How salicylic acid is produced

Abstract

According to the present method, salicylic acid is produced with high productivity by causing a 2-halogenated benzoic acid to react at 155-300°C in an aqueous solvent in the presence of a copper source and a ligand. Preferably, a refinement step A for putting the obtained salicylic acid in contact with a styrene-based synthetic adsorbent, and / or a refinement step B for putting said salicylic acid in contact with zeolite, is further comprised. Source materials (for example, acetylsalicylic acid) for various pharmaceuticals or intermediates thereof can be derived from the compound of the present invention.

Description

[Technical Field]

[0001] The present invention relates to a method for producing salicylic acid, which is useful as a raw material or intermediate for the synthesis of various pharmaceuticals, agricultural chemicals, chemical products, etc. [Background technology]

[0002] Salicylic acid is useful as a synthetic raw material or intermediate for various pharmaceuticals, agricultural chemicals, chemical products, etc. For example, salicylic acid derivatives such as acetylsalicylic acid and methyl salicylate are widely used as antipyretic and analgesic drugs, respectively.

[0003] Conventionally, a method for producing salicylic acid by the Kolbe-Schmitt reaction has been known. For example, a method for producing salicylic acid by reacting sodium phenolate with carbon dioxide under high temperature and pressure conditions according to the following reaction formula has been disclosed (Patent Document 1).

[0004] [ka]

[0005] Recently, methods for producing salicylic acid from 2-chlorobenzoic acid have become known. For example, a method has been disclosed in which 2-chlorobenzoic acid is reacted in an aqueous solvent in the presence of potassium carbonate, copper powder, and pyridine under heating and reflux for 2 hours to produce salicylic acid in a 91% yield according to the following reaction scheme (Non-Patent Document 1).

[0006] [ka]

[0007] Also, methods for producing salicylic acid from 2-chlorobenzoic acid are known. For example, a method is known in which 2-bromobenzoic acid is reacted in the presence of sodium carbonate, copper(I) bromide, and N,N'-dimethylcyclohexane-1,2-diamine in an aqueous solvent at 100°C for 3 hours according to the following reaction formula, producing salicylic acid in an 85% yield (Patent Document 2).

[0008] [ka]

[0009] The methods of Non-Patent Document 1 and Patent Document 2 have a long reaction time, and there is a demand for an industrially advantageous production method with higher productivity, that is, an industrial production method that is highly productive, inexpensive, and allows stable production. Furthermore, judging from the production methods and yields, the salicylic acid obtained by these methods is thought to contain several percent of by-products such as aromatic compounds.

[0010] In general, high purity is required for raw materials and intermediates used in pharmaceutical synthesis to prevent unexpected side effects due to impurities contained in them. Examples of impurities include by-products generated during their manufacture. In some cases, by-products can be removed during purification or the manufacturing process of the target pharmaceutical. However, when pharmaceuticals are manufactured industrially and in large quantities, it is desirable to further reduce manufacturing and purification costs to ensure a stable supply of pharmaceuticals and control prices. Therefore, high-purity raw materials and intermediates for pharmaceutical synthesis with fewer impurities are desired. For these reasons, it is desirable to produce salicylic acid with a smaller content of by-products that become impurities. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Japanese Patent Application Publication No. 58-15939 [Patent Document 2] Special Publication No. 2010-511043 [Non-patent literature]

[0012] [Non-Patent Document 1] SYNTHETIC COMMUNICATIONS,32(13),2055-2059(2002) Summary of the Invention [Problem to be solved by the invention]

[0013] An object of the present invention is to provide a method for producing salicylic acid that is highly productive, inexpensive, and capable of 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. [Means for solving the problem]

[0014] The present inventors have found that salicylic acid can be produced stably, inexpensively, and with high productivity 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. Furthermore, it has been found that this method makes it possible to obtain salicylic acid with a lower content of by-products than conventionally known methods. The present invention provides the following.

[0015] [1] A method for producing salicylic acid, comprising a hydroxylation step of reacting a 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 155°C to 300°C to obtain salicylic acid.

[0016] [2] The method for producing salicylic acid according to [1], wherein the reaction pressure of the reaction is 0.1 MPa or more and 10 MPa or less.

[0017] [3] The method for producing salicylic acid according to [1] or [2], wherein the ligand is a compound having one or more optionally substituted amino groups.

[0018] [4] The method for producing salicylic acid according to any one of [1] to [3], wherein the copper source is a copper compound.

[0019] [5] The method for producing salicylic acid according to any one of [1] to [4], further comprising a purification step B in which the salicylic acid obtained in the hydroxylation step is brought into contact with zeolite.

[0020] [6] The method for producing salicylic acid according to any one of [1] to [5], comprising a purification step A in which the salicylic acid obtained in the hydroxylation step is brought into contact with a synthetic adsorbent.

[0021] [7] The method for producing salicylic acid according to any one of [1] to [6], wherein the reaction system is a flow synthesis reaction.

[0022] [8] The method for producing salicylic acid according to [5] or [6], wherein the HPLC purity of the salicylic acid that has been subjected to the purification step A or B is 95 area % or more, and the salicylic acid contains, as impurities, one or more aromatic compounds selected from the aromatic compounds represented by the following formulas (a) to (g), each of which contains 0.5 area % or less:

[0023] [ka] [Effects of the Invention]

[0024] According to the method for producing salicylic acid of the present invention, salicylic acid with a low content of by-products can be produced stably, inexpensively, and with high productivity. According to the present invention, salicylic acid with a low impurity content can be produced. The salicylic acid produced according to the present invention is useful as a raw material or synthetic intermediate for various pharmaceuticals, agricultural chemicals, chemical products, etc. In particular, due to its high purity, it is useful as a raw material for synthesizing various pharmaceuticals or their intermediates, such as acetylsalicylic acid. [Brief explanation of the drawings]

[0025] [Figure 1] 1 is a system diagram of a flow synthesis reactor showing an example of an embodiment of the method for producing salicylic acid of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] Hereinafter, an embodiment of the method for producing salicylic acid of the present invention will be described in detail.

[0027] The method for producing salicylic acid of the present invention is characterized by comprising a hydroxylation step of reacting a 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 include a purification step A in which the salicylic acid obtained in the hydroxylation step is brought into contact with a synthetic adsorbent and / or a purification step B in which the salicylic acid is brought into contact with a zeolite.

[0028] [Hydroxylation process] The method for producing salicylic acid of the present invention is a method for producing salicylic acid by hydrolyzing a 2-halogenated benzoic acid in an aqueous solvent in the presence of a copper source, a ligand, and a base.

[0029] Examples of methods for practicing the present invention include a method in which 2-halogenated benzoic acid, an aqueous solvent, a base, a copper source, and a ligand are mixed in a batch synthesis reactor and reacted under reaction conditions; and a method using a flow synthesis reactor, as shown in FIG. 1 , in which a mixed solution of 2-halogenated benzoic acid, a base, an aqueous solvent, a copper source, and a ligand prepared in preparation tank 1 is continuously fed by pump 2, 2-halogenated benzoic acid is continuously hydrolyzed in flow reactor 3 under reaction conditions, and the reaction solution containing salicylic acid that flows out of flow reactor 3 is recovered in recovery tank 4.

[0030] From the viewpoint of ease of control of reaction temperature and reaction pressure and operability, the method of carrying out the present invention is preferably carried out by a flow synthesis reaction using a flow synthesis reactor, the details of which will be described later.

