Method for producing salicylic acid ester

Abstract

A method for producing a salicylic acid ester represented by general formula (2), characterized in that salicylic acid and an alcohol represented by general formula (1) are brought into contact with a solid acid catalyst at a reaction temperature of 50-200°C.　Formula (1): X-R-OH (In formula (1), R represents a C1-6 linear or branched alkyl group. X represents a hydrogen atom or a hydroxyl group.) (In formula (2), R and X are each as defined in formula (1).)

Description

Manufacturing method for salicylic acid esters

[0001] The present invention relates to a method for producing salicylic acid esters useful as pharmaceuticals.

[0002] Salicylic acid esters, methyl salicylate and glycol salicylate, have long been widely used as analgesic and anti-inflammatory agents.

[0003] Conventionally, a method for producing methyl salicylate using a batch reactor has been known (Non-Patent Document 1). For example, a method is known in which salicylic acid, methanol, and concentrated sulfuric acid are added to a batch reactor and subjected to an esterification reaction at a high temperature to produce methyl salicylate as shown in the following reaction formula:

[0004]

[0005] Also, a method for producing glycol salicylate using a batch reactor is known (Patent Document 1). For example, a method is known in which salicylic acid, ethylene glycol, and concentrated sulfuric acid are added to a batch reactor and subjected to an esterification reaction at high temperature to produce glycol salicylate according to the following reaction formula:

[0006]

[0007] However, the methods of Non-Patent Document 1 and Patent Document 1 use concentrated sulfuric acid as a catalyst, and a large amount of alkaline water is used to neutralize the concentrated sulfuric acid and unreacted salicylic acid in the reaction solution, generating a large amount of acid waste liquid, which requires a lot of time, cost, and effort to separate from the target product and to treat the waste acid. Thus, more than 15 million tons of sulfuric acid are consumed annually as a "non-recyclable catalyst," resulting in a huge waste of energy and waste emissions, which place a heavy burden on the environment (Patent Document 4). Furthermore, because sulfuric acid is highly toxic and corrosive, the time, cost, and effort required to ensure safety and maintain the plant cannot be ignored. For these reasons, it is desirable to replace the conventional acid-catalyzed reaction process that relies on sulfuric acid with a highly efficient production method that places as little burden on the environment as possible.

[0008] It is generally known that esterification reactions are reversible. In esterification reactions, the ester produced after the reaction undergoes a reverse reaction with water. Therefore, in order to obtain the target ester in high yield, it is necessary to shift the equilibrium of the esterification reaction toward the product system. Known methods for shifting the equilibrium of the esterification reaction toward the product system typically involve using an excess of either the alcohol or carboxylic acid reagent, or using it to remove water and expel it from the system. When performing an esterification reaction in a batch reactor, it is often difficult to remove the water produced in the system, and the reaction requires a lot of time and energy. As is clear from Comparative Example 1 described below, the method of Patent Document 1 requires a long reaction time, resulting in the production of large amounts of impurities represented by the following formulae (a) and (b) (hereinafter, the compound represented by formula (a) may be referred to as SEE, and the compound represented by formula (b) may be referred to as DSE), resulting in a high purification load.

[0009]

[0010] Therefore, there is a need for a highly productive method for producing salicylic acid esters that can produce salicylic acid esters with high selectivity and high yield in a short reaction time, and that is safer, has a lower environmental impact, produces less impurities, and is industrially advantageous. Here, productivity generally means the relative proportion of the product obtained by inputting production factors (equipment, land, buildings, energy, raw materials, labor, time, etc.) into production activities.

[0011] Esterification reactions using an acid catalyst can be divided into two types: one in which the acid catalyst is dissolved in the reaction fluid (homogeneous system), and one in which the acid catalyst exists as a solid in the reaction fluid (heterogeneous system). Heterogeneous systems are further classified into fluidized beds, in which the acid catalyst flows together with the reaction fluid, and fixed beds, in which the acid catalyst is stationary. Esterification reactions using fixed beds are known to enable a higher catalyst concentration per unit space than fluidized beds or homogeneous systems, and also to facilitate separation of the reaction fluid and catalyst. For example, production methods are known in which a fixed bed is used to continuously perform an esterification reaction in order to increase the productivity of the esterification reaction (Patent Document 2, Patent Document 3).

