include, for example, batch processing and continuous processing. In a batch process, for example, an adsorbent can be added to an aqueous solution containing hydroxybenzoic acid, stirred to allow adsorption, and then the adsorbent can be recovered by filtration. The processing atmosphere can be air or an inert gas (nitrogen, argon, helium, or carbon dioxide). In the case of a continuous process, for example, contact can be maintained by continuously processing using a column packed with an adsorbent. The liquid flow conditions can be set as appropriate.

[0023] The contact temperature between the aqueous solution containing hydroxybenzoic acid and the adsorbent is preferably 40°C or higher, more preferably 50°C or higher, and even more preferably 60°C or higher, from the viewpoint of the solubility of hydroxybenzoic acid, in order to prevent hydroxybenzoic acid from precipitating and adsorbing onto the adsorbent. Furthermore, from the viewpoint of industrial productivity, it is preferably 150°C or lower, more preferably 135°C or lower, even more preferably 120°C or lower, and even more preferably 95°C or lower. The contact temperature is preferably 40 to 150°C, more preferably 50 to 135°C, even more preferably 60 to 120°C, and even more preferably 60 to 95°C.

[0024] The contact time can be appropriately selected depending on the contact means and scale size, but from the viewpoint of adsorption equilibrium of the coloring component to the adsorbent, it is preferably 5 minutes or more, more preferably 10 minutes or more, and even more preferably 20 minutes or more. Furthermore, from the viewpoint of industrial productivity, it is preferably within 10 hours, more preferably within 5 hours, and even more preferably within 3 hours. The contact time is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours, and even more preferably 20 minutes to 3 hours. The pressure can be atmospheric pressure, pressurized pressure, or reduced pressure.

[0025] After contacting the adsorbent with an aqueous solution containing hydroxybenzoic acid, the adsorbent is separated. Filtration is preferred as the separation method, and any of the following filtration methods are possible: suction filtration, pressure filtration, centrifugal filtration, etc.

[0026] The absorbance at a wavelength of 470 nm of the aqueous solution containing hydroxybenzoic acid after the operation to separate the adsorbent is preferably 1 or less, more preferably 0.5 or less, and even more preferably 0.4 or less.

[0027] In the present invention, a step of concentrating the aqueous solution containing hydroxybenzoic acid may be performed prior to crystallization, but it is preferable to perform crystallization without performing the concentration step. The hydroxybenzoic acid content in the aqueous solution containing hydroxybenzoic acid before crystallization is preferably less than 15% by mass, and more preferably less than 10% by mass. The lower limit is not particularly limited, but is preferably 1% by mass or more.

[0028] (Nonionic surfactant) Examples of nonionic surfactants include those having polyoxyethylene chains, such as polyoxyethylene alkyl ethers, polyoxyethylene alkenyl ethers, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene alkenyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene resin acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkylamines, and polyoxyethylene alkyl ethers (C12-14 secondary alcohols); polyglycerin fatty acid esters, glycerin fatty acid esters, ethylene glycol fatty acid esters, propylene glycol fatty acid esters, butylene glycol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, and alkyl glucosides. The nonionic surfactant may be one type or a mixture of two or more types. In particular, from the viewpoint of suppressing discoloration of the crystals, it is preferably at least one selected from a nonionic surfactant having a polyoxyethylene chain, glycerin fatty acid ester, and sorbitan fatty acid ester, more preferably at least one selected from polyoxyethylene alkyl ether, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil, and even more preferably at least one selected from polyoxyethylene alkyl ether and polyoxyethylene hydrogenated castor oil.

[0029] The number of moles of ethylene oxide added to the polyoxyethylene chain is expressed as an average value and is preferably 2 or more, more preferably 3 or more, even more preferably 4 or more, and also preferably 60 or less, more preferably 50 or less, even more preferably 40 or less, even more preferably 30 or less, even more preferably 25 or less, and even more preferably 20 or less. Furthermore, the number of carbon atoms in the fatty acid portion, alkyl portion, and alkenyl portion of the nonionic surfactant, including the carbonyl carbon atom in the case of an ester compound, is preferably 6 or more, more preferably 8 or more, even more preferably 10 or more, and also preferably 24 or less, more preferably 22 or less, and even more preferably 20 or less. Furthermore, "having a polyoxyethylene chain" means that the nonionic surfactant molecule has a structure in which one mole or more of ethylene oxide is added.

