WO2023027168A1 - サリチル酸の製造方法 - Google Patents

サリチル酸の製造方法 Download PDF

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WO2023027168A1
WO2023027168A1 PCT/JP2022/032190 JP2022032190W WO2023027168A1 WO 2023027168 A1 WO2023027168 A1 WO 2023027168A1 JP 2022032190 W JP2022032190 W JP 2022032190W WO 2023027168 A1 WO2023027168 A1 WO 2023027168A1
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Prior art keywords
salicylic acid
reaction
copper
acid
purification step
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English (en)
French (fr)
Japanese (ja)
Inventor
裕次 谷池
駿佑 辻
正樹 長濱
百合恵 古場
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API Corp
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API Corp
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Priority to US18/681,328 priority Critical patent/US20240391860A1/en
Priority to EP22861456.6A priority patent/EP4393905A4/en
Priority to KR1020247001188A priority patent/KR20240026994A/ko
Priority to JP2023543998A priority patent/JP7827069B2/ja
Priority to CN202280051154.6A priority patent/CN117715884A/zh
Publication of WO2023027168A1 publication Critical patent/WO2023027168A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/02—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor with moving adsorbents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing salicylic acid, which is useful as a synthetic raw material or synthetic intermediate for various pharmaceuticals, agricultural chemicals, chemical products, and the like.
  • Salicylic acid is useful as a synthetic raw material or synthetic intermediate for various pharmaceuticals, agricultural chemicals, chemical products, etc.
  • acetylsalicylic acid which is a salicylic acid derivative
  • methyl salicylate is widely used as an antiphlogistic analgesic.
  • a production method using the Kolbe-Schmidt reaction is known as a method for producing salicylic acid.
  • a method for producing salicylic acid by reacting sodium phenolate and carbon dioxide under high temperature and high pressure conditions according to the following reaction formula is disclosed (Patent Document 1).
  • Non-Patent Document 1 a method for producing salicylic acid from 2-chlorobenzoic acid is known.
  • 2-chlorobenzoic acid is reacted in the presence of potassium carbonate, copper powder and pyridine in an aqueous solvent while heating and refluxing for 2 hours to produce salicylic acid with a yield of 91%.
  • a method for producing salicylic acid from 2-chlorobenzoic acid is also known.
  • 2-bromobenzoic acid is reacted with sodium carbonate, copper(I) bromide and N,N'-dimethylcyclohexane-1,2-diamine in an aqueous solvent at 100° C. for 3 hours.
  • a method of producing salicylic acid with a yield of 85% by performing a time reaction is known (Patent Document 2).
  • Non-Patent Document 1 and Patent Document 2 require a long reaction time and an industrially advantageous production method with higher productivity, that is, an industrial production method capable of high productivity, low cost and stable production. It is rare.
  • the salicylic acid obtained by these methods is considered to contain about several percent of by-products such as aromatic compounds, judging from the production method and yield.
  • raw materials and intermediates for the synthesis of pharmaceuticals are required to have a high degree of purity so that impurities contained therein do not cause unexpected side effects.
  • Impurities include, for example, by-products generated during their manufacture. By-products may sometimes be removable during the purification or manufacturing process of the desired pharmaceutical product.
  • An object of the present invention is to provide a method for producing salicylic acid with high productivity, low cost and stable production. Another object of the present invention is to provide a method for producing salicylic acid with a low content of by-products that become impurities.
  • the present inventors have found that by reacting a 2-halogenated benzoic acid in an aqueous solvent in the presence of a copper source, a ligand and a base under specific temperature conditions, salicylic acid can be stably produced at high productivity at a low cost. found that it is possible to obtain In addition, the present inventors have found that salicylic acid containing less by-products than conventionally known methods can be obtained by this method.
  • the gist of the present invention is as follows.
  • HPLC purity of salicylic acid that has undergone the purification step A or purification step B is 95 area % or more, and one or more selected from aromatic compounds represented by the following formulas (a) to (g) as impurities
  • salicylic acid of the present invention it is possible to stably produce salicylic acid with low by-product content with high productivity at a low cost.
  • salicylic acid with low impurity content can be produced.
  • the salicylic acid produced by the present invention is useful as synthetic raw materials and synthetic intermediates for various pharmaceuticals, agricultural chemicals, chemical products, and the like. In particular, due to its high purity, it is useful as a starting material for synthesizing various pharmaceuticals or intermediates thereof, such as acetylsalicylic acid.
  • FIG. 1 is a system diagram of a flow synthesis reactor showing an embodiment of the method for producing salicylic acid of the present invention.
  • the method for producing salicylic acid of the present invention includes a hydroxylation step of reacting 2-halogenated benzoic acid in the presence of a copper source, a ligand and a base in an aqueous solvent at a reaction temperature of 145° C. to 300° C. to obtain salicylic acid.
  • the method for producing salicylic acid of the present invention may have a purification step A in which salicylic acid obtained in the hydroxylation step is brought into contact with a synthetic adsorbent and/or a purification step B in which salicylic acid is brought into contact with zeolite.
  • the method for producing salicylic acid of the present invention is a method for producing salicylic acid by hydrolyzing 2-halogenated benzoic acid in an aqueous solvent in the presence of a copper source, a ligand and a base.
  • a method of carrying out the present invention for example, a method of mixing a 2-halogenated benzoic acid, an aqueous solvent, a base, a copper source and a ligand in a batch synthesis reactor and reacting them under reaction conditions; As shown in , the mixture of 2-halogenated benzoic acid, base, aqueous solvent, copper source and ligand prepared in the preparation tank 1 is continuously fed by the pump 2, and in the flow reactor 3 A method using a flow synthesis reactor in which 2-halogenated benzoic acid is continuously hydrolyzed under the reaction conditions and the reaction liquid containing salicylic acid flowing out from the flow reactor 3 is recovered in the recovery tank 4 is exemplified.
  • 2-halogenated benzoic acid at least one selected from 2-chlorobenzoic acid, 2-bromobenzoic acid, and 2-iodobenzoic acid can be used.
  • a commercially available 2-halogenated benzoic acid may be used, or one obtained by a known method or a method analogous thereto may be used.
  • 2-halogenated benzoic acid 2-chlorobenzoic acid is preferable from the viewpoint of cost and reactivity.