[0031] <2-Halogenated benzoic acids> The 2-halogenated benzoic acid may be at least one selected from 2-chlorobenzoic acid, 2-bromobenzoic acid, and 2-iodobenzoic acid. The 2-halogenated benzoic acid may be a commercially available product, or may be obtained by a known method or a method similar thereto. As the 2-halogenated benzoic acid, 2-chlorobenzoic acid is preferred from the viewpoints of cost and reactivity.

[0032] <base> The base may be an inorganic base or an organic base. It is preferable to use an inorganic base in order to enhance the reactivity in an aqueous solvent, which will be described later. Two or more bases may be used in any ratio, but from the viewpoints of cost and reactivity, it is preferable to use one base alone.

[0033] Examples of inorganic bases that can be used include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc. Among these, from the viewpoints of cost and reactivity, sodium carbonate or potassium carbonate is preferred, and sodium carbonate is particularly preferred.

[0034] The organic base is not particularly limited as long as the reaction proceeds, but examples thereof include tertiary alkylamines such as triethylamine and pyridine.

[0035] The amount of base used is generally 1 mol or more as the lower limit and generally 10 mol or less as the upper limit, preferably 5 mol or less and particularly preferably 2 mol or less, per mol of 2-halogenated benzoic acid.

[0036] <Aqueous solvent> The aqueous solvent is selected from water or a water-soluble organic solvent, which may be used alone or in any combination of two or more in any proportion, as long as they do not adversely affect the reaction. In the present invention, it is preferable to use water substantially alone from the viewpoints of cost, reactivity, and reducing the environmental load. Here, "using water substantially alone" means that the proportion of water in the solvent is 95 mass % or more. By using water substantially alone, the reaction can be carried out efficiently in a homogeneous system in a short time.

[0037] The water-soluble organic solvent may be any one that does not inhibit the hydroxylation of 2-halogenated benzoic acid, and examples thereof include tetrahydrofuran and dioxane.

[0038] From the viewpoints of productivity and reactivity, the upper limit of the amount of the aqueous solvent used, relative to 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 or more, and 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. By setting the amount of the aqueous solvent used within the above range, the fluidity of the solution is improved, and the reaction can be carried out efficiently.

[0039] In the present invention, it is usually preferable that the raw material 2-halogenated benzoic acid is dissolved in an aqueous solvent to form a homogeneous solution and the reaction proceeds, but if the reaction proceeds, it may not be completely dissolved and may be in the form of a slurry.

[0040] <Copper source> In the method for producing salicylic acid of the present invention, salicylic acid can be produced with high productivity by using a copper source.

[0041] The copper source may be copper alone or a copper compound such as copper halide, copper oxide, an inorganic copper salt, or an organic copper salt. Among these, from the viewpoints of cost, reactivity, and solubility in aqueous solvents, copper compounds are preferred, copper halide, an inorganic copper salt, or an organic copper salt is more preferred, and copper halide is particularly preferred. The copper source may be either an anhydride or a hydrate, provided that the reaction proceeds.

[0042] Examples of copper halides that can be used include copper chloride such as CuCl or CuCl, copper bromide such as CuBr or CuBr, and copper iodide such as CuI. Among these, copper chloride is preferred, and CuCl is particularly preferred, from the viewpoints of cost and reactivity. As the copper oxide, for example, Cu2O or CuO can be used. Examples of copper inorganic acid salts that can be used include CuSO4, copper (II) nitrate, copper (II) carbonate, and copper (II) hydroxide. Examples of copper organic acid salts that can be used include copper(II) formate, copper(II) citrate, copper(II) gluconate, copper(II) acetate, and copper(I) acetate.

[0043] The amount of copper source used may be any amount as long as the reaction proceeds, and is usually 1 mol or more per 1 mol of 2-halogenated benzoic acid. In the present invention, by using a ligand described below, the reaction can be carried out using a catalytic amount of copper source. When a copper source is used together with a ligand, the amount of copper source used is usually 0.0001 mol to 1 mol, preferably 0.001 mol to 0.5 mol, per mol of 2-halogenated benzoic acid. By reducing the amount of copper source used, it is possible to reduce costs and the copper content of the produced salicylic acid.

[0044] <ligand> In the present invention, by using a ligand together with a copper source, the amount of copper source used can be reduced to a catalytic amount, and salicylic acid can be produced inexpensively and with high productivity.

[0045] The ligand reacts with the copper source to form a complex, which is thought to function as a catalyst. Known examples of complexes of copper sources and ligands include copper amine complexes such as copper ethylenediamine complexes and copper amino acid complexes such as copper histidine complexes. The ligand is preferably one that enhances the activity of the copper source and promotes the progress of the reaction, and is usually an amine, where amine refers to a compound having one or more optionally substituted amino groups.

[0046] The amine in the present invention includes aliphatic amines, heterocyclic amines, and amine derivatives. From the viewpoints of cost and reactivity, aliphatic amines are preferred. The lower limit of the number of carbon atoms in the amine used in the present invention is usually 1 or more, preferably 2 or more, and the upper limit is usually 12 or less, preferably 8 or less, more preferably 6 or less, and particularly preferably 4 or less.

[0047] Examples of aliphatic amines that can be used include monoamines such as dimethylamine and diethylamine; diamines such as ethylenediamine, N,N'-dimethylethylenediamine, N,N'-tetramethylethylenediamine, 1,3-propyldiamine, and N,N'-dimethylcyclohexane-1,2-diamine; triamines such as spermidine; and tetraamines such as triethylenetetramine, N,N'-bis(2-aminoethyl)-1,3-propanediamine, and N,N'-bis(3-aminopropyl)-1,4-butanediamine (spermine). Among these, from the viewpoints of cost, reactivity and suppression of impurities, diamines are preferred, and ethylenediamine is particularly preferred.

[0048] As the heterocyclic amine, for example, pyridine, piperidine, dipyridyl, 2,2'-dipyridylamine, or 1,10-phenanthroline can be used.

[0049] Examples of amine derivatives that can be used 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, and β-alanine.

[0050] The amount of the ligand used may vary depending on the copper source and the type of the ligand used, but the lower limit of the amount of the ligand used is usually 0.05 mol or more, preferably 1 mol or more, and the upper limit is usually 300 mol or less, preferably 200 mol or less, per mol of the copper source. If the amount of the ligand used is too small, the reaction may not proceed efficiently, and the amount of copper source used may not be reduced, whereas if the amount of the ligand used is too large, there may be an increase in by-products.

[0051] <Reaction conditions> (Reaction temperature) From the viewpoints of reactivity and productivity, the lower limit of the reaction temperature is usually 155° C. or higher, preferably 165° C. or higher, more preferably 175° C. or higher, even more preferably 185° C. or higher, and particularly preferably 195° C. or higher. 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, even more preferably 230° C. or lower, and particularly preferably 220° C. or lower. If the reaction temperature is too low, the reactivity may decrease, whereas if the reaction temperature is too high, the complex may decompose or side reactions may occur, resulting in an increase in impurities and a decrease in productivity and purity of the target product.

[0052] (reaction pressure) The reaction pressure can be normal pressure or elevated pressure, but when the reaction is carried out under high-temperature conditions above the boiling point of the solvent, it is preferable to apply elevated pressure to achieve the 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 lower, preferably 8 MPa or lower, more preferably 6 MPa or lower, and particularly preferably 4 MPa or lower.

[0053] When a batch reactor is used, the reaction can be carried out efficiently at a desired reaction pressure by adjusting the pressure using a pressure-resistant vessel.

[0054] When a flow reactor is used, the reaction can be carried out efficiently at a desired reaction pressure by adjusting the pressure by applying back pressure to the flow path using a back pressure valve or the like.