[0030] The weight-average molecular weight of the nonionic surfactant is preferably less than 1,000, and more preferably between 200 and 950, from the viewpoint of suppressing discoloration of the crystals. The weight-average molecular weight of nonionic surfactants can be measured, for example, by gel permeation chromatography (GPC).

[0031] The HLB of the nonionic surfactant is preferably 4 or higher, more preferably 6 or higher, even more preferably 8 or higher, and also preferably 19 or lower, even more preferably 18 or lower, from the viewpoint of suppressing discoloration of the crystals. The HLB of the nonionic surfactant is preferably 4 to 19, more preferably 6 to 18, and even more preferably 8 to 18. In this invention, HLB is an index indicating the hydrophilic-lipophilic balance, and is a numerical value calculated from the inorganic and organic values ​​by Oda, Teramura, et al. The HLB, calculated from the inorganic and organic values, is specifically calculated as HLB = (Σ inorganic value / Σ organic value) × 10. Here, for each of the "inorganic value" and "organic value," values ​​are set according to various atoms or functional groups. For example, one carbon atom in a molecule has an "organic value" of 20, and one hydroxyl group has an "inorganic value" of 100 (see, for example, Yoshio Koda, "Organic Concept Diagram - Fundamentals and Applications," pp. 11-17, Sankyo Publishing, 1984). The HLB of an organic compound is calculated by summing the "inorganic value" and "organic value" of all atoms and functional groups in the organic compound. Generally, the HLB of nonionic surfactants is a value between 1 and 20. Furthermore, when the product is composed of two or more nonionic surfactants, the HLB is calculated by the phase-averaged sum of the HLB values ​​of each nonionic surfactant based on their respective mass ratios, as shown in the following formula. Mixed HLB=Σ(HLBx×Wx) / ΣWx (In the formula, HLBx represents the HLB of the nonionic surfactant X, and Wx represents the mass (g) of the nonionic surfactant X having the value of HLBx.)

[0032] Nonionic surfactants can be commercially available. Furthermore, based on previously reported information, it is possible to produce the same substance as commercially available products, or compositions containing it, through chemical synthesis.

[0033] (Content of nonionic surfactant in aqueous solution) The content of the nonionic surfactant in the aqueous solution is preferably 1 ppm or more, more preferably 2.5 ppm or more, even more preferably 4 ppm or more, even more preferably 8 ppm or more, and even more preferably 10 ppm or more, from the viewpoint of suppressing discoloration of crystals, and from the viewpoint of industrial operability such as foaming and cost, it is preferably 10,000 ppm or less, more preferably 1,200 ppm or less, and even more preferably 1,000 ppm or less. The content of the nonionic surfactant in the aqueous solution is preferably 1 ppm to 10,000 ppm, even more preferably 2.5 ppm to 10,000 ppm, even more preferably 4 ppm to 10,000 ppm, even more preferably 4 ppm to 1,000 ppm, even more preferably 8 ppm to 1,000 ppm or less, and even more preferably 10 ppm to 1,000 ppm.

[0034] In the present invention, the mass ratio % of the content of the nonionic surfactant to the content of hydroxybenzoic acid in the aqueous solution (g-nonionic surfactant / g-hydroxybenzoic acid) is preferably 0.002% or more, more preferably 0.02% or more, from the viewpoint of suppressing discoloration of crystals, and preferably 20% or less, more preferably 2% or less, from the viewpoint of industrial productivity, cost, liquid viscosity, and purity. The mass ratio % of the content of the nonionic surfactant to the content of hydroxybenzoic acid in the aqueous solution is preferably 0.002 to 20%, more preferably 0.002 to 2%, and even more preferably 0.02 to 2%.

[0035] (Crystallization) In this invention, crystallization refers to generally known crystallization methods or processes, which involve precipitating a solute as crystals by reducing its solubility or decreasing the amount of solvent. Examples of crystallization methods include cooling, pH adjustment, evaporation, addition of a poor solvent, or chemical reactions (for example, reactions to form salts with low solubility by neutralization). Crystallization may be carried out by a single method or by a combination of multiple methods. Among these, in this invention, crystallization by cooling (also called cooling crystallization) is preferred from the viewpoint of crystal quality and industrial productivity.