  • Bases include inorganic bases and organic bases. It is preferable to use an inorganic base in order to increase the reactivity in an aqueous solvent, which will be described later. Two or more types of bases may be used in any ratio, but from the viewpoint of cost and reactivity, it is preferable to use one type alone.
  • sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, or the like can be used as the inorganic base.
  • sodium carbonate or potassium carbonate is preferred, and sodium carbonate is particularly preferred.
  • the organic base is not particularly limited as long as the reaction proceeds, but includes tertiary alkylamines such as triethylamine and pyridine.
  • the amount of the base to be used is usually 1 mol or more as the lower limit and usually 10 mol or less as the upper limit, and preferably 5 mol or less, particularly preferably 2 mol or less, from the viewpoint of cost, per 1 mol of the 2-halogenated benzoic acid. .
  • Aqueous solvents are selected from water or water-soluble organic solvents. These may be used singly or in combination of two or more in any ratio as long as they do not adversely affect the reaction.
  • water substantially alone it is preferable to use water substantially alone from the viewpoint of cost, reactivity, and reduction of environmental load.
  • water is used substantially alone means that the proportion of water in the solvent is 95% by mass or more.
  • Any water-soluble organic solvent may be used as long as it does not inhibit the hydroxylation of the 2-halogenated benzoic acid.
  • tetrahydrofuran, dioxane, and the like can be used.
  • the upper limit of the amount of the aqueous solvent used per 1 kg of 2-halogenated benzoic acid is usually 1 L or more, preferably 2 L or more, more preferably 5 L or more, and particularly preferably 9 L.
  • the lower limit is usually 30 L or less, preferably 25 L or less, more preferably 20 L or less, and particularly preferably 18 L or less.
  • the 2-halogenated benzoic acid as a raw material is usually dissolved in an aqueous solvent to form a uniform solution, and the reaction proceeds. It may be.
  • copper copper alone or a copper compound such as copper halide, copper oxide, copper inorganic acid salt, or copper organic acid salt can be used.
  • copper compounds are preferred, copper halides, copper inorganic acid salts or copper organic acid salts are more preferred, and copper halides are particularly preferred, from the viewpoints of cost, reactivity and solubility in aqueous solvents.
  • the copper source may be an anhydride or a hydrate as long as the reaction proceeds.
  • CuCl or CuCl 2 can be used as copper chloride
  • CuBr or CuBr 2 can be used as copper bromide
  • CuI can be used as copper iodide.
  • copper chloride is preferred, and CuCl2 is particularly preferred, from the viewpoint of cost and reactivity.
  • copper oxide for example, Cu 2 O or CuO can be used.
  • copper inorganic acid salt for example, CuSO 4
  • copper(II) nitrate, copper(II) carbonate, or copper(II) hydroxide can be used.
  • copper organic acid salt for example, copper (II) formate, copper (II) citrate, copper (II) gluconate, copper (II) acetate, or copper (I) acetate can be used.
  • the amount of the copper source to be used is sufficient as long as the reaction proceeds, and is usually 1 mol or more per 1 mol of the 2-halogenated benzoic acid.
  • the reaction can be carried out with a catalytic amount of the copper source.
  • the amount of copper source used is generally 0.0001 mol to 1 mol, preferably 0.001 mol to 0.5 mol, per 1 mol of 2-halogenated benzoic acid.
  • ⁇ Ligand> by using a ligand together with a copper source, the amount of the copper source used can be reduced to a catalytic amount, and salicylic acid can be produced at low cost and with high productivity.
  • the ligand is believed to form a complex by reacting with the copper source, which functions as a catalyst.
  • copper amine complexes such as copper ethylenediamine complexes
  • copper amino acid complexes such as copper histidine complexes
  • the ligand those that enhance the activity of the copper source and promote the progress of the reaction are preferred, and amines are usually used.
  • amine means a compound having one or more optionally substituted amino groups.
  • Amines in the present invention include aliphatic amines, heterocyclic amines, and amine derivatives. Aliphatic amines are preferred from the viewpoint of cost and reactivity.
  • the number of carbon atoms in the amine used in the present invention is generally 1 or more, preferably 2 or more, as a lower limit, and is generally 12 or less, preferably 8 or less, more preferably 6 or less, and particularly preferably 4 or less. is.
  • aliphatic amines include monoamines such as dimethylamine or diethylamine; ethylenediamine, N,N'-dimethylethylenediamine, N,N'-tetramethylethylenediamine, 1,3-propyldiamine, or N,N'-dimethyl diamines such as cyclohexane-1,2-diamine; triamines such as spermidine; triethylenetetramine, N,N'-bis(2-aminoethyl)-1,3-propanediamine, or N,N'-bis(3- Tetraamines such as aminopropyl)-1,4-butanediamine (spermine) can be used.
  • diamine is preferred, and ethylenediamine is particularly preferred, from the viewpoint of cost, reactivity and impurity suppression.
  • heterocyclic amine for example, pyridine, piperidine, dipyridyl, 2,2'-dipyridylamine, or 1,10-phenanthroline can be used.
  • Amine derivatives include iminodiacetic acid, 4-aminobutyric acid, L-histidine, N-methyl-L-proline, L-proline, L-valine, L-aspartic acid, L-serine, L-lysine, N-methyl- L-alanine, L-alanine, L-phenylalanine, D-methionine, ethylenediaminetetraacetic acid, ⁇ -alanine, or the like can be used.
  • the amount of ligand used may vary depending on the type of copper source and ligand used.
  • the lower limit is usually 0.05 mol or more, preferably 1 mol or more
  • the upper limit is usually 300 mol or less, preferably 200 mol or less, relative to 1 mol of the copper source. If the amount of ligand used is too small, the reaction may not proceed efficiently and the amount of copper source used may not be reduced. If the amount of ligand used is too large, a large amount of by-products may be produced.
  • reaction temperature The lower limit of the reaction temperature is usually 155° C. or higher, preferably 165° C. or higher, more preferably 175° C. or higher, still more preferably 185° C. or higher, and particularly preferably 195° C. or higher, from the viewpoint of reactivity and productivity.
  • the upper limit of the reaction temperature is not particularly limited as long as the reaction proceeds, but is usually 300°C or lower, preferably 250°C or lower, more preferably 240°C or lower, still more preferably 230°C or lower, and particularly preferably 220°C or lower. If the reaction temperature is too low, the reactivity may decrease. If the reaction temperature is too high, the complex may be decomposed or a side reaction may occur, resulting in an increase in impurities and a decrease in productivity and purity of the target product.