[0055] For example, when water is used as the aqueous solvent, the reaction pressure is preferably 0.54 MPa or more to achieve a reaction temperature of 155°C or higher, 0.70 MPa or more to achieve a reaction temperature of 165°C or higher, 0.89 MPa or more to achieve a reaction temperature of 175°C or higher, 1.12 MPa or more to achieve a reaction temperature of 185°C or higher, 1.56 MPa or more to achieve a reaction temperature of 200°C or higher, 2.32 MPa or more to achieve a reaction temperature of 220°C or higher, 2.80 MPa or more to achieve a reaction temperature of 230°C or higher, 3.35 MPa or more to achieve a reaction temperature of 240°C or higher, 3.98 MPa or more to achieve a reaction temperature of 250°C or higher, 5.51 MPa or more to achieve a reaction temperature of 270°C or higher, and 8.59 MPa or more to achieve a reaction temperature of 300°C or higher.

[0056] (Reaction time) The reaction time means the time during which the raw material mixture (a mixed solution of 2-halogenated benzoic acid, a base, a copper source, a ligand, and an aqueous solvent) remains in the reactor used in the present invention, and may vary depending on the reaction temperature and reaction pressure. The reaction time is usually 0.1 to 60 minutes, preferably 0.5 to 30 minutes, and particularly preferably 1 to 10 minutes, in order to improve the amount of salicylic acid produced per unit time.

[0057] (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 the presence of a base in an aqueous solvent. The reaction method is not particularly limited, but as mentioned above, it is industrially preferable to carry out the reaction using a flow synthesis reactor (a flow reactor). Specifically, as shown in FIG. 1 , a mixture of a 2-halogenated benzoic acid, a base, a copper source, a ligand, and an aqueous solvent is prepared in preparation tank 1, and this mixture is supplied to flow synthesis reactor (a flow reactor) 3 by pump 2. The reaction is carried out by heating in flow synthesis reactor 3, and the reaction solution is recovered in recovery tank 4.

[0058] (Reactor) The reactor is not particularly limited as long as the reaction proceeds, and examples thereof include a flow reactor and a batch synthesis reactor. The batch synthesis reactor may be equipped with a flow path for introducing and discharging the substrate, a jacket capable of controlling the reaction temperature, a device capable of controlling the reaction pressure, an agitator, and the like. The flow synthesis reactor is preferably tubular, and the tubular shape may be straight, curved, spiral, etc. From the viewpoint of reactor volume, the flow synthesis reactor is particularly preferably spiral.

[0059] The size of the flow synthesis reactor is selected depending on the production scale, for example, the inner diameter is 1 mm to 50 mm, and the length is selected according to the desired residence time. The flow synthesis reactor may be equipped with a temperature control mechanism. The introduction and discharge of the substrate and the like into the flow synthesis reactor can be carried out quantitatively by liquid delivery using a syringe pump, a cylinder pump, a diaphragm pump, a plunger pump, etc. A back pressure valve or an in-line analyzer capable of controlling the reaction pressure may be provided in the flow path on the reaction liquid outlet side from the flow synthesis reactor.

[0060] (heating device) In the hydroxylation step, the reaction solution can be heated using any means that can adjust the reaction temperature, such as a hot water bath, an oil bath, or microwaves.

[0061] Post-processing A method for isolating the target product, salicylic acid, from the resulting reaction solution includes mixing the resulting reaction solution with an acid, precipitating salicylic acid, and performing solid-liquid separation to obtain crystals of salicylic acid (the crystallization step described below). The obtained crystals may be further purified by known purification means such as recrystallization or column chromatography, or may be purified by a purification step using an adsorbent, for example, the purification step A and / or purification step B described below. Furthermore, the solution of salicylic acid obtained in the hydroxylation step may be purified in the purification step A and / or purification step B described below, and then further purified by known purification means such as recrystallization or column chromatography.

[0062] In the purification step according to the present invention, salicylic acid purified by the purification step A described below may be further purified by the purification step B described below, or salicylic acid purified by the purification step B may be further purified by the purification step A. From the viewpoints of impurity removal efficiency and industrial productivity, it is preferable to further purify the salicylic acid purified by the purification step A by the purification step B.

[0063] <Adsorbent> The adsorbent used in the purification step according to the present invention may be one or more of zeolite, synthetic adsorbents, and ion exchange resins.

[0064] (Zeolite) In the present invention, zeolite refers to an aluminosilicate containing an alkali metal and / or alkaline earth metal. It is known that zeolites become more hydrophobic as the SiO2 / Al2O3 ratio increases.

[0065] The SiO2 / Al2O3 ratio of the zeolite used in the present invention has a lower limit of usually 10 or more, preferably 100 or more, more preferably 500 or more, even more preferably 1000 or more, and particularly preferably 1500 or more, and an upper limit of usually 10000 or less, preferably 4000 or less, more preferably 3000 or less, even more preferably 2500 or less, and particularly preferably 2000 or less. By using a zeolite having the above SiO2 / Al2O3 ratio, aromatic compounds represented by the formula (b) described below can be efficiently removed.

[0066] The BET specific surface area of ​​zeolite is usually 100 m to improve reactivity. 2 / g~1000m 2 / g, preferably 200m 2 / g~500m 2 / g. The pore frequency radius of the zeolite is usually 0.1 nm to 10 nm, preferably 0.3 nm to 5 nm, and particularly preferably 0.5 nm to 1 nm, for the purpose of improving the efficiency of removing impurities. The BET specific surface area and the most frequent pore radius of a zeolite can be measured by a nitrogen gas adsorption method in accordance with a conventional method.

[0067] The shape of the zeolite may be any shape that can be brought into contact with the salicylic acid solution, and may be in the form of powder, pellets, film, or cylinder. Among these, particulate zeolite is preferred from the viewpoint of impurity removal efficiency, as it has a large contact area with the salicylic acid solution.

[0068] The particle size of the particulate zeolite is usually in the range of 0.01 μm to 100 μm, and from the viewpoint of industrial handleability, etc., it is preferably 0.1 μm to 100 μm, and particularly preferably 1 μm to 50 μm.

[0069] The particle size of the zeolite is an average particle size measured by a laser diffraction particle size distribution measurement method according to a conventional method.

[0070] As the zeolite, for example, commercially available products such as HSZ (registered trademark)-900, HSZ (registered trademark)-891HOA, HSZ (registered trademark)-800, HSZ (registered trademark)-700, HSZ (registered trademark)-600, HSZ (registered trademark)-500, or HSZ (registered trademark)-300 manufactured by Tosoh Corporation can be used. Among these, from the viewpoint of impurity removal efficiency, HSZ (registered trademark)-891HOA or HSZ (registered trademark)-800 is preferred, and HSZ (registered trademark)-891HOA is particularly preferred.

[0071] (synthetic adsorbent) In the present invention, the synthetic adsorbent is a porous synthetic adsorbent made of a porous organic polymer produced by chemical synthesis.

[0072] Examples of the base material of the synthetic adsorbent used in the present invention include aromatic, substituted aromatic, and acrylic polymers or copolymers (hereinafter, "polymers or copolymers" may be referred to as "(co)polymers"). Examples of aromatic (co)polymers include styrene / divinylbenzene copolymers and divinylbenzene polymers. The substituted aromatic (co)polymer may include a bromostyrene / divinylbenzene copolymer. Examples of the acrylic (co)polymer include methacrylic acid ester (co)polymers such as methyl methacrylate / ethylene glycol bis(methacrylic acid) copolymer.