[0036] (Crystallization due to cooling) Crystallization by cooling allows for the crystallization of hydroxybenzoic acid by increasing its concentration above its solubility level through cooling the aqueous solution from a high temperature to a low temperature. The temperature of the aqueous solution containing hydroxybenzoic acid after the adsorbent treatment before cooling (the temperature at which cooling begins) is preferably the same as the contact temperature between the aqueous solution and the adsorbent. For example, it is preferably 40°C or higher, more preferably 50°C or higher, and even more preferably 60°C or higher. Furthermore, from the viewpoint of industrial productivity, it is preferably 150°C or lower, more preferably 135°C or lower, even more preferably 120°C or lower, and even more preferably 95°C or lower. Preferably 40-150°C, more preferably 50-135°C, even more preferably 60-120°C, and even more preferably 60-95°C. The cooling completion temperature is preferably 50°C or lower, more preferably 40°C or lower, even more preferably 30°C or lower, and also preferably 0°C or higher, more preferably 5°C or higher, and even more preferably 8°C or higher, from the viewpoint of crystallization yield. The cooling completion temperature is preferably 0 to 50°C, more preferably 5 to 40°C, and even more preferably 8 to 30°C.

[0037] When cooling an aqueous solution containing hydroxybenzoic acid during crystallization, it is preferable to cool it at a rate of 1°C / min or less, more preferably 0.8°C / min or less, and even more preferably 0.5°C / min or less, from the viewpoint of suppressing discoloration of the crystals. Depending on the discoloration of the crystallization and the state of the crystals, the above cooling rate may be applied to one period of the cooling process or to the entire process. Furthermore, in this specification, the average cooling rate is defined by dividing the difference (°C) between the cooling start temperature and the cooling end temperature by the time (min) required to reach the cooling end temperature from the cooling start temperature. After starting cooling, it is also possible to temporarily stop cooling to maintain a constant temperature, i.e., to provide a period with a cooling rate of 0°C / min, but care should be taken to prevent the precipitation of impurities other than hydroxybenzoic acid. The average cooling rate is preferably 1°C / min or less, more preferably 0.5°C / min or less, and even more preferably 0.3°C / min or less, from the viewpoint of suppressing discoloration of the crystals, and is preferably 0.03°C / min or more, from the viewpoint of industrial productivity. The average cooling rate is preferably 0.03 to 1°C / min, more preferably 0.03 to 0.5°C / min, and even more preferably 0.03 to 0.3°C / min.

[0038] Furthermore, the cooling of the aqueous solution is carried out under conditions where the pH during crystallization is 1.0 to 7.0, preferably 3.0 or higher, more preferably 4.0 or higher, preferably 6.5 or lower, more preferably 6.0 or lower, from the viewpoint of suppressing discoloration of the crystals and the recovery rate of hydroxybenzoic acid. The pH during crystallization should be within the range of 1.0 to 7.0, preferably 3.0 or higher, more preferably 4.0 or higher, and preferably 6.5 or lower, more preferably 6.0 or lower, and preferably the pH at the start of crystallization. Moreover, it is even more preferable that the pH remains within this range during crystallization. More preferably, the pH is 3.5 or higher, even more preferably 4.0 or higher, and also, from the viewpoint of crystallization yield, preferably 6.0 or lower. The pH during crystallization, preferably the pH at the start of crystallization, and more preferably the pH during crystallization is 1.0 to 7.0, preferably 3.0 to 6.5, more preferably 3.5 to 6.0, and even more preferably 4.0 to 6.0. Since the pH may fluctuate between the start and end of precipitation, the present invention may involve adjusting the pH during crystallization. Regardless of whether the pH is adjusted or not, the pH at the end of crystallization is preferably 3.5 to 6.0, or 3.5 to 6.0, and more preferably above 4.5 by the end of crystallization. In the present invention, from the viewpoint of suppressing discoloration of the crystals, it is preferable to include a step of adjusting the pH of the aqueous solution containing hydroxybenzoic acid to the above pH before adding the nonionic surfactant, before cooling. To adjust the pH, the aforementioned acids or alkaline agents may be used, and as alkaline agents, ammonia and aqueous solutions of sodium hydroxide or potassium hydroxide can be used.