  • reaction pressure The reaction pressure can be normal pressure or increased pressure, but when the reaction is carried out under high temperature conditions equal to or higher than the boiling point of the solvent, it is preferable to pressurize so as to achieve desired high temperature conditions.
  • the lower limit of the reaction pressure is usually 0.1 MPa or higher, preferably 0.2 MPa or higher, more preferably 0.3 MPa or higher, and particularly preferably 0.4 MPa or higher.
  • the upper limit of the reaction pressure is usually 10 MPa or less, preferably 8 MPa or less, more preferably 6 MPa or less, and particularly preferably 4 MPa or less.
  • the reaction can be efficiently performed at the desired reaction pressure by adjusting the pressure using a pressure-resistant container.
  • the reaction can be efficiently performed at the desired reaction pressure by adjusting the pressure by applying back pressure to the flow path using a back pressure valve or the like.
  • the reaction pressure is 0.54 MPa or higher for a reaction temperature of 155° C. or higher, 0.70 MPa or higher for 165° C. or higher, and 0.70 MPa for 175° C. or higher.
  • 89 MPa or higher 1.12 MPa or higher for 185°C or higher, 1.56 MPa or higher for 200°C or higher, 2.32 MPa or higher for 220°C or higher, 2.80 MPa or higher for 230°C or higher , 3.35 MPa or higher for 240°C or higher, 3.98 MPa or higher for 250°C or higher, 5.51 MPa or higher for 270°C or higher, and 8.59 MPa or higher for 300°C or higher is preferred.
  • reaction time means the residence time of the raw material mixture (mixture of 2-halogenated benzoic acid, base, copper source, ligand and aqueous solvent) in the reactor used in the present invention. It can also vary with pressure.
  • the reaction time is generally 0.1 to 60 minutes, preferably 0.5 to 30 minutes, particularly preferably 1 to 10 minutes, in order to improve the amount of salicylic acid produced per unit time.
  • reaction method In the present invention, a 2-halogenated benzoic acid is reacted with a complex formed by a copper source and a ligand in an aqueous solvent in the presence of a base.
  • the reaction method is not particularly limited, but as described above, it is industrially preferable to use a flow synthesis reactor (circulation reactor). That is, as shown in FIG. 1, a mixed solution of 2-halogenated benzoic acid, a base, a copper source, a ligand and an aqueous solvent is prepared in a preparation tank 1, and this is pumped into a flow synthesis reactor (flow type Reactor) 3, the reaction is carried out by heating in the flow synthesis reactor 3, and the reaction liquid is recovered in the recovery tank 4.
  • flow synthesis reactor flow type Reactor
  • the reactor is not particularly limited as long as the reaction proceeds, but includes a flow reactor and a batch synthesis reactor.
  • a batch-type synthesis reactor a reactor equipped with a channel for introducing and discharging substrates and the like, a jacket capable of controlling reaction temperature, a device capable of controlling reaction pressure, a stirrer, and the like can be used.
  • the flow synthesis reactor is desirably tubular, and the tubular shape may be straight, curved, spiral, or the like. From the point of view of reactor volume, the spiral flow synthesis reactor is particularly preferred.
  • the size of the flow synthesis reactor is selected according to the scale of production, eg, 1 mm to 50 mm internal diameter, and the length is selected according to the desired residence time.
  • the flow synthesis reactor may be provided with a temperature control mechanism. Substrates and the like can be introduced into and discharged from the flow synthesis reactor quantitatively by liquid transfer using a syringe pump, cylinder pump, diaphragm pump, plunger pump, or the like.
  • a back pressure valve capable of controlling the reaction pressure or an in-line analyzer may be provided in the channel on the outflow side of the reaction liquid from the flow synthesis reactor.
  • the hydroxylation step is not particularly limited as long as the reaction temperature can be adjusted, and the reaction solution can be heated using a hot water bath, an oil bath, microwaves, or the like.
  • the solution of salicylic acid obtained in the hydroxylation step may be purified in a purification step A and/or a purification step B, which will be described later, and then purified by known purification means such as recrystallization and column chromatography.
  • the salicylic acid purified in the purification step A described later may be further purified in the purification step B described later, or the salicylic acid purified in the purification step B may be further purified in the purification step A.
  • adsorbent used in the purification process according to the present invention one or more of zeolites, synthetic adsorbents, and ion exchange resins can be used.
  • Zeolites in the context of the present invention mean aluminosilicates containing alkali metals and/or alkaline earth metals. Zeolite is known to be more hydrophobic as the SiO 2 /Al 2 O 3 ratio increases.
  • the lower limit of the SiO 2 /Al 2 O 3 ratio of the zeolite used in the present invention is usually 10 or more, preferably 100 or more, more preferably 500 or more, still more preferably 1000 or more, particularly preferably 1500 or more, and the upper limit is is usually 10,000 or less, preferably 4,000 or less, more preferably 3,000 or less, still more preferably 2,500 or less, and particularly preferably 2,000 or less.
  • the aromatic compound represented by the formula (b) described below can be efficiently removed.
  • the BET specific surface area of zeolite is generally 100 m 2 /g to 1000 m 2 /g, preferably 200 m 2 / g to 500 m 2 /g, for the purpose of improving reactivity.
  • the most frequent pore radius of zeolite is usually 0.1 nm to 10 nm, preferably 0.3 nm to 5 nm, particularly preferably 0.5 nm to 1 nm, for the purpose of improving impurity removal efficiency.
  • the BET specific surface area and modal pore frequency radius of zeolite can be measured according to a conventional method by a nitrogen gas adsorption method.
  • the shape of the zeolite may be any shape as long as it can come into contact with the salicylic acid solution, and powder, pellet, film, and columnar shapes can be used. Among these, from the viewpoint of impurity removal efficiency, a particulate one having a large contact area with the solution of salicylic acid is preferable.
  • the particle size of particulate zeolite is usually in the range of 0.01 ⁇ m to 100 ⁇ m, preferably 0.1 ⁇ m to 100 ⁇ m, particularly preferably 1 ⁇ m to 50 ⁇ m, from the viewpoint of industrial handling.