[0073] Among these, from the viewpoint of insolubility in organic solvents and stability in acidic and alkaline solutions, aromatic (co)polymers are preferred, styrene / divinylbenzene copolymers such as styrene / divinylbenzene copolymers or bromostyrene / divinylbenzene copolymers are more preferred, and styrene / divinylbenzene copolymers are particularly preferred.

[0074] The synthetic adsorbent used in the present invention is preferably one that is substantially free of functional groups such as ion exchange groups, for example, one that has an ion exchange capacity of less than 1 meq / g or one that is non-polar.

[0075] 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, and particularly preferably 1 mL / mL / g to 1.5 mL / g, for the purpose of improving reactivity. The BET specific surface area of ​​synthetic adsorbents is usually 200 m to improve reactivity. 2 / g~2000m 2 / g, preferably 300m 2 / g~1500m 2 / g, more preferably 400m 2 / g~1000m 2 / g, particularly preferably 500m 2 / g~700m 2 / g. The pore mode radius of the synthetic adsorbent is usually 1 nm to 50 nm, preferably 5 nm to 40 nm, and particularly preferably 10 nm to 30 nm, for the purpose of improving reactivity. By using a synthetic adsorbent within the above range, it is possible to efficiently remove one or more aromatic compounds selected from the aromatic compounds represented by the formulas (f), (g), and (e) described below.

[0076] The pore volume, BET specific surface area and pore frequency radius of the synthetic adsorbent can be measured by a nitrogen gas adsorption method in accordance with a conventional method.

[0077] The shape and size of the synthetic adsorbent are not particularly limited as long as they can be packed into a column and do not interfere with the flow of the salicylic acid solution. Synthetic adsorbents can be in the form of particles, pellets, membranes, or cylinders, but particles are more preferred from the viewpoint of ease of packing.

[0078] The particle size of the particulate synthetic adsorbent is usually in the range of 1 μm to 2000 μm, preferably in the range of 3 μm to 2000 μm. From the viewpoint of industrial handleability, the particle size of the synthetic adsorbent is preferably in the range of 4 μm to 1000 μm, and the most frequent particle size is preferably 50 μm or more, preferably 150 μm or more, and particularly preferably 250 μm or more. The particle size of the synthetic adsorbent is an average particle size measured by a laser diffraction particle size distribution measurement method according to a conventional method.

[0079] Examples of synthetic adsorbents include Mitsubishi Chemical Corporation's Diaion (registered trademark) HP20SS, HP20, HP21, HP2MG, and HP2MGL, and Sepabeads (registered trademark) SP20SS, SP70, SP207, SP700, SP850, and XAD. TM -2, XAD TM 4. XAD TM 1600N or XAD TM Commercially available products such as 7HP can be used. Among these, Diaion (registered trademark) HP21 or XAD are preferred from the viewpoint of impurity removal efficiency. TM 4 is preferred. The physical properties of these commercially available synthetic adsorbents are shown in Table 1.

[0080] [Table 1]

[0081] (ion exchange resin) In the present invention, the ion exchange resin is a synthetic adsorbent provided with ion exchange groups. The ion exchange group may be any group capable of adsorbing copper ions, and a cation exchange group is usually used, preferably an iminodiacetic acid group.

[0082] 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, and particularly preferably 1 mL / mL / g to 2 mL / g, for the purpose of improving the efficiency of removing impurities. The BET specific surface area of ​​ion exchange resins is usually set to 200 m to improve the efficiency of impurity removal. 2 / g~2000m 2 / g, preferably 300m 2 / g~1500m 2 / g, particularly preferably 400m 2 / g~1000m 2 / g. The pore mode radius of the ion exchange resin is usually 1 nm to 100 nm, preferably 5 nm to 50 nm, and particularly preferably 10 nm to 25 nm, for the purpose of improving the efficiency of removing impurities. By using the above-mentioned ion exchange resin, copper ions can be efficiently removed during the reaction.

[0083] The pore volume, BET specific surface area and pore mode radius of the ion exchange resin can be measured by a conventional nitrogen gas adsorption method.

[0084] The shape and size of the ion exchange resin are not particularly limited as long as they can be packed into a column and do not interfere with the flow of the salicylic acid solution. The ion exchange resin may be in the form of particles, pellets, membranes, or cylinders, but particles are more preferred from the viewpoint of packing properties. The harmonic mean diameter of the particulate ion exchange resin is usually in the range of 0.1 mm to 1 mm, and from the viewpoint of industrial handleability, etc., it is preferably in the range of 0.3 mm to 0.8 mm.

[0085] The particle size of the ion exchange resin is an average particle size measured by a laser diffraction particle size distribution measurement method according to a conventional method.

[0086] Examples of ion exchange resins include Diaion (registered trademark) CR11, CR20, CRB03, and CRB05 manufactured by Mitsubishi Chemical Corporation, and AmberSep manufactured by Organo Corporation. TM IRC748, Ambercep TM Commercially available products such as IRC747UPS can be used. Among these, CR11 is preferred from the viewpoint of copper ion removal efficiency.

[0087] <Other refining methods> In order to remove copper from the reaction solution, in addition to the above-mentioned ion exchange resin, a known method of precipitating copper using a reducing agent such as hydrosulfite or hydrazine may be used.

[0088] Another method is to use activated carbon to adsorb and remove impurities from the reaction solution. As the activated carbon, for example, Shirasagi, Strong Shirasagi, Purified Shirasagi, etc., manufactured by Osaka Gas Chemical Co., Ltd., can be used. Among these, Strong Shirasagi is preferred 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, and more preferably 5% by mass to 25% by mass, based on the 2-halogenated benzoic acid used in the reaction.

[0089] <Purification process A> The purification step A is a step in which the salicylic acid obtained in the hydroxylation step or the salicylic acid obtained in the purification step B described below is contacted with a synthetic adsorbent to reduce impurities in the salicylic acid and increase the purity of the salicylic acid.

[0090] In the purification step A, salicylic acid is brought into contact with the specific adsorbent to remove at least one of the aromatic compounds represented by the formulas (a) to (g) described below, particularly at least one selected from the aromatic compounds represented by the formulas (b), (f), (g), and (e).

[0091] (Salicylic Acid) The salicylic acid purified in purification step A is usually a solution, preferably an aqueous solution, and the solution of salicylic acid obtained in the above-mentioned hydroxylation step or the solution of salicylic acid obtained in purification step B and / or purification step C described below can be used. The salicylic acid contained in the salicylic acid solution may be dissolved when the salicylic acid comes into contact with the adsorbent. From the viewpoints of productivity and reactivity, 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, and particularly preferably 5% by mass to 70% by mass.

[0092] (adsorbent) In the purification step A, among the above-mentioned adsorbents, a styrene-based synthetic adsorbent is particularly used, preferably a styrene / divinylbenzene copolymer such as a styrene / divinylbenzene copolymer or a bromostyrene / divinylbenzene copolymer, and particularly preferably a styrene / divinylbenzene copolymer. As mentioned above, since the styrene-based synthetic adsorbent has little effect on the reaction, it is preferable to use one that is substantially free of functional groups such as ion-exchange groups, for example, one with an ion-exchange capacity of less than 1 meq / g or one that is nonpolar.

[0093] For the purpose of improving reactivity, the pore mode 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, and particularly preferably 3 nm to 40 nm. By using a styrene-based synthetic adsorbent within the above range, it is possible to efficiently remove aromatic compounds represented by the formulas (f), (g), and (e) described below.

[0094] 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 above in the section on adsorbents.