[0012] However, Patent Documents 2 and 3 do not describe a production method for salicylic acid esters such as methyl salicylate and glycol salicylate in which a continuous esterification reaction is carried out using a fixed bed.

[0013] West German Patent No. 164128 JP 2019-172665 A JP 10-279523 A International Publication No. 2007 / 032188

[0014] Akira Shimada, Chemistry and Education, Vol. 59, No. 8 (2011), pp. 422-425

[0015] The present invention provides a highly productive method for producing salicylic acid esters, which can produce salicylic acid esters in a short reaction time with high selectivity and high yield, and which is safer, has a lower environmental impact, produces fewer impurities, and is industrially advantageous. In this specification, "selectivity" refers to the proportion of salicylic acid esters produced among multiple products, and "productivity" is an index of the yield of the target product obtained per unit time.

[0016] The present inventors have discovered that salicylic acid esters can be produced in high selectivity and good yield in a short reaction time by continuously passing salicylic acid and an alcohol through a column packed with a solid acid catalyst. This method is safer than conventional methods, produces fewer impurities, has a low environmental impact, and is an industrially advantageous method for producing salicylic acid esters continuously and inexpensively with high productivity. The present invention has the following features.

[0017] [1] A method for producing a salicylic acid ester represented by the following general formula (2), which comprises contacting salicylic acid and an alcohol represented by the following general formula (1) with a solid acid catalyst at a reaction temperature of 50°C to 200°C: X-R-OH (1) (In formula (1), R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and X represents a hydrogen atom or a hydroxyl group.)

[0018]

[0019] (In formula (2), R and X are as defined in formula (1)).

[0020] [2] The method for producing a salicylic acid ester according to [1], wherein the contact method is a method of passing the salicylic acid and the alcohol through a column packed with the solid acid catalyst.

[0021] [3] The method for producing a salicylic acid ester according to [1] or [2], wherein the solid acid catalyst is based on an organic or inorganic adsorbent and has a strongly acidic ion exchange group.

[0022] [4] The method for producing a salicylic acid ester according to any one of [1] to [3], wherein the solid acid catalyst has an average particle size of 1 μm to 2000 μm.

[0023] [5] The specific surface area of ​​the solid acid catalyst is 200 m ２ / g to 2000m ２ / g, [1] to [4].

[0024] [6] The method for producing a salicylic acid ester according to any one of [1] to [5], wherein the reaction temperature is 70°C to 180°C.

[0025]

[0026] Fig. 1 is a flow diagram of a flow synthesis system showing one embodiment of the method for producing a salicylic acid ester of the present invention. Fig. 2 is a flow diagram of a flow synthesis system equipped with a back pressure valve showing another embodiment of the method for producing a salicylic acid ester of the present invention.

[0027] The present invention will be described in detail below.

[0028] [Method for Producing Salicylic Acid Ester] The method for producing a salicylic acid ester of the present invention involves contacting a solution (hereinafter sometimes referred to as a salicylic acid solution) of salicylic acid and an alcohol represented by the following general formula (1) (hereinafter sometimes referred to as "alcohol (1)") with a solid acid catalyst. Preferably, the solution of salicylic acid and the alcohol is continuously passed through a column packed with the solid acid catalyst to cause an esterification reaction (hereinafter sometimes referred to as the "esterification reaction of the present invention"), thereby continuously producing a salicylic acid ester represented by the following general formula (2) (hereinafter sometimes referred to as "salicylic acid ester (2)") (hereinafter sometimes referred to as the "esterification step of the present invention"). X-R-OH ... (1) (In formula (1), R represents a linear or branched alkyl group having 1 to 6 carbon atoms, and X represents a hydrogen atom or a hydroxyl group.)

[0029]

[0030] (In formula (2), R and X are as defined in formula (1)).

[0031] Specific examples of the linear or branched alkyl group having 1 to 6 carbon atoms represented by R in the above formulas (1) and (2) include lower alkyl groups such as methyl, ethyl, linear or branched propyl, linear or branched butyl, linear or branched pentyl, and linear or branched hexyl. When X is a hydrogen atom, alcohol (1) is a monohydric alcohol, and when X is a hydroxyl group, alcohol (1) is a dihydric alcohol.