  • the particle size of zeolite is the average particle size measured according to a conventional method using a laser diffraction particle size distribution measurement method.
  • Zeolites include, for example, Tosoh Corporation HSZ (registered trademark)-900, HSZ (registered trademark)-891HOA, HSZ (registered trademark)-800, HSZ (registered trademark)-700, HSZ (registered trademark)-600, Commercially available products such as HSZ (registered trademark)-500 and HSZ (registered trademark)-300 can be used.
  • HSZ (registered trademark)-891HOA or HSZ (registered trademark)-800 is preferable, and HSZ (registered trademark)-891HOA is particularly preferable, from the viewpoint of impurity removal efficiency.
  • the synthetic adsorbent is a porous synthetic adsorbent made of a porous organic polymer produced by chemical synthesis.
  • an aromatic, substituted aromatic or acrylic polymer or copolymer (hereinafter, "polymer or copolymer” is referred to as “(co)polymer” may be called.).
  • aromatic (co)polymers include styrene/divinylbenzene copolymers and divinylbenzene polymers.
  • substituted aromatic (co)polymers include bromostyrene/divinylbenzene copolymers.
  • acrylic (co)polymers include methacrylic ester (co)polymers such as methyl methacrylate/bis(methacrylic acid) ethylene glycol copolymers.
  • aromatic (co)polymers are preferred from the viewpoint of insolubility in organic solvents and stability in acidic and alkaline solutions, and styrene/divinylbenzene copolymers or bromostyrene/divinylbenzene copolymers Styrene/divinylbenzene copolymers such as coalescence are more preferred, and styrene/divinylbenzene copolymers are particularly preferred.
  • the synthetic adsorbent used in the present invention preferably has substantially no functional group such as an ion-exchange group, for example, an ion-exchange capacity of less than 1 meq/g or a non-polar one.
  • the pore volume of the synthetic adsorbent used in the present invention is usually 0.1 mL/g to 3 mL/g, preferably 0.5 mL/g to 2 mL/g, particularly preferably 1 mL/mL, for the purpose of improving reactivity. /g to 1.5 mL/g.
  • the BET specific surface area of the synthetic adsorbent is usually 200 m 2 /g to 2000 m 2 /g, preferably 300 m 2 /g to 1500 m 2 /g, more preferably 400 m 2 /g to 1000 m 2 for the purpose of improving reactivity. /g, particularly preferably 500 m 2 /g to 700 m 2 /g.
  • the most frequent pore radius of the synthetic adsorbent is usually 1 nm to 50 nm, preferably 5 nm to 40 nm, particularly preferably 10 nm to 30 nm, for the purpose of improving reactivity.
  • the pore volume, BET specific surface area and modal pore frequency radius of the synthetic adsorbent can be measured according to a conventional method by the nitrogen gas adsorption method.
  • the shape and size of the synthetic adsorbent are not particularly limited as long as they can be packed in a column and do not interfere with the distribution of the salicylic acid solution.
  • the synthetic adsorbent particles, pellets, films, and cylinders can be used, but from the viewpoint of ease of filling, particles are more preferable.
  • the particle size of the particulate synthetic adsorbent is usually in the range of 1 ⁇ m to 2000 ⁇ m, preferably in the range of 3 ⁇ m to 2000 ⁇ m. From the viewpoint of industrial handling, the particle size of the synthetic adsorbent is preferably in the range of 4 ⁇ m to 1000 ⁇ m, and the mode particle size is preferably 50 ⁇ m or more, preferably 150 ⁇ m or more, and particularly preferably 250 ⁇ m or more.
  • the particle size of the synthetic adsorbent is the average particle size measured according to a conventional method by laser diffraction particle size distribution measurement.
  • Synthetic adsorbents include, for example, Mitsubishi Chemical's Diaion (registered trademark) HP20SS, HP20, HP21, HP2MG, HP2MGL, Sepabeads (registered trademark) SP20SS, SP70, SP207, SP700, SP850, XAD TM -2, and XAD.
  • Commercially available products such as TM 4, XAD TM 1600N, or XAD TM 7HP can be used.
  • Diaion (registered trademark) HP21 or XAD TM 4 is preferable from the viewpoint of impurity removal efficiency. Table 1 shows the physical properties of these commercially available synthetic adsorbents.
  • the ion-exchange resin is a synthetic adsorbent provided with ion-exchange groups. Any ion-exchange group can be used as long as it can adsorb copper ions, and a cation-exchange group is usually used. As the cation exchange group, an iminodiacetic acid group is preferred.
  • the pore volume of the ion exchange resin used in the present invention is usually 0.1 mL/g to 4 mL/g, preferably 0.5 mL/g to 3 mL/g, particularly preferably 1 mL, for the purpose of improving impurity removal efficiency. /mL/g to 2 mL/g.
  • the BET specific surface area of the ion exchange resin is usually 200 m 2 /g to 2000 m 2 /g, preferably 300 m 2 /g to 1500 m 2 /g, particularly preferably 400 m 2 /g to 400 m 2 /g, for the purpose of improving the impurity removal efficiency. 1000 m 2 /g.
  • the most frequent pore radius of the ion-exchange resin is usually 1 nm to 100 nm, preferably 5 nm to 50 nm, particularly preferably 10 nm to 25 nm, for the purpose of improving impurity removal efficiency. Copper ions during the reaction can be efficiently removed by using the ion exchange resin described above.
  • the pore volume, BET specific surface area, and most frequent pore radius of the ion exchange resin can be measured according to a conventional method by a nitrogen gas adsorption method.
  • the shape and size of the ion exchange resin are not particularly limited as long as they can be packed in a column and do not interfere with the flow of the salicylic acid solution.
  • the ion-exchange resin those in the form of particles, pellets, membranes, and cylinders can be used, but from the viewpoint of filling properties, the particles are more preferable.
  • the harmonic mean diameter of the particulate ion exchange resin is usually in the range of 0.1 mm to 1 mm, preferably in the range of 0.3 mm to 0.8 mm from the viewpoint of industrial handling.
  • the particle size of the ion-exchange resin is the average particle size measured according to a conventional method using a laser diffraction particle size distribution measurement method.
  • ion exchange resin for example, commercially available products such as Diaion (registered trademark) CR11, CR20, CRB03, CRB05 manufactured by Mitsubishi Chemical Corporation, Ambersep TM IRC748 and Ambersep TM IRC747UPS manufactured by Organo can be used.