[0095] As the styrene-based synthetic adsorbent used in the purification step A, commercially available products such as Diaion (registered trademark) HP20SS, HP20, HP21, Sepabeads (registered trademark) SP20SS, SP700, etc., manufactured by Mitsubishi Chemical Corporation, can be used. Among these, HP21 is preferred from the viewpoint of impurity removal efficiency.

[0096] (Purification conditions for purification step A) <Contact temperature> The contact temperature for contacting the salicylic acid solution with the styrene-based synthetic adsorbent is usually 5°C to 100°C, and from the viewpoint of impurity removal efficiency and solubility, it is preferably 50°C to 95°C, and particularly preferably 60°C to 90°C.

[0097] <Contact time> The contact time for contacting the salicylic acid solution with the styrene-based synthetic adsorbent is not particularly limited as long as impurities are sufficiently removed, but is usually 0.1 to 24 hours.

[0098] <Contact pressure> The contact pressure when the salicylic acid solution is brought into contact with the styrene-based synthetic adsorbent is usually atmospheric pressure, but may be increased.

[0099] <ph> The pH of the salicylic acid solution when contacting it 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. From the viewpoint of impurity removal efficiency, the pH is preferably pH 3 to 7, more preferably pH 3 to 6, and particularly preferably pH 3 to 5. By adjusting the pH within the above range, it is possible to efficiently remove at least one or more aromatic compounds selected from those represented by the formulas (b), (e), (f), and (g) described below.

[0100] (Post-processing) A method for isolating the target salicylic acid from the salicylic acid solution obtained through the purification step A includes a method of mixing the obtained treatment solution with a strong acid, precipitating salicylic acid, and performing solid-liquid separation to obtain crystals of salicylic acid (crystallization step described below). The obtained crystals may be further purified by known purification means such as recrystallization or column chromatography, or may be purified by the purification step B and / or purification step C described below.

[0101] <Purification process B> The purification step B is a step in which the salicylic acid obtained in the hydroxide step or the salicylic acid that has been subjected to the purification step A is contacted with zeolite to reduce impurities in the salicylic acid and increase the purity of the salicylic acid.

[0102] In the purification step B, by contacting salicylic acid with the above-mentioned adsorbent, at least one of the aromatic compounds represented by the formulas (a) to (g) described below, particularly at least one selected from the aromatic compounds represented by the formulas (b), (e), (f) and (g), can be removed.

[0103] (Salicylic Acid) As the salicylic acid purified in the purification step B, the solution of salicylic acid obtained in the above-mentioned hydroxylation step or the solution of salicylic acid obtained in the above-mentioned purification step A can be used. From the viewpoints of productivity and reactivity, the concentration of the salicylic acid solution is usually 0.1% by mass to 80% by mass, preferably 1% by mass to 75% by mass, and particularly preferably 5% by mass to 70% by mass.

[0104] (adsorbent) In the purification step B, the above-mentioned adsorbent can be used, but from the viewpoint of efficiently removing at least one or more aromatic compounds selected from the group consisting of the aromatic compounds represented by formulas (b), (e), (f) and (g), it is preferable to use the above-mentioned zeolite.

[0105] (Purification conditions for purification step B) <Contact temperature> The contact temperature for contacting the salicylic acid solution with the zeolite 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 impurity removal efficiency and solubility.

[0106] <Contact time> The contact time when the salicylic acid solution is brought into contact with the zeolite is not particularly limited as long as impurities are sufficiently removed, but is usually 0.1 to 24 hours.

[0107] <Contact pressure> The pressure when the salicylic acid solution is brought into contact with the zeolite is usually atmospheric pressure, but may be increased.

[0108] <pH upon contact> The pH of the salicylic acid solution when contacting the salicylic acid solution with zeolite is within a range in which salicylic acid does not precipitate, and is usually from pH 3 to 8, and from the viewpoint of impurity removal efficiency, is preferably from pH 3 to 7, and particularly preferably from pH 3 to 6. By adjusting the pH within the above range, at least one selected from the aromatic compounds represented by the formulas (b), (e), (f), and (g) described below can be efficiently removed.

[0109] (Post-processing) A method for isolating the target salicylic acid from the salicylic acid solution obtained through purification step B includes a method of mixing the obtained treatment solution with a strong acid, precipitating salicylic acid, and performing solid-liquid separation to obtain crystals of salicylic acid (crystallization step described below). The obtained crystals may be further purified by known purification means such as recrystallization or column chromatography, or may be purified by the above-mentioned purification step A and / or the below-mentioned purification step C.

[0110] <Purification process C> The purification step C is a step in which the salicylic acid obtained in the hydroxylation step or the salicylic acid obtained in the purification step A and / or B is brought into contact with an ion exchange resin to reduce the copper ions in the salicylic acid and increase the purity of the salicylic acid.

[0111] (Salicylic Acid) The salicylic acid purified in purification step C is usually a solution, preferably an aqueous solution, and the solution of salicylic acid obtained in the above-mentioned hydroxylation step or the solution of salicylic acid obtained in the above-mentioned purification step A and / or purification step B can be used. The salicylic acid contained in the salicylic acid solution may be dissolved when the salicylic acid contacts the ion exchange resin. From the viewpoints of productivity and reactivity, 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, and particularly preferably 5% by mass to 70% by mass.

[0112] (ion exchange resin) The ion exchange resin used in the purification step C may be any of the ion exchange resins described above.

[0113] (Purification conditions for purification step C) <Contact temperature> The contact temperature at which the salicylic acid solution is brought into contact with the ion exchange resin 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.

[0114] <Contact time> The contact time for contacting the salicylic acid solution with the ion exchange resin is not particularly limited as long as impurities are sufficiently removed, but is usually 0.1 to 24 hours.

[0115] <Contact pressure> The contact pressure when the salicylic acid solution is brought into contact with the ion exchange resin is usually atmospheric pressure, but may be increased.

[0116] <ph> The pH of the salicylic acid solution when contacting it with the ion exchange resin may be within a range in which salicylic acid does not precipitate, and is usually from pH 3 to 8, and from the viewpoint of impurity removal efficiency, is preferably from pH 3 to 7, more preferably from pH 3 to 6, and particularly preferably from pH 3 to 5. By adjusting the pH within the above range, copper ions can be removed efficiently.

[0117] (Post-processing) A method for isolating the target salicylic acid from the salicylic acid solution obtained in the purification step C includes mixing the obtained treatment solution with a strong acid, precipitating salicylic acid, and performing solid-liquid separation to obtain crystals of salicylic acid (the crystallization step described below). The obtained crystals may be further purified by known purification means such as recrystallization or column chromatography, or may be purified by the above-mentioned purification step A and / or purification step B.

[0118] <Crystallization process> In the crystallization step of the present invention, a pH adjuster is added to the reaction liquid containing salicylic acid obtained in the hydroxylation step and to a salicylic acid solution that has been subjected to one or more of the purification steps A, B, and C described above (hereinafter, this may be simply referred to as a salicylic acid solution), thereby precipitating crystals of salicylic acid, which can be recovered by a separation method such as solid-liquid separation.

[0119] (pH adjuster) Examples of pH adjusters that can be used to adjust the salicylic acid solution include water; acidic pH adjusters such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; and basic pH adjusters such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Among these, acidic pH adjusters, particularly sulfuric acid, are preferred from the viewpoints of reactivity, productivity, workability, and cost. The amount of the pH adjuster used is not particularly limited, but may be any amount that can adjust the pH to the above-mentioned range.