[0032] <Esterification Step> The esterification step of the present invention refers to a step of esterifying salicylic acid with an alcohol. There are no particular limitations on the method for carrying out the esterification step. For example, as shown in Figures 1 and 2, a flow synthesis system may be used in which a salicylic acid solution prepared in a preparation tank 1 is continuously passed through a reaction vessel 3 equipped with a column packed with a solid acid catalyst 2 of the present invention, the salicylic acid is continuously esterified with an alcohol in the presence of the solid acid catalyst in the column, and the reaction product liquid containing a salicylic acid ester flowing out of the column is collected in a recovery tank 4.

[0033] The flow synthesis system of Figure 2 has the same configuration as the flow synthesis system of Figure 1, except that a back pressure valve 5 is provided in the flow path that feeds the reaction product liquid from the reaction vessel 3 to the recovery tank 4. This flow synthesis system will be described later.

[0034] <Salicylic Acid Solution> Salicylic acid, which is a raw material for producing the salicylic acid ester (2), may be a commercially available product or may be obtained by a known method.

[0035] As the alcohol (1), an alcohol corresponding to the target salicylic acid ester (2) is usually used. For example, when producing methyl salicylate, it is preferable to use methanol, and when producing ethylene glycol salicylate, it is preferable to use ethylene glycol.

[0036] The number of carbon atoms in R in the formula (1) is usually 1 to 6, preferably 1 to 4, and particularly preferably 1 to 2. R is a linear or branched alkyl group, preferably a linear alkyl group.

[0037] The amount of alcohol (1) used is not particularly limited as long as it is an amount that allows the esterification reaction of the present invention to proceed, but it is usually 1 g to 100 g, and from the viewpoint of productivity, preferably 3 g to 20 g, per 1 g of salicylic acid.

[0038] The solvent used for the salicylic acid solution can be any solvent that can dissolve salicylic acid and does not inhibit the progress of the reaction. The solvent used in the present invention is usually preferably an alcohol (1) that can give the target salicylic acid ester (2) through an esterification reaction. For example, from the viewpoint of suppressing the formation of impurities, when methyl salicylate is produced, the alcohol (1) is preferably methanol, and when glycol salicylate is produced, the alcohol (1) is preferably ethylene glycol.

[0039] These solvents may be used alone or in any combination and ratio of two or more. From the viewpoint of ease of solvent removal and suppression of impurities, it is preferable to use the solvent alone.

[0040] The concentration of salicylic acid in the salicylic acid solution is not particularly limited as long as it does not interfere with flow through the column. 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 5% by mass to 75% by mass, and particularly preferably 10% by mass to 70% by mass. If the concentration of salicylic acid is too low, the reaction time may be prolonged, and if it is too high, the reaction may not proceed sufficiently.

[0041] <Solid Acid Catalyst> The solid acid catalyst used is one that promotes the esterification reaction between salicylic acid and the alcohol (1). The solid acid catalyst used in the present invention is usually a solid acid catalyst having a substrate and an ion exchange group. The substrate can be an organic or inorganic adsorbent.

[0042] Examples of organic adsorbents include aromatic adsorbents such as styrene / divinylbenzene copolymers and divinylbenzene polymers, and acrylic (co)polymers such as methyl methacrylate / bis(methacrylic acid)ethylene glycol copolymers. From the viewpoints of reactivity and durability of the solid acid catalyst, aromatic adsorbents are preferred, and styrene / divinylbenzene copolymers are particularly preferred.

[0043] When an organic adsorbent is used as the substrate of the solid acid catalyst, the degree of crosslinking of the organic adsorbent is usually 1% by mass to 20% by mass, preferably 2% by mass to 10% by mass. For example, in the case of a styrene / divinylbenzene copolymer, the degree of crosslinking represents the content (% by mass) of divinylbenzene as a crosslinking agent. If the degree of crosslinking is within the above range, the reactivity and durability of the solid acid catalyst can be improved.

[0044] Examples of inorganic adsorbents include silica gel and alumina, with silica gel being preferred from the standpoints of cost and reactivity.

[0045] As the ion exchange group of the solid acid catalyst, generally, a strongly acidic ion exchange group or a weakly acidic ion exchange group can be used. From the viewpoint of promoting the esterification reaction between salicylic acid and the alcohol (1), a strongly acidic ion exchange group is preferred, and among them, a sulfonic acid group or an alkylsulfonic acid group is particularly preferred.