  • CR11 is preferable from the viewpoint of copper ion removal efficiency.
  • ⁇ Other refining means> In order to remove copper in the reaction solution, a known method of precipitating copper using a reducing agent such as hydrosulfite or hydrazine may be used other than the ion exchange resin described above.
  • a reducing agent such as hydrosulfite or hydrazine
  • a method of adsorbing and removing impurities in the reaction solution using activated carbon is also available.
  • the activated carbon for example, Shirasagi manufactured by Osaka Gas Chemical Co., Ltd., Strong Shirasagi, Purified Shirasagi, and the like can be used. Among these, strong white heron is preferable from the viewpoint of impurity removal efficiency.
  • the amount of activated carbon used is 1% by mass to 100% by mass, preferably 5% by mass to 50% by mass, more preferably 5% by mass to 25% by mass, relative to the 2-halogenated benzoic acid used in the reaction. .
  • ⁇ Purification step A> the salicylic acid obtained in the hydroxylation step or the salicylic acid obtained in the purification step B described later is brought into contact with a synthetic adsorbent to reduce impurities in salicylic acid and increase the purity of salicylic acid. It is a process.
  • the purification step A by bringing salicylic acid into contact with the specific adsorbent, at least one of the aromatic compounds represented by formulas (a) to (g) described later, particularly formulas (b) and (f ) At least one selected from the aromatic compounds represented by (g) and (e) is removed.
  • the salicylic acid to be purified in the purification step A is usually a solution, preferably an aqueous solution, and the salicylic acid solution obtained in the above-described hydroxylation step or the salicylic acid solution obtained in the purification step B and/or the purification step C described later is used. be able to.
  • the salicylic acid contained in the salicylic acid solution should be dissolved when the salicylic acid and the adsorbent come into contact with each other.
  • the concentration of salicylic acid in the salicylic acid solution is usually 0.1% by mass to 80% by mass, preferably 1% by mass to 75% by mass, particularly preferably 5% by mass to 70% by mass, from the viewpoint of productivity and reactivity. be.
  • a styrene-based synthetic adsorbent preferably a styrene/divinylbenzene-based copolymer such as a styrene/divinylbenzene copolymer or a bromostyrene/divinylbenzene copolymer, particularly A styrene/divinylbenzene copolymer is preferably used.
  • the styrene-based synthetic adsorbent has little effect on the reaction, so it has substantially no functional group such as an ion-exchange group, for example, an ion-exchange capacity of less than 1 meq/g or a nonpolar adsorbent. Sex is preferred.
  • the most frequent pore radius of the styrene-based synthetic adsorbent used in the purification step A is usually 1 nm to 50 nm, preferably 2 nm to 45 nm, particularly preferably 3 nm to 40 nm, for the purpose of improving reactivity.
  • the preferred pore volume, BET specific surface area, shape, and other physical properties of the styrene-based synthetic adsorbent used in the purification step A are as described in the adsorbent section above.
  • styrene-based synthetic adsorbent used in the purification step A for example, commercially available products such as Mitsubishi Chemical's Diaion (registered trademark) HP20SS, HP20, HP21, Sepabeads (registered trademark) SP20SS, and SP700 can be used. .
  • HP21 is preferable from the viewpoint of impurity removal efficiency.
  • the contact temperature for contacting the salicylic acid solution with the styrene-based synthetic adsorbent is usually 5° C. to 100° C., preferably 50° C. to 95° C., particularly preferably 60° C. to 60° C., from the viewpoint of impurity removal efficiency and solubility. 90°C.
  • the contact time for bringing the salicylic acid solution and the styrene-based synthetic adsorbent into contact is not particularly limited as long as the impurities are sufficiently removed, but is usually 0.1 hour to 24 hours.
  • the contact pressure when the salicylic acid solution and the styrene-based synthetic adsorbent are brought into contact is usually normal pressure, but may be pressurized.
  • the pH of the salicylic acid solution when the salicylic acid solution is brought into contact with the styrene-based synthetic adsorbent may be within a range in which salicylic acid does not precipitate, and is usually pH 3 to 8, and from the viewpoint of impurity removal efficiency, preferably pH 3 to 7, or more. pH 3-6 is preferred, pH 3-5 is particularly preferred.
  • Purification step B is a step for reducing impurities in salicylic acid and increasing the purity of salicylic acid by bringing the salicylic acid obtained in the hydroxylation step or the salicylic acid that has undergone the purification step A described above into contact with zeolite.
  • salicylic acid As the salicylic acid to be purified in the purification step B, the salicylic acid solution obtained in the above-described hydroxylation step or the salicylic acid solution obtained in the above-described purification step A can be used.
  • concentration of the salicylic acid solution is usually 0.1% to 80% by mass, preferably 1% to 75% by mass, particularly preferably 5% to 70% by mass, from the viewpoint of productivity and reactivity.
  • the adsorbent described above can be used, and at least one selected from the aromatic compounds represented by the formulas (b), (e), (f) and (g) is efficiently From the viewpoint of good removal, it is preferable to use the above zeolite.
  • the contact temperature at which the salicylic acid solution and zeolite are brought into contact is usually 5° C. to 100° C., preferably 50° C. to 95° C., particularly preferably 60° C. to 90° C., from the viewpoint of impurity removal efficiency and solubility. .
  • the contact time for bringing the salicylic acid solution and the zeolite into contact is not particularly limited as long as the impurities are sufficiently removed, but it is usually 0.1 to 24 hours.
  • the pressure when the salicylic acid solution and the zeolite are brought into contact is usually normal pressure, but may be increased.
  • the pH of the salicylic acid solution when the salicylic acid solution is brought into contact with the zeolite is within a range in which salicylic acid does not precipitate, and is usually pH 3 to 8, preferably pH 3 to 7, and particularly preferably pH 3 to 6 from the viewpoint of impurity removal efficiency. be.
  • ⁇ Purification step C> the salicylic acid obtained in the hydroxylation step, or the salicylic acid obtained in the purification step A and/or the purification step B described above is brought into contact with an ion exchange resin to reduce copper ions in salicylic acid. and to increase the purity of salicylic acid.