[0120] (crystallization temperature) The crystallization temperature refers to the temperature of the solution when salicylic acid is crystallized from the salicylic acid solution. The upper limit of the crystallization temperature is usually 100°C or lower, preferably 95°C or lower, and particularly preferably 90°C or lower, and the lower limit is usually 0°C or higher, preferably 50°C or higher, and particularly preferably 70°C or higher. By setting the crystallization temperature within the above range, impurities can be efficiently removed, and salicylic acid with a crystalline structure that is easy to filter can be obtained.

[0121] (crystallization time) The crystallization time means the time required for precipitating salicylic acid from a salicylic acid solution, and is not particularly limited as long as impurities are sufficiently removed, but is usually 0.1 to 24 hours.

[0122] (crystallization pressure) The crystallization pressure means the pressure of the reaction system when precipitating salicylic acid from the salicylic acid solution, and is usually atmospheric pressure, but may be increased.

[0123] <ph> The pH of the salicylic acid solution to be subjected to crystallization is within a pH range that suppresses the precipitation of impurities and efficiently precipitates salicylic acid, and is usually pH 0 to 4, and from the viewpoint of the efficiency of impurity removal, pH 0.5 to 3.5 is preferred, and pH 1 to 3 is particularly preferred. By adjusting the pH within the above range, salicylic acid precipitates, and at least one or more aromatic compounds selected from the aromatic compounds represented by the formulae (a), (b), (c), and (d) described below can be efficiently removed.

[0124] (solid-liquid separation temperature) The solid-liquid separation temperature means the temperature of the slurry when the salicylic acid crystals are subjected to solid-liquid separation after precipitating salicylic acid, and is usually 0°C to 100°C, and from the viewpoint of improving the impurity removal efficiency and yield, it is preferably 5°C to 40°C, and particularly preferably 10°C to 30°C.

[0125] (Solid-liquid separation method) The method for solid-liquid separation of the precipitated salicylic acid crystals is not particularly limited, but in industrial production, solid-liquid separation is usually performed using a centrifuge. The salicylic acid crystals obtained by solid-liquid separation can be washed with a solvent in which salicylic acid is poorly soluble, such as water.

[0126] The filter cloth used for the solid-liquid separation may be any filter cloth that can sufficiently filter out salicylic acid, and a general-purpose filter cloth may be used.

[0127] (drying temperature) The drying temperature for drying the crystals of salicylic acid obtained by solid-liquid separation may be a temperature at which salicylic acid does not sublime, and is usually 20°C to 40°C.

[0128] (drying pressure) 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 sublimate, and drying may be performed at normal pressure or under reduced pressure.

[0129] (Post-processing) The crystals obtained by crystallization may be further purified by known purification means such as recrystallization or column chromatography, or may be further purified by one or more of the above-mentioned purification steps A, B, and C.

[0130] [Salicylic acid purification] In the method for producing salicylic acid of the present invention, salicylic acid obtained in the above-mentioned hydroxylation step is purified by a purification step, for example, one or more of the above-mentioned purification steps A, B, and C, or a crystallization step, to reduce the amount of by-products that are produced as copper sources or by-products in the hydroxylation step and that are mixed into salicylic acid as impurities, specifically, aromatic compounds represented by the following formulas (a) to (g), thereby making it possible to obtain high-purity salicylic acid.

[0131] Specifically, high-purity salicylic acid having an HPLC purity of 95 area % or more and containing 0.5 area % or less of each of the aromatic compounds represented by the following formulas (a) to (g) is obtained.

[0132] [ka]

[0133] The aromatic compounds represented by the above formulas (a) to (g) are highly reactive and may cause side reactions when converting salicylic acid into a pharmaceutical product, so it is preferable not to allow them to remain in salicylic acid. Furthermore, the aromatic compounds represented by the above formulas (a) to (g) have similar physical properties to the target salicylic acid, so they are difficult to remove by purification procedures such as solid-liquid separation by conventional crystallization. It is preferable to remove these compounds before solid-liquid separation by crystallization.

[0134] 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.

[0135] When salicylic acid is used as a raw material for pharmaceuticals, the content of each 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 0.3 area % or less, even more preferably 0.2 area % or less, and particularly preferably 0.1 area % or less. [Example]

[0136] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the following examples as long as the gist of the present invention is not exceeded.

[0137] [Calculation of the amount of salicylic acid produced per unit time] The amount of salicylic acid produced per unit time, SA / T, which is used to evaluate the productivity of salicylic acid, was calculated according to the following formula.

[0138]

number

[0139] [Abbreviation] The abbreviations used below are as follows: SA: Salicylic acid 2ABA: 2-aminobenzoic acid (formula (d)) 2CBA: 2-chlorobenzoic acid (formula (c)) DABA: 2,2'-iminodibenzoic acid (formula (f)) EDABA: N,N'-ethylenediaminedianthranilic acid (formula (g)) CuCl : Copper(I) chloride CuCl2: Copper(II) chloride CuBr :Copper(I) bromide CuBr2: Copper(II) bromide CuI: Copper(I) iodide Cu2O: Copper(I) oxide CuO: Copper(II) oxide Cu(OH)2:Copper(II) hydroxide Cu(NO3)2:Copper(II) nitrate CuSO4: Copper(II) sulfate Cu(OAc): Copper(I) acetate Cu(OAc)2: Copper(II) acetate EDA: Ethylenediamine L-Pro: L-proline N-Me-L-Pro: N-methyl-L-proline N-Me-L-PAla: N-methyl-L-alanine L-His: L-histidine L-Val: L-valine L-Asp: L-aspartic acid L-Ser: L-serine L-Lys: L-lysine L-Ala: L-alanine L-Phe: L-phenylalanine D-Met: D-methionine EDTA: Ethylenediaminetetraacetic acid N,N'-DMEDA: N,N'-dimethylethylenediamine N,N'-TMEDA: N,N'-tetramethylethylenediamine In the following description, the aromatic compounds represented by the formulas (a) to (g) will be referred to as (a) to (g), respectively.

[0140] [Flow synthesis reactor] In the following examples and comparative examples, a flow synthesis reactor shown in FIG. 1 was used.

[0141] [Microwave reaction synthesis equipment] Anton Paar M400 Maximum temperature 300℃, pressure resistance 30bar

[0142] [Analysis method (HPLC)] The apparatus and conditions used for analyzing the reaction solutions in the following Examples and Comparative Examples are shown in Tables 2A and 2B below.

[0143] [Table 2A]

[0144] [Table 2B]

[0145] [Example 1] A solution of 780 mg (4.98 mmol) of 2-chlorobenzoic acid, 554 mg (5.24 mmol) of sodium carbonate, 0.49 mg (0.05 mmol, 0.04 mol per 1 mol of 2-chlorobenzoic acid), and L-proline (0.20 mmol, 0.001 mol per 1 mol of 2-chlorobenzoic acid) mixed with 3.12 mL of water (4 L per 1 kg of 2-chlorobenzoic acid) at room temperature was added, and the mixture was heated to 210°C under microwave irradiation using a microwave device and reacted for 5 minutes. After the reaction, the reaction solution was cooled to room temperature and analyzed using Analysis Method 1, yielding salicylic acid at 97.5 area %. The resulting reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 3. The resulting reaction solution contained salicylic acid (chemical purity 97.5% by area), and the amount of salicylic acid produced per unit time was 19.5% by area / min.

[0146] [Comparative Examples 1 to 3: 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. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 4. In Table 3, "MR" indicates the number of moles per mole of 2-chlorobenzoic acid. The same applies hereinafter.

[0147] [Table 3]

[0148] [Examples 2-3: 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. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 4.

[0149] [Table 4]

[0150] Examples 2 and 3 in Table 4 show that salicylic acid can be obtained efficiently even when a copper halide other than copper (I) chloride is used as the copper source.