[0046] The structure of the solid acid catalyst is not particularly limited, and gel-type, porous-type, hyperporous-type, or macroporous-type catalysts can be used. The shape of the solid acid catalyst is not particularly limited, and particulate, pellet-type, film-like, or cylindrical solid acid catalysts can be used. From the viewpoint of column packing, particulate or pellet-like catalysts are preferred, and particulate catalysts are more preferred. The solid acid catalyst is usually packed into a column as shown in Figures 1 and 2 before use. The size of the solid acid catalyst is not particularly limited, as long as it can be packed into a column and can catalyze a reaction.

[0047] When the solid acid catalyst is in the form of particles, the particle size of the solid acid catalyst is usually 1 μm to 2000 μm, and from the viewpoint of industrial handleability, etc., it is preferably 4 μm to 1000 μm. The most frequent particle size of the solid acid catalyst is usually 50 μm to 2000 μm, preferably 150 μm to 1500 μm, and particularly preferably 250 μm to 1000 μm. Here, the particle size of the solid acid catalyst is the average particle size measured in accordance with a standard method using a laser diffraction particle size distribution measurement method.

[0048] The specific surface area of ​​the solid acid catalyst used in the present invention is 100 m ２ / g to 2000m ２ From the viewpoint of reactivity, it is preferably 200 m ２ / g to 1000m ２ By using a solid acid catalyst having a specific surface area within the above range, the reaction can be carried out efficiently, and productivity can be increased.

[0049] Any solid acid catalyst that satisfies the above conditions can be used as the solid acid catalyst for use in the present invention, and examples thereof include commercially available products such as DIAION (registered trademark) SK104H, SK1BH, UBK530K, and RCP145H manufactured by Mitsubishi Chemical Corporation; Amberlite (registered trademark) XH2071H manufactured by Organo Corporation; and TAYCACURE (registered trademark) SAC-6 manufactured by Tayca Corporation. Among these, SK104H, SK1BH, and UBK530K are preferred from the viewpoints of reactivity and productivity. Details of these commercially available solid acid catalysts are shown in Table 1 below.

[0050]

[0051] In Table 1 above, "styrene-DVB" refers to "styrene / divinylbenzene copolymer."

[0052] These solid acid catalysts may be used alone or in combination of two or more.

[0053] <Flow Synthesis System> A flow synthesis system suitable for carrying out the method for producing a salicylic acid ester of the present invention is a system that uses a reaction vessel having an inlet and an outlet, and simultaneously performs "feeding of raw materials through the inlet," "reaction," and "recovery of product from the outlet." This concept is well known to those skilled in the art (for example, "Flow Micro Synthesis" (Kagaku Dojin), published in 2014, p. 9). In the flow synthesis system of the present invention, the shape of the column packed with the solid acid catalyst is not particularly limited as long as it can be packed with the solid acid catalyst and is suitable for the reaction, but a tubular column can usually be used.

[0054] The material of the column according to the present invention is not particularly limited. Examples of the column material include glass, stainless steel (SUS), Hastelloy, and Teflon (registered trademark), with stainless steel or Hastelloy being preferred. The size of the column is not particularly limited as long as it is suitable for the reaction. For example, a thin tubular column having a diameter of 10 mm and a length of 100 mm, or a diameter of 10 mm and a length of 250 mm can be used.

[0055] An example of a catalyst-packed column is a 4.6 mm x 100 mm SUS column or Hastelloy column closely packed with a solid acid catalyst.

[0056] The tubes used for the flow path for introducing a salicylic acid solution containing the reaction substrate salicylic acid and the alcohol (1) into the column and for discharging the reaction product liquid from the column are not particularly limited, and a specific example of the tubes is a Teflon (registered trademark) tube with an inner diameter of 1 mm.

[0057] The introduction of the salicylic acid solution containing the reaction substrates salicylic acid and alcohol (1) into the column and the discharge of the reaction product liquid can be carried out by liquid transfer using a syringe pump, a diaphragm pump, a mass controller, or the like.

[0058] A back pressure valve and an in-line analyzer may be provided in the flow path on the reaction product liquid outflow side from the column.