  • the salicylic acid to be purified in the purification step C is usually a solution, preferably an aqueous solution, and the salicylic acid solution obtained in the above-described hydroxylation step or the salicylic acid solution obtained in the above-described purification step A and/or purification step B is used. can be done.
  • the salicylic acid contained in the salicylic acid solution should be dissolved when the salicylic acid and the ion exchange resin are brought into contact with each other.
  • the concentration of salicylic acid in the salicylic acid solution is usually 0.1% by mass to 80% by mass, preferably 1% by mass to 75% by mass, particularly preferably 5% by mass to 70% by mass, from the viewpoint of productivity and reactivity. be.
  • the contact temperature at which the salicylic acid solution and the ion exchange resin are brought into contact is usually 5°C to 100°C, preferably 50°C to 95°C, and particularly preferably 60°C to 90°C from the viewpoint of copper ion removal efficiency. .
  • the contact time of the salicylic acid solution and the ion exchange resin is not particularly limited as long as the impurities are sufficiently removed, but is usually 0.1 hour to 24 hours.
  • the contact pressure when the salicylic acid solution and the ion exchange resin are brought into contact is usually normal pressure, but may be pressurized.
  • the pH of the salicylic acid solution when the salicylic acid solution and the ion-exchange resin are brought into contact with each other may be within a range in which salicylic acid does not precipitate, and is usually pH 3 to 8, preferably pH 3 to 7, more preferably pH 3 to 7, more preferably pH 3 to 7, from the viewpoint of impurity removal efficiency. pH 3-6, particularly preferably pH 3-5. By setting the pH within the above range, it is possible to efficiently remove copper ions.
  • ⁇ Crystallization step> the reaction solution containing salicylic acid obtained in the hydroxylation step, the salicylic acid solution (hereinafter simply referred to as the salicylic acid solution) that has undergone one or more purification steps of the purification step A, purification step B, and purification step C described above
  • a pH adjuster is added to the crystals of salicylic acid to precipitate crystals of salicylic acid, which can be recovered by a separation method such as solid-liquid separation.
  • pH adjuster examples include water; acidic pH adjusters such as hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid; sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or A basic pH adjuster such as potassium hydrogen carbonate; and the like can be used.
  • acidic pH adjuster particularly sulfuric acid
  • the amount of the pH adjuster to be used is not particularly limited, and any amount that can be used to adjust the pH within the range described above may be used.
  • the crystallization temperature means the temperature of the solution when salicylic acid is crystallized from the salicylic acid solution.
  • the upper limit of the crystallization temperature is generally 100°C or lower, preferably 95°C or lower, particularly preferably 90°C or lower, and the lower limit is generally 0°C or higher, preferably 50°C or higher, and particularly preferably 70°C or higher. is.
  • the crystallization time means the time for precipitating salicylic acid from the salicylic acid solution, and is not particularly limited as long as impurities are sufficiently removed, but is usually 0.1 hour to 24 hours.
  • crystallization pressure means the pressure of the reaction system when salicylic acid is deposited from the salicylic acid solution, which is usually normal pressure, but may be pressurized.
  • the pH of the salicylic acid solution to be subjected to crystallization is a pH range that suppresses precipitation of impurities and efficiently precipitates salicylic acid. , particularly preferably pH 1-3.
  • pH range preferably pH 1-3.
  • the solid-liquid separation temperature means the temperature of the slurry when the salicylic acid crystals are solid-liquid separated after the salicylic acid is precipitated, and is usually 0 ° C. to 100 ° C., and is preferable from the viewpoint of impurity removal efficiency and yield improvement. is 5°C to 40°C, particularly preferably 10°C to 30°C.
  • Solid-liquid separation method The precipitated salicylic acid crystals are not particularly limited in solid-liquid separation method, but in industrial production, solid-liquid separation is usually performed using a centrifugal separator.
  • the salicylic acid crystals obtained by solid-liquid separation can be washed with a solvent in which salicylic acid is difficult to dissolve, such as water.
  • a general-purpose product may be used as long as it can sufficiently filter out salicylic acid.
  • the drying temperature for drying the salicylic acid crystals obtained by solid-liquid separation may be a temperature at which salicylic acid does not sublimate, and is usually 20°C to 40°C.
  • the drying pressure for drying the crystals of salicylic acid obtained by solid-liquid separation may be a pressure at which salicylic acid does not sublime, and may be normal pressure or reduced pressure.
  • the crystals obtained by crystallization may be further purified by known purification means such as recrystallization and column chromatography, or by one or more of the purification steps A, B and C described above. It may be further purified.
  • the salicylic acid obtained in the above-described hydroxylation step is subjected to a purification step, for example, one or more of the purification steps A, B, and C described above, and a crystallization step, to copper By-products that are produced as a by-product in the source or in the hydroxylation process and are mixed as impurities in salicylic acid, specifically, by performing purification to reduce the aromatic compounds represented by the following formulas (a) to (g), High purity salicylic acid can be obtained.
  • a purification step for example, one or more of the purification steps A, B, and C described above
  • a crystallization step to copper By-products that are produced as a by-product in the source or in the hydroxylation process and are mixed as impurities in salicylic acid, specifically, by performing purification to reduce the aromatic compounds represented by the following formulas (a) to (g), High purity salicylic acid can be obtained.
  • high-purity salicylic acid having an HPLC purity of 95 area% or more and a content of each of the aromatic compounds represented by the following formulas (a) to (g) of 0.5 area% or less obtain.
  • the aromatic compounds represented by the above formulas (a) to (g) are highly reactive and may cause side reactions when salicylic acid is derived into pharmaceuticals, so it is preferable not to leave them in salicylic acid. Furthermore, since the aromatic compounds represented by the above formulas (a) to (g) have physical properties similar to those of the target salicylic acid, they are compounds that are difficult to remove by ordinary purification operations such as solid-liquid separation by crystallization. . These compounds are preferably removed before solid-liquid separation by crystallization.
  • the HPLC purity of salicylic acid obtained by the method for producing salicylic acid of the present invention is usually 95 area% or more, preferably 97 area% or more, more preferably 98 area% or more, and particularly preferably 99 area% or more.
  • the content of the aromatic compounds represented by the above formulas (a) to (g) is usually 0.5 area% or less, preferably 0.4 area% or less, more preferably 0.4 area% or less. is 0.3 area % or less, more preferably 0.2 area % or less, and particularly preferably 0.1 area % or less.