[0039] Crystallization may be carried out under static conditions, or it may be carried out while stirring using a reaction vessel equipped with a stirring blade. The stirring blades can be of any shape, but paddle blades, turbine blades, propeller blades, anchor blades, large-diameter paddle blades, and Maxblend blades are preferred in order to ensure good crystal mixing. The peripheral speed of stirring is preferably 0.2 m / s or more, more preferably 0.3 m / s or more, and even more preferably 0.5 m / s or more, from the viewpoint of preventing the slurry from solidifying, and preferably 10 m / s or less, more preferably 5 m / s or less, and even more preferably 3 m / s or less, from the viewpoint of suppressing the crushing of hydroxybenzoic acid crystals. By adding an acid anhydride during crystallization, more purified hydroxybenzoic acid crystals can be obtained.

[0040] (Separation and washing of hydroxybenzoic acid crystals) Hydroxybenzoic acid crystals can be separated by solid-liquid separation operations such as centrifugation, filtration, and decantation. The hydroxybenzoic acid crystals may be washed if necessary. Examples of solvents that can be used for washing include water, ethanol, acetone, and toluene.

[0041] (Drying of hydroxybenzoic acid crystals) The drying method for hydroxybenzoic acid crystals is not particularly limited as long as moisture can be removed. For example, conventional dryers such as shelf dryers, conical dryers, paddle dryers, Nauter mixers, fluidized bed dryers, vacuum agitation dryers, and disc dryers can be used. It is preferable to use a drying method that does not apply high shear to maintain the hydroxybenzoic acid crystal structure. The drying temperature is preferably -50°C or higher, more preferably -30°C or higher, even more preferably -20°C or higher, and also preferably 110°C or lower, more preferably 90°C or lower, and even more preferably 70°C or lower. Vacuum drying may also be performed. The dried hydroxybenzoic acid crystals may be subjected to further treatment, such as sieving, if necessary.

[0042] [Hydroxybenzoic acid crystals] Thus, hydroxybenzoic acid crystals are obtained. The hydroxybenzoic acid crystals obtained by the manufacturing method of the present invention have suppressed discoloration and good color. The absorbance at a wavelength of 400 nm, measured by the method described in the examples below, is preferably 0.60 or less, and more preferably 0.30 or less.

[0043] The hydroxybenzoic acid crystals of the present invention are useful not only for their own use but also as an intermediate raw material for producing various derivatives. [Examples]

[0044] [Method for measuring pH] The pH of the aqueous solution (stock solution) at 70°C was measured using a Horiba F-52 analyzer.

[0045] [Evaluation of the color of 4-hydroxybenzoic acid after crystallization] After crystallization, the obtained 4-hydroxybenzoic acid was dissolved in ethanol to prepare a 100 g / L solution. The solution was passed through a 0.20 μm pore size membrane filter, and the absorbance at a wavelength of 400 nm was measured using a Shimadzu UV-1800 ultraviolet-visible spectrophotometer with a 1 cm path length cell. A lower absorbance value indicates better color.

[0046] [Reference example 1] (Preparation of fermentation liquid) A culture solution containing 4-hydroxybenzoic acid was obtained by fermentation using transformed organisms of the genus Corynebacterium. After sterilization at 70°C for 1 hour, the bacterial cells and solution were separated using a pressure filter, and the aqueous solution of 4-hydroxybenzoic acid was recovered.

[0047] (Activated carbon treatment [treatment involving contact with adsorbent]) (1) Next, the pH of the aqueous solution containing 4-hydroxybenzoic acid was adjusted to 5.5 with sulfuric acid, and 1.0% (g / g- solution) of activated carbon (Osaka Gas Chemical Co., Ltd.) was added as an adsorbent. The solution was then stirred at 70°C for 1 hour to perform activated carbon treatment. After that, the activated carbon was removed by passing the solution through a membrane filter with a pore size of 0.20 μm. The concentration of 4-hydroxybenzoic acid in the resulting aqueous solution before crystallization was 90 g / L (9 mass%). Furthermore, the absorbance of the obtained aqueous solution at a wavelength of 470 nm was measured using a Shimadzu UV-1800 ultraviolet-visible spectrophotometer and a cell with a path length of 1 cm, and was found to be 0.37.