[0059] <Reaction Conditions> The reaction temperature of the esterification reaction of the present invention means the external temperature of a column packed with the solid acid catalyst of the present invention. From the viewpoints of reactivity, productivity, etc., the upper limit of the reaction temperature is usually 50°C or higher, preferably 70°C or higher, more preferably 90°C or higher, even more preferably 100°C or higher, and particularly preferably 105°C or higher, and the lower limit is usually 200°C or lower, preferably 180°C or lower, more preferably 160°C or lower, even more preferably 150°C or lower, and particularly preferably 140°C or lower. If the reaction temperature is lower than the above lower limit, the reactivity may decrease. If the reaction temperature is higher than the above upper limit, the yield and purity may decrease due to side reactions, or the solid acid catalyst may deteriorate.

[0060] The lower limit of the reaction pressure for the esterification reaction of the present invention is usually 0.1 MPa or more, preferably 0.2 MPa or more, and particularly preferably 0.3 MPa or more, and the upper limit is usually 1 MPa or less, preferably 0.8 MPa or less, and particularly preferably 0.6 MPa or less. By carrying out the esterification reaction at a reaction pressure within the above range, the reaction can be carried out efficiently in a homogeneous system even at temperatures above the boiling point of the solvent. The reaction pressure can be adjusted by applying back pressure to the flow path after passing through the column packed with the solid acid catalyst of the present invention, using a back pressure valve or the like. When the reaction temperature is set to be above the boiling point of the solvent used, the reaction can be carried out by adjusting the pressure so that the solvent remains liquid even at the desired reaction temperature. The reaction pressure is not particularly limited, but is usually 0.1 MPa to 1 MPa.

[0061] The reaction time of the esterification reaction of the present invention refers to the time (residence time) during which the reaction solution remains in the column packed with the solid acid catalyst. The reaction time varies depending on the reaction temperature and reaction pressure, but is typically 1 minute to 120 minutes. When producing ethylene glycol salicylate, it is difficult to remove the by-products SEE and DSE by purification procedures such as distillation, resulting in a high purification load. Therefore, it is preferable to suppress the amount of by-products produced by using the reaction conditions described above.

[0062] <Post-treatment> Isolation of the target salicylic acid ester (2) from the reaction product solution obtained in the esterification step of the present invention may be carried out by treatments such as neutralization, separation, concentration, and filtration of the reaction product solution, or by known purification means such as crystallization and column chromatography.

[0063] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples.

[0064] [Abbreviations] In the examples, the abbreviations represent the following compounds: SA: salicylic acid SE: ethylene glycol salicylate SM: methyl salicylate SEE: ethylene glycol ether salicylate DSE: ethylene glycol ether disalicylate SEE and DSE are by-products. The structural formulas of each compound are as follows:

[0065]

[0066] [Flow synthesis apparatus] The following flow synthesis apparatus was used in the following examples and comparative examples: "MCR-1000" manufactured by EYELA

[0067] [Analysis Method 1 (HPLC)] The apparatus and conditions used for analyzing the reaction product liquid in the following Examples and Comparative Examples are as follows: <Apparatus and Conditions> Instrument: Agilent 1290 infinity Column: Eclipse XDB-C8 5 μm, 4.6 × 150 μm Mobile phase A: 50 mM ammonium acetate Mobile phase B: acetonitrile Gradient conditions: Mobile phase B % (min) 0 (0) - 20 (5) - 85 (10) - 100 (15) Flow rate: 1 mL / min Wavelength: 280 nm

[0068] Comparative Example 1: Production of ethylene glycol salicylate, acid catalyst: sulfuric acid. 5 g (0.036 mol) of salicylic acid, 7.78 g (1.40 VR, 0.125 mol) of ethylene glycol, and 0.296 g (0.16 VR, 0.003 mol) of 98% sulfuric acid were added to a ChemStation (EYELA) test tube, and the internal temperature was raised to 115°C. After stirring at an internal temperature of 115°C for 3 hours, the internal temperature was increased to 107°C for 9 hours. The resulting reaction product solution was analyzed using Analysis Method 1. The yields were SA: 7.3%, SE: 77.3%, SEE: 11.2%, DSE: 4.3%, conversion: 92.7%, and selectivity: 83.3%. The results are shown in Table 2.