  • Example 1 Reaction temperature
  • the reaction was carried out in the same manner as in Example 1 except that the amount of copper (I) chloride used was changed from 0.001 MR to 0.005 MR, and the reaction time and reaction temperature were changed as shown in Table 3.
  • Table 4 shows the results of analyzing the obtained reaction solution in the same manner as in Example 1.
  • MR in Table 3 indicates the number of moles per 1 mole of 2-chlorobenzoic acid. The same applies to the following.
  • Examples 2 and 3 Copper source
  • the reaction was carried out in the same manner as in Example 1, except that the copper source was changed as shown in Table 4.
  • Table 4 shows the results of analyzing the obtained reaction solution in the same manner as in Example 1.
  • Example 4 to 15 Ligands
  • the reaction was carried out in the same manner as in Example 1, except that the ligand was changed as shown in Table 5.
  • Table 5 shows the results of analyzing the obtained reaction solution in the same manner as in Example 1.
  • Examples 4 to 15 in Table 5 show that salicylic acid can be produced with high productivity by using various ligands.
  • 2-chlorobenzoic acid, sodium carbonate (1.05 mol per 1 mol of 2-chlorobenzoic acid), copper (II) chloride (0.002 mol per 1 mol of 2-chlorobenzoic acid), ethylenediamine (per 1 mol of 2-chlorobenzoic acid 0.08 mol) and water (9 L for 1 kg of 2-chlorobenzoic acid) were mixed and dissolved in the preparation tank 1, and a solution (hereinafter referred to as 2-chlorobenzoic acid solution) was added to the flow reactor 3,
  • the pump discharge pressure was maintained at about 3 MPa using a back pressure valve so that the reaction time was 5 minutes, and the mixture was continuously circulated.
  • Table 6 shows the results of analyzing the reaction product liquid obtained by circulating for 30 minutes by analysis method 1.
  • the obtained reaction product liquid was analyzed by analysis method 1 and contained salicylic acid (chemical purity 96.5 area %, amount of salicylic acid produced per unit time: 19.30 area %/min).
  • the 2-chlorobenzoic acid solution was supplied at a rate of 2.34 mL/min using a plunger pump, and the flow reactor 3 was kept at a reactor outlet temperature of 200°C.
  • Example 16 Reaction temperature and reaction time
  • the copper species was changed from copper (II) chloride to copper (I) chloride
  • the amount used was changed from 0.002 mol to 0.001 mol per 1 mol of 2-chlorobenzoic acid
  • the reaction time and reaction temperature were changed.
  • the reaction was carried out in the same manner as in Example 16, except that each was changed as shown in Table 6.
  • Table 6 shows the results of analysis of the obtained reaction liquid by analysis method 2.
  • Example 16 [Examples 19 to 24: reaction temperature]
  • the reaction was carried out in the same manner as in Example 16 except that the amount of water was changed to 18 L per 1 kg of 2-chlorobenzoic acid and the reaction temperature shown in Table 7 was used.
  • Table 7 shows the results of analysis of the obtained reaction liquid by analysis method 1.
  • Example 1 and Comparative Examples 1 to 3 in Table 3 Examples 16 to 18 and Comparative Examples 4 to 6 in Table 6, and Examples 19 to 24 in Table 7, the reaction temperature was 155°C to 300°C. By doing so, salicylic acid can be obtained with high selectivity and high productivity in a short reaction time.
  • Example 16 [Examples 25 to 27 and Comparative Example 7: Amount of ligand used]
  • the reaction was carried out in the same manner as in Example 16, except that the reaction temperature was 210° C., the length of the reaction vessel was changed from 5 m to 4 m, and the amount of ligand used was changed as shown in Table 8. rice field.
  • Table 8 shows the results of analysis of the obtained reaction liquid by analysis method 1.
  • the productivity can be further increased by adding an equivalent amount or more of the ligand to the copper source.
  • Example 16 the reaction was carried out in the same manner as in Example 27, except that the reaction temperature was 210° C., the length of the reaction vessel was changed from 5 m to 4 m, and the reaction temperature and copper source were changed as shown in Table 9. .
  • Table 9 shows the results of analysis of the obtained reaction liquid by analysis method 1.
  • Example 42 Base
  • Example 16 the reaction was carried out in the same manner as in Example 16, except that the base was changed from sodium carbonate to potassium carbonate.
  • Table 10 shows the results of analysis of the obtained reaction liquid by analysis method 1 together with the results of Example 16.
  • Example 43-54 Ligands
  • the reaction was carried out in the same manner as in Example 16, except that the ligands were changed as shown in Table 11.
  • Table 11 shows the results of analysis of the obtained reaction liquid by analysis method 1.
  • Example 55 The reaction was carried out in the same manner as in Example 16, except that the amount of water used was changed from 9 times (9 L) to 18 times (18 L) the amount of 2-chlorobenzoic acid.
  • Table 12 shows the results of analysis of the obtained reaction liquid by analysis method 1.
  • Example 56-64 Adsorbent (synthetic adsorbent)] 1 mL of the reaction solution obtained in Example 55 was adjusted to pH 3.7 with 50% by mass sulfuric acid, and about 10 mg of the adsorbent (synthetic adsorbent manufactured by Mitsubishi Chemical Corporation) shown in Table 12 (per 2-chlorobenzoic acid 20% by mass), and shaken at 35° C. and 1000 rpm for 5 hours using a shaker (TS100C manufactured by biosan). Table 12 shows the results of analysis of the obtained purified salicylic acid solution by analytical method 1.
  • Example 65-66 and Comparative Example 8 Adsorbent (synthetic adsorbent)] 1 mL of the reaction solution obtained in Example 55 was adjusted to pH 3.7 with 50% by mass sulfuric acid, and about 10 mg of the adsorbent (synthetic adsorbent manufactured by Mitsubishi Chemical Corporation) shown in Table 13 (per 2-chlorobenzoic acid and 20% by mass)), and then shaken at 35°C and 1000 rpm for 5 hours using a shaker (TS100C manufactured by biosan). Table 13 shows the results of analysis of the resulting purified salicylic acid solution by analytical method 1.