[0048] (Crystallization of 4-hydroxybenzoic acid) (1) The aqueous solution containing 4-hydroxybenzoic acid after activated carbon treatment was adjusted to pH 4.0 with sulfuric acid. 30 mL of the aqueous solution was placed in a 50 mL screw-top bottle and sealed. Crystallization was induced by cooling from 70°C to 10°C at a cooling rate of 0.1°C / min (the same average cooling rate) while shaking back and forth at 180 rpm. The precipitated crystals were then collected by passing them through a membrane filter with a pore size of 0.45 μm. The recovered crystals were dispersed in 30 g of deionized water at 8°C, and then washed again by passing them through a membrane filter with a pore size of 0.45 μm. This crystal washing procedure was performed a total of two times. After washing, the crystals were collected in aluminum cups and dried at 105°C for more than 3 hours to obtain 4-hydroxybenzoic acid crystals.

[0049] [Example 1] (Preparation of fermentation liquid) and (activated carbon treatment [treatment involving contact with adsorbent]) The procedure was carried out in the same manner as in Reference Example 1.

[0050] (Crystallization of 4-hydroxybenzoic acid) (2) The fermentation liquid obtained in Example 1 was treated with activated carbon. Then, 30 mL of an aqueous solution of 4-hydroxybenzoic acid, whose pH was adjusted to 4.0 with sulfuric acid, was placed in a 50 mL screw-top bottle. Polyoxyethylene lauryl ether (Emulgen 102 KG, manufactured by Kao Corporation) was added to the aqueous solution to a concentration of 1000 ppm, and the bottle was sealed. The solution was cooled from 70°C to 10°C at a cooling rate of 0.1°C / min (the average cooling rate was also the same) while reciprocating shaking at 180 rpm to induce crystallization. After that, the precipitated crystals were collected by passing them through a membrane filter with a pore size of 0.45 μm. The recovered crystals were dispersed in 30 g of deionized water at 8°C, and then washed again by passing them through a membrane filter with a pore size of 0.45 μm. This crystal washing procedure was performed a total of two times. After washing, the crystals were collected in aluminum cups and dried at 105°C for more than 3 hours to obtain 4-hydroxybenzoic acid crystals.

[0051] [Example 2]~[Example 6] The procedure was carried out in the same manner as in Example 1, except that the type of nonionic surfactant was changed to the additive shown in Table 1. The product names and compounds of the nonionic surfactants are listed below. • Emulgen 102KG: Polyoxyethylene lauryl ether with an average ethylene oxide addition number of 2 moles, manufactured by Kao Corporation. • Emulgen 103: Polyoxyethylene lauryl ether with an average ethylene oxide addition number of 3 moles, manufactured by Kao Corporation. • Emulgen 105: Polyoxyethylene lauryl ether with an average ethylene oxide addition number of 4 moles, manufactured by Kao Corporation. • Emulgen 108: Polyoxyethylene lauryl ether with an average ethylene oxide addition number of 6 moles, manufactured by Kao Corporation. • Emulgen 120: Polyoxyethylene lauryl ether with an average ethylene oxide addition number of 12 moles, manufactured by Kao Corporation. • Emanon CH60(K): Polyoxyethylene hydrogenated castor oil with an average number of 60 moles of ethylene oxide added, manufactured by Kao Corporation.

[0052] Table 1 shows the absorbance of hydroxybenzoic acid at a wavelength of 400 nm in Examples 1-6 and Reference Example 1.

[0053] [Table 1]

[0054] [Reference example 2] (Preparation of fermentation liquid) The procedure was carried out in the same manner as in Reference Example 1.