[0069] Example 1: Production of ethylene glycol salicylate Solid acid catalyst: Solid acid catalyst 1 (DIAION (registered trademark) SK104H) 5.86 g of solid acid catalyst 1 [Mitsubishi Chemical Corporation, trade name: DIAION (registered trademark) SK104H, degree of crosslinking: 4%, average particle size: 730 μm] was packed into a stainless steel column tube (Tokyo Rikakikai, inner diameter 10 mm, length 100 mm) (the void space in the column is as shown in Table 2) and attached to a column-type flow reactor (EYELA, MCR-1000 model). 5 g (0.036 mol) of salicylic acid and 32.3 g (5.8 VR, 0.52 mol) of ethylene glycol were added to a 100 mL dissolution vessel and dissolved at room temperature. The resulting solution was drawn into a 10 mL syringe pump and sent to the column-type flow reactor set at a flow rate of 0.039 mL / min (residence time 60 minutes) and a column temperature of 105 ° C., and the reaction was initiated. The resulting reaction product solution was analyzed by analysis method 1, and the yield was SA: 11.2%, SE: 82.7%, SEE: 5.5%, DSE: 0.7%, conversion rate 88.8%, and selectivity 93.1%. The results are shown in Table 2.

[0070] Example 2: Production of ethylene glycol salicylate Solid acid catalyst: Solid acid catalyst 3 (DIAION (registered trademark) UBK530K)] The reaction was carried out in the same manner as in Example 1, except that 5.86 g of Solid Acid Catalyst 1 was replaced with 5.97 g of Solid Acid Catalyst 3 [Mitsubishi Chemical Corporation, trade name: DIAION (registered trademark) UBK530K, average particle size: 360 μm] (the void space in the column is as shown in Table 2), the flow rate was changed from 0.039 mL / min (residence time 60 min) to 0.042 mL / min (residence time 60 min), and the column set temperature was changed from 105° C. to 110° C. The resulting reaction product solution was analyzed by Analysis Method 1, and the yields were SA: 7.2%, SE: 82.3%, SEE: 10.2%, DES: 0.3%, the conversion rate was 92.8%, and the selectivity was 88.7%. The results are shown in Table 2.

[0071] Example 3: Production of ethylene glycol salicylate Solid acid catalyst: Solid acid catalyst 5 (Amberlite® XH2071H) The reaction was carried out in the same manner as in Example 1, except that 5.86 g of Solid Acid Catalyst 1 was replaced with 5.30 g of Solid Acid Catalyst 5 [Organo Corporation, trade name: Amberlite® XH2071H] (the void space in the column is as shown in Table 2), and the flow rate was changed from 0.039 mL / min (retention time 60 min) to 0.036 mL / min (retention time 90 min). The resulting reaction product solution was analyzed using Analysis Method 1. The yield was SA 13.2%, SE 81.2%, SEE 4.8%, DSE 0.5%, conversion 86.8%, and selectivity 93.5%. The results are shown in Table 2.

[0072] Example 4: Production of ethylene glycol salicylate Solid acid catalyst: Solid acid catalyst 6 (TAYCACURE (registered trademark) SAC-6) In Example 1, 5.86 g of solid acid catalyst 1 was replaced with solid acid catalyst 6 [Tayca Corporation, trade name: TAYCACURE (registered trademark) SAC-6, average particle size: 200 μm, specific surface area: 450 m ２ / g] 5.0 g (void in the column as shown in Table 2), the flow rate was changed from 0.039 mL / min (residence time 60 minutes) to 0.049 mL / min (residence time 90 minutes), and the column set temperature was changed from 105 ° C. to 130 ° C. The reaction was carried out in the same manner except that. The obtained reaction product solution was analyzed by analysis method 1, and the yield was SA 10.9%, SE 81.0%, SEE 7.7%, DSE 0.4%, conversion 89.1%, and selectivity 90.9%. The results are shown in Table 2.

[0073] In Table 2 and Table 3 shown later, "productivity" represents the yield of the target product obtained per unit time, and is the value obtained by dividing the yield of the target product by the reaction time.

[0074]

[0075] As is clear from Examples 1 to 4 and Comparative Example 1 in Table 2, by using a solid acid catalyst and adopting a flow reaction system, ethylene glycol salicylate can be produced with high productivity while eliminating the need for waste acid treatment and suppressing the generation of impurities.