  • Example 67 to 70 Adsorbent (activated carbon)] 15 mL of the reaction solution obtained in Example 16 was adjusted to pH 3.5 with 50% by mass sulfuric acid, and about 10 mg of the adsorbent (activated carbon manufactured by Osaka Gas Chemical Co., Ltd.) shown in Table 14 (per 2-chlorobenzoic acid 10% by mass) and stirred at 75° C. for 5 hours. Table 14 shows the results of analysis of the obtained purified salicylic acid solution by analytical method 1.
  • Example 71 and Comparative Examples 9-12 Adsorbent (zeolite)] 1 mL of the solution obtained in Example 55 was adjusted to pH 3.7 with 50% by mass sulfuric acid, and about 10 mg of the adsorbent (zeolite manufactured by Tosoh Corporation) shown in Table 15 (20% by mass with respect to 2-chlorobenzoic acid ) and then shaken at 35° C. and 1000 rpm for 5 hours using a shaker (TS100C manufactured by biosan). Table 15 shows the results of analysis of the obtained purified salicylic acid solution by analytical method 1.
  • Example 71 and Comparative Examples 9 to 12 in Table 15 the use of zeolite with a high SiO 2 /Al 2 O 3 ratio selectively removes the aromatic compound represented by formula (b). be able to.
  • Example 72 and Comparative Examples 14 to 16 Adsorbent (ion exchange resin)]
  • a column (5 mm ⁇ 100 mm) filled with ion exchange resin (manufactured by Mitsubishi Chemical Corporation) (0.90 g) and water shown in Table 16 was set in a column type flow reactor (manufactured by EYELA, model: MCR-1000 type). . 90 g of the reaction solution obtained in Example 55 was passed through the above column at a rate of 0.9 mL/min to obtain a purified salicylic acid solution.
  • Table 16 shows the results of ICP analysis of the copper ion content of the obtained purified salicylic acid solution.
  • Example 72 As is clear from Example 72 and Comparative Examples 14 to 16 in Table 16, it is possible to efficiently adsorb and remove copper ions by using an ion exchange resin having a chelate ion exchange resin such as an iminodiacetic acid group. can.
  • reaction was carried out while the coil reactor was immersed in an oil bath set so that the temperature of the reaction solution was 190°C. After flowing for 30 minutes (44.7 g of 2-chlorobenzoic acid as the starting material was used for the reaction), 873.7 g of the resulting reaction liquid was analyzed by analytical method 1 and found to contain 97.7 area % of salicylic acid. .
  • (iii) purification step II 196.5 g of the resulting purified salicylic acid solution I was heated to 75° C. using a 200 mL separable flask, and adjusted to pH 3.5 using 50 mass % sulfuric acid.
  • a synthetic adsorbent Diaion (registered trademark) HP21 (20% by mass relative to the 2-chlorobenzoic acid used in the reaction) was added thereto, and after stirring for 2 hours, filtration was performed to remove the synthetic adsorbent and purification.
  • a salicylic acid solution II was obtained.
  • Example 74 Crystallization pH 94.7 g of the purified salicylic acid solution II obtained in Example 73 was heated to 85° C., and 50 mass % sulfuric acid was added dropwise over 1 hour until the pH reached 2.6. After that, it was cooled to 25°C at 5°C/hour. After cooling, filtration was carried out to obtain 2.4 g of salicylic acid crystals.
  • Table 17 shows the results of analysis of the obtained salicylic acid crystals by analytical method 1.
  • Example 75 Crystallization pH
  • 190.0 g of the purified salicylic acid solution II obtained in Example 73 was heated to 85° C., and 50 mass % sulfuric acid was added dropwise over 1 hour until the pH reached 1.8. After that, it was cooled to 25°C at 10°C/hour. After cooling, filtration was carried out to obtain 8.0 g of salicylic acid crystals.
  • Table 17 shows the results of analysis of the obtained salicylic acid crystals by analytical method 1.
  • Example 76 Crystallization pH 92.1 g of the purified salicylic acid solution II obtained in Example 73 was heated to 85° C., and 50 mass % sulfuric acid was added dropwise over 1 hour until the pH reached 0.9. After that, it was cooled to 25°C at 10°C/hour. After cooling, filtration was carried out to obtain 4.3 g of salicylic acid crystals. Table 17 shows the results of analysis of the obtained salicylic acid crystals by analytical method 1.
  • reaction was carried out while the coil reactor was immersed in an oil bath set so that the temperature of the reaction solution was 200°C. After flowing for 30 minutes (38.0 g of 2-chlorobenzoic acid as the starting material was used for the reaction), 393.9 g of the resulting reaction liquid was analyzed by analytical method 1, and found to contain 99.4 area % of salicylic acid. .
  • purification step III 95.0 g of the purified salicylic acid solution II obtained in (iii) (8.4 g as 2-chlorobenzoic acid) was heated using a 200 mL separable flask so that the internal temperature was 75 ° C., and then 50 mass % sulfuric acid to adjust the pH to 3.6. Zeolite (HSZ-891HOA manufactured by Tosoh Corporation, 20% by mass relative to the 2-chlorobenzoic acid used in the reaction) was added to the pH-adjusted solution, stirred for 1 hour, and then filtered to remove the zeolite and purified. 88.7 g of salicylic acid solution III were obtained.
  • salicylic acid useful as an intermediate for pharmaceuticals can be produced from 2-halogenated benzoic acid at low cost and with high productivity.
  • the obtained salicylic acid is industrially useful because it can be used as a raw material for pharmaceuticals such as methyl salicylate or intermediates thereof.

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JPS5553240A (en) * 1978-10-17 1980-04-18 Nippon Kayaku Co Ltd Preparation of m-substituted benzoic acid
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JP2001064230A (ja) * 1999-08-24 2001-03-13 Nissan Chem Ind Ltd ５−ヒドロキシイソフタル酸の製造法
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JP2021139134A (ja) 2020-03-03 2021-09-16 日本製鉄株式会社 耐力壁及び木造建物

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JPS5553240A (en) * 1978-10-17 1980-04-18 Nippon Kayaku Co Ltd Preparation of m-substituted benzoic acid
JPS5815939A (ja) 1981-07-07 1983-01-29 ギヤ−ト・ジアンセン サリチル酸ナトリウムの製造方法
JP2001064230A (ja) * 1999-08-24 2001-03-13 Nissan Chem Ind Ltd ５−ヒドロキシイソフタル酸の製造法
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