[0151] [Examples 4 to 15: Ligands] The reaction was carried out in the same manner as in Example 1, except that the ligand in Example 1 was changed as shown in Table 5. The obtained reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 5.

[0152] [Table 5]

[0153] Examples 4 to 15 in Table 5 show that salicylic acid can be produced with high productivity by using various ligands.

[0154] [Example 16] A stainless steel cylinder with an inner diameter of 1.7 mm and a length of 5 m was immersed in a temperature-controllable oil bath to serve as a flow reactor. Salicylic acid was synthesized using the flow synthesis system shown in Figure 1.

[0155] A solution (hereinafter referred to as the 2-chlorobenzoic acid solution) prepared by mixing and dissolving 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 (0.08 mol per 1 mol of 2-chlorobenzoic acid), and water (9 L per 1 kg of 2-chlorobenzoic acid) in preparation tank 1 was continuously passed through flow reactor 3, using a back pressure valve to maintain the pump discharge pressure at approximately 3 MPa so that the reaction time was 5 minutes. The reaction product solution obtained after 30 minutes of flow was analyzed using analytical method 1, and the results are shown in Table 6. The resulting reaction product liquid was analyzed by analytical method 1 and was found to contain salicylic acid (chemical purity 96.5 area %, amount of salicylic acid produced per unit time: 19.30 area % / min). The supply rate of the 2-chlorobenzoic acid solution was 2.34 mL / min using a plunger pump, and the reactor outlet temperature of the flow-type reactor 3 was maintained at 200°C.

[0156] [Examples 17 to 18 and Comparative Examples 4 to 6: Reaction Temperature and Reaction Time] The reaction was carried out in the same manner as in Example 16, except that 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 mol of 2-chlorobenzoic acid, and the reaction time and reaction temperature were changed as shown in Table 6. The obtained reaction solution was analyzed by analytical method 2, and the results are shown in Table 6.

[0157] [Table 6]

[0158] [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 was set as shown in Table 7. The obtained reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 7.

[0159] [Table 7]

[0160] As is clear from 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, by setting the reaction temperature to 155°C to 300°C, salicylic acid can be obtained with high selectivity and high productivity in a short reaction time.

[0161] [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 changed to 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. The obtained reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 8.

[0162] [Table 8]

[0163] As is clear from Examples 25 to 27 and Comparative Example 7 in Table 8, productivity can be further increased by adding an equivalent or greater amount of ligand to the copper source.

[0164] Examples 28 to 41: Copper Source The reaction was carried out in the same manner as in Example 27, except that in Example 16, the reaction temperature was changed to 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. The obtained reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 9.

[0165] [Table 9]

[0166] As is clear from Examples 2 and 3 in Table 4 and Examples 28 to 41 in Table 9, salicylic acid can be obtained with high selectivity and productivity by using various copper sources.

[0167] Example 42: Bases 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. The obtained reaction solution was analyzed by analytical method 1, and the results are shown in Table 10 together with the results of Example 16.

[0168] [Table 10]

[0169] As is clear from Examples 16 and 42 in Table 10, salicylic acid can be obtained with high selectivity and high productivity even when inorganic bases other than sodium carbonate are used.

[0170] [Examples 43 to 54: Ligands] The reaction was carried out in the same manner as in Example 16, except that the ligands in Example 16 were changed as shown in Table 11. The obtained reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 11.

[0171] [Table 11]

[0172] As is clear from Examples 4 to 15 in Table 5 and Examples 43 to 54 in Table 11, by using an amine such as an aliphatic amine, a heterocyclic amine, or an amine derivative as a ligand, salicylic acid can be obtained with high selectivity and high productivity.

[0173] 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. The obtained reaction solution was analyzed by Analysis Method 1, and the results are shown in Table 12.

[0174] [Examples 56 to 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 approximately 10 mg (20% by mass based on 2-chlorobenzoic acid) of the adsorbent (synthetic adsorbent manufactured by Mitsubishi Chemical Corporation) shown in Table 12 was added, followed by shaking at 35°C and 1000 rpm for 5 hours using a shaker (TS100C manufactured by Biosan). The results of analyzing the resulting purified salicylic acid solution using Analysis Method 1 are shown in Table 12.

[0175] [Table 12]

[0176] As is clear from Examples 56 to 64 in Table 12, impurities can be removed efficiently by using a synthetic adsorbent.

[0177] [Examples 65 to 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 approximately 10 mg (20% by mass based on 2-chlorobenzoic acid) of the adsorbent (synthetic adsorbent manufactured by Mitsubishi Chemical Corporation) shown in Table 13 was added, followed by shaking at 35°C and 1000 rpm for 5 hours using a shaker (TS100C manufactured by Biosan). The results of analyzing the resulting purified salicylic acid solution using Analysis Method 1 are shown in Table 13.

[0178] [Table 13]

[0179] As is clear from Examples 65 to 66 in Table 13, impurities can be removed efficiently by using a styrene-based synthetic adsorbent.

[0180] [Examples 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 (10% by mass relative to 2-chlorobenzoic acid) of an adsorbent (activated carbon manufactured by Osaka Gas Chemical Co., Ltd.) shown in Table 14 was added thereto, followed by stirring for 5 hours at 75° C. The purified salicylic acid solution obtained was analyzed by Analysis Method 1, and the results are shown in Table 14.

[0181] [Table 14]

[0182] As is clear from Examples 67 to 70 in Table 14, impurities can be removed efficiently by using activated carbon.

[0183] [Example 71 and Comparative Examples 9 to 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 approximately 10 mg (20% by mass based on 2-chlorobenzoic acid) of the adsorbent (zeolite manufactured by Tosoh Corporation) shown in Table 15 was added, followed by shaking at 35°C and 1000 rpm for 5 hours using a shaker (TS100C manufactured by Biosan). The results of analyzing the obtained purified salicylic acid solution using Analysis Method 1 are shown in Table 15.

[0184] [Table 15]

[0185] As is clear from Example 71 and Comparative Examples 9 to 12 in Table 15, the aromatic compounds represented by formula (b) can be selectively removed by using a zeolite with a high SiO2 / Al2O3 ratio.

[0186] [Example 72 and Comparative Examples 14 to 16: Adsorbent (ion exchange resin)] A column (5 mm x 100 mm) packed with 0.90 g of an ion exchange resin (manufactured by Mitsubishi Chemical Corporation) shown in Table 16 and water was set in a column-type flow reactor (manufactured by EYELA, model: MCR-1000). 90 g of the reaction solution obtained in Example 55 was passed through the column at a rate of 0.9 mL / min to obtain a purified salicylic acid solution. The copper ion content of the obtained purified salicylic acid solution was analyzed by ICP analysis, and the results are shown in Table 16.

[0187] [Table 16]

[0188] As is clear from Example 72 and Comparative Examples 14 to 16 in Table 16, copper ions can be efficiently adsorbed and removed by using an ion exchange resin having a chelating type ion exchange resin such as an iminodiacetic acid group.

[0189] [Example 73] (i) Hydroxylation process An aqueous solution (18 L of water per 1 kg of 2-chlorobenzoic acid) containing sodium carbonate (1.05 molar equivalents relative to 2-chlorobenzoic acid), 2-chlorobenzoic acid, copper(II) chloride (0.002 molar equivalents relative to 2-chlorobenzoic acid), and ethylenediamine (0.08 molar equivalents relative to 2-chlorobenzoic acid) was supplied to and circulated through a coil reactor. The supply rate of the mixed solution was adjusted to 2.34 mL / min (reaction time: 5 min) using a plunger pump. The coil reactor was immersed in an oil bath set to maintain the temperature of the reaction solution at 190 °C during the reaction. After 30 minutes of circulation (44.7 g of the starting material 2-chlorobenzoic acid was used in the reaction), 873.7 g of the resulting reaction solution was analyzed by analytical method 1, and it was found to contain 97.7 area % of salicylic acid.