[0076] Comparative Example 2: Production of methyl salicylate, acid catalyst: sulfuric acid. 5 g (0.036 mol) of salicylic acid, 10.2 g (2.57 VR, 0.317 mol) of methanol, and 0.353 g (0.0036 mol) of 98% sulfuric acid were added to a test tube of a ChemStation (EYELA Corporation), and the jacket temperature was raised to 115°C (reflux) and the mixture was stirred for 4 hours. The resulting reaction product solution was analyzed using Analysis Method 1, and the yields were SA: 60.8% and SM: 39.2%. The results are shown in Table 3.

[0077] Example 5: Production of methyl salicylate Solid acid catalyst: Solid acid catalyst 1 (DIAION® SK104H) Solid acid catalyst 1 [Mitsubishi Chemical Corporation, product name: DIAION® SK104H] (5.86 g) was packed into a stainless steel column tube (Tokyo Rikakikai, inner diameter 10 mm, length 100 mm) (the void space within the column is as shown in Table 3) and attached to a column-type flow reactor (EYELA, MCR-1000 model). 5 g (0.036 mol) of salicylic acid and 19.8 g (5VR, 0.616 mol) of methanol were added to a 100 mL dissolution vessel and dissolved at room temperature. The resulting solution was drawn into a 10 mL syringe pump and delivered to the column-type flow reactor, which was set at a flow rate of 0.305 mL / min (retention time 10 min) and a column temperature of 120°C, to initiate the reaction. The resulting reaction product solution was analyzed by analytical method 1, and the yields were SA: 12.7% and SM: 87.3%. The results are shown in Table 3.

[0078] Example 6: Production of methyl salicylate Solid acid catalyst: Solid acid catalyst 2 (DIAION® SK1BH) The reaction was carried out in the same manner as in Example 5, except that 5.86 g of Solid Acid Catalyst 1 was replaced with 5.85 g of Solid Acid Catalyst 2 [Mitsubishi Chemical Corporation, product name: DIAION® SK1BH] (the void space in the column is as shown in Table 3), and the flow rate was changed from 0.305 mL / min (retention time 10 min) to 0.155 mL / min (retention time 20 min). The resulting reaction product solution was analyzed using Analysis Method 1, and the yield was SA 6.9% and SM 93.1%. The results are shown in Table 3.

[0079]

[0080] As is clear from Examples 5 and 6 and Comparative Example 2 in Table 3, by using a solid acid catalyst and adopting a flow reaction system, waste acid treatment is not required and methyl salicylate can be produced with high productivity.

[0081] The method for producing a salicylic acid ester of the present invention can produce a salicylic acid ester in a short reaction time with high selectivity and high yield, and with high productivity. Furthermore, the method is safe, has a low environmental impact, and produces only a small amount of impurities. Furthermore, the method is capable of continuously producing a salicylic acid ester, and is therefore industrially useful.

[0082] Although the present invention has been described in detail using 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 present invention. This application is based on Japanese Patent Application No. 2022-047108, filed on March 23, 2022, and is incorporated by reference in its entirety.

[0083] 1 Preparation tank 2 Solid acid catalyst 3 Reaction vessel 4 Recovery tank 5 Back pressure valve

Claims

1. A method for producing a salicylic acid ester represented by the following general formula (2), comprising contacting salicylic acid and an alcohol represented by the following general formula (1) with a solid acid catalyst at a reaction temperature of 50°C to 200°C. X-R-OH...(1) (In formula (1), R represents a linear or branched alkyl group having 1 to 6 carbon atoms. X represents a hydrogen atom or a hydroxyl group.) 【Chemistry 1】 (In formula (2), R and X are defined as in formula (1).)

2. 2. The method for producing a salicylic acid ester according to claim 1, wherein the contact method is a method in which the salicylic acid and the alcohol are passed through a column packed with the solid acid catalyst.

3. 2. The method for producing a salicylic acid ester according to claim 1, wherein the solid acid catalyst is based on an organic or inorganic adsorbent and has a strongly acidic ion exchange group.

4. The method for producing a salicylic acid ester according to claim 1, wherein the average particle size of the solid acid catalyst is 1 μm to 2000 μm.

5. The specific surface area of ​​the solid acid catalyst is 200 m ２ / g to 2000m ２ The method for producing a salicylic acid ester according to claim 1, wherein the amount of the salicylic acid ester is 100% by mass / g.

6. The method for producing a salicylic acid ester according to any one of claims 1 to 5, wherein the reaction temperature is from 70°C to 180°C.

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