[0055] (Activated carbon treatment [treatment involving contact with adsorbent]) (2) Reference Example 2 involved activated carbon treatment using the following method. The fermentation liquid was then treated by adjusting the pH of the aqueous solution containing 4-hydroxybenzoic acid to 4.0 with sulfuric acid for efficient decolorization. Activated carbon (Osaka Gas Chemical Co., Ltd.) was added at a concentration of 1.0% (g / g solution) as an adsorbent, and the mixture was stirred at 70°C for 1 hour to perform activated carbon treatment. The activated carbon was then removed by passing the solution through a membrane filter with a pore size of 0.20 μm. The concentration of 4-hydroxybenzoic acid in the resulting aqueous solution before crystallization was 60 g / L (6 mass%). Furthermore, the absorbance of the obtained aqueous solution at a wavelength of 470 nm was measured using a Shimadzu UV-1800 ultraviolet-visible spectrophotometer with a 1 cm path length cell, and was found to be 0.18.

[0056] (Crystallization of 4-hydroxybenzoic acid) (3) Reference Example 2 was crystallized using the following method. 350 mL of an aqueous solution of 4-hydroxybenzoic acid, adjusted to pH 4.0 with sulfuric acid, was placed in a separable flask and cooled from 70°C to 10°C at a cooling rate of 0.1°C / min (average cooling rate was also the same) while stirring at 300 rpm to induce crystallization. Subsequently, the precipitated crystals were collected by passing them through a filter paper with a particle size of 1 μm. The recovered crystals were dispersed in 100g of deionized water at 8°C, and then washed again by passing them through filter paper with a particle size of 1μm. This crystal washing procedure was performed a total of two times. After washing, the crystals were collected in aluminum cups and dried at 105°C for more than 3 hours to obtain 4-hydroxybenzoic acid crystals.

[0057] [Example 7]~[Example 12] (Preparation of fermentation liquid) The procedure was carried out in the same manner as in Reference Example 1.

[0058] (Activated carbon treatment [treatment involving contact with adsorbent]) (2) The procedure was carried out in the same manner as in Reference Example 2.

[0059] (Crystallization of 4-hydroxybenzoic acid) (4) Examples 7-12 were crystallized using the following method, which minimizes the influence of measurement errors due to the low concentration of nonionic surfactants. 350 mL of an aqueous solution of 4-hydroxybenzoic acid, adjusted to pH 4.0 with sulfuric acid, was placed in a separable flask. Polyoxyethylene lauryl ether (Emulgen 108, manufactured by Kao Corporation) was then added to the aqueous solution at concentrations of 1.0 ppm, 2.5 ppm, 5.0 ppm, 10 ppm, 100 ppm, and 1000 ppm. The solution was cooled from 70°C to 10°C at a cooling rate of 0.1°C / min (the average cooling rate was also the same) while stirring at 300 rpm to induce crystallization. The precipitated crystals were then collected by passing the solution through a filter paper with a particle size of 1 μm. The recovered crystals were dispersed in 100g of deionized water at 8°C, and then washed again by passing them through filter paper with a particle size of 1μm. This crystal washing procedure was performed a total of two times. After washing, the crystals were collected in aluminum cups and dried at 105°C for more than 3 hours to obtain 4-hydroxybenzoic acid crystals.

[0060] Table 2 shows the absorbance of hydroxybenzoic acid at a wavelength of 400 nm in Examples 7-12 and Reference Example 2.

[0061] [Table 2]

[0062] As shown in Tables 1 and 2, the hydroxybenzoic acid crystals obtained by the manufacturing method of the present invention were found to have little discoloration and good color.

Claims

1. A method for producing hydroxybenzoic acid crystals, comprising the step of crystallizing hydroxybenzoic acid from an aqueous solution containing hydroxybenzoic acid and a nonionic surfactant.

2. A method for producing hydroxybenzoic acid crystals according to claim 1, wherein the nonionic surfactant is a nonionic surfactant having a polyoxyethylene chain.

3. The method for producing hydroxybenzoic acid crystals according to claim 1, wherein the content of the nonionic surfactant in the aqueous solution is 1 to 10,000 ppm.

4. A method for producing hydroxybenzoic acid crystals according to claim 1, wherein the crystallization step is crystallization by cooling.

5. A method for producing hydroxybenzoic acid crystals according to any one of claims 1 to 4, wherein the aqueous solution is derived from a culture medium of a microorganism.

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