[0190] (ii) Purification process I A column (10 mm × 100 mm) packed with ion exchange resin Diaion (registered trademark) CR11 (4.06 g) and water was set in a column-type flow reactor (EYELA, model: MCR-1000). 860 g of the reaction solution obtained above was passed through the column at a rate of 2.87 mL / min, yielding 865.7 g of purified salicylic acid solution I.

[0191] (iii) Purification step II 196.5 g of the obtained purified salicylic acid solution I was heated to 75°C in a 200 mL separable flask and adjusted to pH 3.5 with 50% by mass sulfuric acid. To this was added the synthetic adsorbent DIAION (registered trademark) HP21 (20% by mass relative to the 2-chlorobenzoic acid used in the reaction), and after stirring for 2 hours, the mixture was filtered to remove the synthetic adsorbent, yielding purified salicylic acid solution II.

[0192] [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% by mass sulfuric acid was added dropwise over 1 hour until the pH reached 2.6. The solution was then cooled to 25°C at a rate of 5°C / hour. After cooling, the solution was filtered to obtain 2.4 g of salicylic acid crystals. The obtained salicylic acid crystals were analyzed using Analysis Method 1, and the results are shown in Table 17.

[0193] [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% by mass sulfuric acid was added dropwise over 1 hour until the pH reached 1.8. The solution was then cooled to 25°C at a rate of 10°C / hour. After cooling, the solution was filtered to obtain 8.0 g of salicylic acid crystals. The obtained salicylic acid crystals were analyzed using analytical method 1, and the results are shown in Table 17.

[0194] [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% by mass sulfuric acid was added dropwise over 1 hour until the pH reached 0.9. The solution was then cooled to 25°C at a rate of 10°C / hour. After cooling, the solution was filtered to obtain 4.3 g of salicylic acid crystals. The obtained salicylic acid crystals were analyzed using analytical method 1, and the results are shown in Table 17.

[0195] [Table 17]

[0196] As is clear from Examples 74 to 76 in Table 17, impurities can be efficiently removed by precipitating salicylic acid at a relatively low pH.

[0197] [Example 77] (i) Hydroxylation process An aqueous solution (9 L of water per 1 kg of 2-chlorobenzoic acid) containing sodium carbonate (1.05 molar equivalents relative to 2-chlorobenzoic acid), 2-chlorobenzoic acid, copper(II) chloride (0.001 molar equivalents relative to 2-chlorobenzoic acid), and N,N'-dimethylethylenediamine (0.04 molar equivalents relative to 2-chlorobenzoic acid) was fed into the coil reactor and allowed to flow. The feed rate of the mixed solution was adjusted to 2.34 mL / min (reaction time: 5 min) using a plunger pump. The coil reactor was immersed in an oil bath set to maintain the temperature of the reaction solution at 200 °C during the reaction. After 30 minutes of circulation (38.0 g of the starting material 2-chlorobenzoic acid was used in the reaction), 393.9 g of the resulting reaction solution was analyzed by analytical method 1, and it was found to contain 99.4 area % of salicylic acid.

[0198] (ii) Purification process I Column A (10 mm x 100 mm) packed with ion exchange resin Diaion (registered trademark) CR11 (3.80 g) and water was set in a column-type flow reactor (EYELA, model: MCR-1000). 393.9 g of the reaction solution obtained in (i) (38.0 g as 2-chlorobenzoic acid) was passed through column A at a rate of 2.87 mL / min, yielding 401.5 g of purified salicylic acid solution I (38.0 g as 2-chlorobenzoic acid).

[0199] (iii) Purification step II Column B (5 mm × 200 mm) packed with synthetic adsorbent Diaion (registered trademark) HP21 (2.24 g) and water was set in a column-type flow reactor (EYELA, model: MCR-1000). 180.5 g (16.8 g as 2-chlorobenzoic acid) of purified salicylic acid solution I obtained in (ii) was passed through column B at a rate of 0.64 mL / min, yielding 191.1 g (16.8 g as 2-chlorobenzoic acid) of purified salicylic acid solution II.

[0200] (iv) Purification step III 95.0 g (8.4 g of 2-chlorobenzoic acid) of the purified salicylic acid solution II obtained in (iii) was placed in a 200 mL separable flask and heated to an internal temperature of 75°C, and then the pH was adjusted to 3.6 with 50% by mass sulfuric acid. Zeolite (HSZ-891HOA manufactured by Tosoh Corporation, 20% by mass based on the 2-chlorobenzoic acid used in the reaction) was added to the pH-adjusted solution, and the mixture was stirred for 1 hour. The zeolite was then removed by filtration, yielding 88.7 g of purified salicylic acid solution III.

[0201] (v) Crystallization process 88.7 g of the purified salicylic acid solution III obtained in (iv) was heated to an internal temperature of 85°C, and 50% by mass sulfuric acid was added dropwise over 1 hour to adjust the pH to 1.8. The pH-adjusted solution was cooled from 85°C to 25°C at a cooling rate of 10°C / hr. After cooling, the solution was filtered to obtain 6.4 g of salicylic acid crystals (yield 89.9%). When the salicylic acid crystals were analyzed using Analysis Method 1, the salicylic acid purity was found to be 99.95 area %. [Industrial Applicability]

[0202] According to the method for producing salicylic acid of the present invention, salicylic acid, which is useful as an intermediate for pharmaceuticals, can be produced from 2-halogenated benzoic acids at low cost and with high productivity. The resulting salicylic acid is industrially useful because it can be used as a raw material for pharmaceuticals such as methyl salicylate or their intermediates.

[0203] Although the present invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various modifications can be made without departing from the spirit and scope of the invention. This application is based on Japanese Patent Application No. 2021-139134, filed on August 27, 2021, the entire contents of which are incorporated by reference. [Explanation of symbols]

[0204] 1 Preparation tank 2 pumps 3 Flow reactor 4. Collection tank 5 Back pressure valve< / ph> < / ph> < / ph>

Claims

1. A method for producing salicylic acid, comprising a hydroxylation step of reacting a 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 155°C to 300°C to obtain salicylic acid.

2. 2. The method for producing salicylic acid according to claim 1, wherein the reaction pressure is 0.1 MPa or more and 10 MPa or less.

3. 2. The method for producing salicylic acid according to claim 1, wherein the ligand is a compound having one or more optionally substituted amino groups.

4. 2. The method for producing salicylic acid according to claim 1, wherein the copper source is a copper compound.

5. 2. The method for producing salicylic acid according to claim 1, further comprising a purification step B of contacting the salicylic acid obtained in the hydroxide step with a zeolite.

6. 2. The method for producing salicylic acid according to claim 1, further comprising a purification step A in which the salicylic acid obtained in the hydroxylation step is brought into contact with a synthetic adsorbent.

7. 2. The method for producing salicylic acid according to claim 1, wherein the reaction is a flow synthesis reaction.

8. 7. The method for producing salicylic acid according to claim 5 or 6, wherein the salicylic acid that has been subjected to the purification step A or B has an HPLC purity of 95 area % or more, contains one or more impurities selected from the aromatic compounds represented by the following formulas (a) to (d), (f) and (g), and the content of each aromatic compound is 0.5 area % or less: 【Chemistry 1】

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