Method for producing acetaminophen

Abstract

A method for producing acetaminophen, the method comprising passing a p-nitrophenol-containing solution, together with an acetylating agent and hydrogen, through a column packed with a catalyst to thereby cause the p-nitrophenol to undergo an acetamination reaction. The method is characterized in that the catalyst is a supported-metal catalyst comprising a synthetic adsorbent and a metal element supported thereon and the acetamination reaction is conducted at a temperature of 0-60°C and a pressure of 0.1-1 MPa. By this method, acetaminophen can be safely, inexpensively, and continuously produced at a low reaction temperature and a low reaction pressure, while attaining high selectivity and satisfactory yield.

Description

Technical Field

[0001] The present invention relates to a method for producing acetaminophen useful as a pharmaceutical.

Background Art

[0002] Acetaminophen is an antipyretic analgesic that has been widely used for a long time and is a highly safe drug that can be administered not only to adults but also to children.

[0003] Conventionally, as a method for producing acetaminophen, a batch-type reaction method is known. For example, a method is known in which paranitrophenol, acetic acid, and a metal catalyst are added to a reaction vessel, hydrogen is added, and the reaction is carried out at a high temperature to produce acetaminophen (Patent Document 1). However, in the method of Patent Document 1, the reaction temperature is high, and furthermore, since it is accompanied by intense heat generation when the catalyst is added, it is difficult to control the reaction. Therefore, a safer and more productive industrial production method is desired.

[0004] As a method for increasing productivity, there is a continuous reaction method. For example, a method is known in which paranitrophenol is added to an acetic anhydride / acetic acid solution to form a solution, and the solution is passed through a column filled with a noble metal catalyst, specifically a Pd / C catalyst, at a hydrogen pressure of 8 MPa to 10 MPa and a reaction temperature of 90 to 140 °C to continuously produce acetaminophen (Patent Document 2). However, the method of Patent Document 2 requires equipment that can withstand very high pressure conditions, and the reaction temperature is also high. In addition, when reacting continuously under high temperature and high pressure for a long time, the catalyst may deteriorate more quickly.

[0005] Therefore, as a continuous production method, a production method that can carry out the reaction under milder conditions, is energy-saving, and has a low cost for equipment and the like is desired.

[0006]

Patent Document 1

[0007] An object of the present invention is to provide a method for continuously producing acetaminophen safely and inexpensively with high selectivity and good yield at a low reaction temperature and a low reaction pressure.

[0008] The present inventors have found that when a solution containing p-nitrophenol is continuously passed through a column filled with a catalyst in which a metal element is supported on a synthetic adsorbent together with an acetylating agent and hydrogen for reaction, acetaminophen can be obtained safely and inexpensively with high selectivity and good yield even at a low reaction pressure and a low reaction temperature. The present invention is characterized by the following.

[0009] [1] A method for producing acetaminophen by subjecting a solution containing p-nitrophenol to an acetamidation reaction by passing it through a column filled with a catalyst together with an acetylating agent and hydrogen, wherein the catalyst is a metal-supported catalyst in which a metal element is supported on a synthetic adsorbent, and the reaction temperature of the acetamidation reaction is 0°C to 60°C and the reaction pressure is 0.1 MPa to 1 MPa. A method for producing acetaminophen, characterized by the above.

[0010] [2] The method for producing acetaminophen according to [1], characterized in that the synthetic adsorbent is a styrene / divinylbenzene copolymer.

[0011] [3] The method for producing acetaminophen according to [1] or [2], characterized in that the styrene / divinylbenzene copolymer is a styrene / divinylbenzene copolymer and the metal element is palladium and / or platinum.

[0012] [4] The method for producing acetaminophen according to any one of [1] to [3], characterized in that the synthetic adsorbent is a porous synthetic adsorbent having a pore volume of 0.1 mL / g to 3.0 mL / g.

[0013] [5] The synthetic adsorbent has a BET specific surface area of 200 m 2 / g to 2000 m 2 / g, and the method for producing acetaminophen according to any one of [1] to [4].

[0014] [6] The method for producing acetaminophen according to any one of [1] to [5], characterized in that the synthetic adsorbent is a porous synthetic adsorbent having a most frequent pore radius of 1 nm to 50 nm.

[0015] [7] The method for producing acetaminophen according to any one of [1] to [6], characterized in that the metal element loading amount of the metal-supported catalyst is 1% by mass to 25% by mass based on the metal-supported catalyst. [Advantages of the Invention]

[0016] According to the method for producing acetaminophen of the present invention, acetaminophen can be continuously produced safely and inexpensively with high selectivity and good yield at a low reaction temperature and a low reaction pressure. [Brief Description of the Drawings]

[0017]

Figure 1

Figure 2

[0018] Hereinafter, the present invention will be described in detail.

[0019] [Method for producing acetaminophen] The method for producing acetaminophen of the present invention is a method of continuously producing acetaminophen by subjecting a solution containing p-nitrophenol (hereinafter sometimes referred to as "p-nitrophenol solution") to an acetamidation reaction by continuously passing it through a column filled with a catalyst together with an acetylating agent and hydrogen. (Hereinafter, this step may sometimes be referred to as "the acetamidation step of the present invention"). The catalyst is a metal-supported catalyst in which a metal element is supported on a synthetic adsorbent (hereinafter sometimes referred to as "the metal-supported catalyst of the present invention"), and the reaction temperature of the acetamidation reaction is 0°C to 60°C, and the reaction pressure is 0.1 MPa to 1 MPa.

[0020] [Acetamidation step] There are no particular restrictions on the method for carrying out the acetamidation step of the present invention. For example, as shown in FIGS. 1 and 2, a reaction vessel 3 equipped with a column 2 filled with the metal-supported catalyst 1 of the present invention is continuously passed with a p-nitrophenol solution together with an acetylating agent and hydrogen, and p-nitrophenol in the column 2 is continuously subjected to an acetamidation reaction with an acetylating agent and hydrogen in the presence of the metal-supported catalyst of the present invention, and a reaction product solution containing acetaminophen flowing out from the column 2 is received in a recovery tank 4 by a flow synthesis system. The flow synthesis system of FIG. 2 is different from the flow synthesis system of FIG. 1 in that a back pressure valve 5 is provided in the flow path for feeding the reaction product solution from the reaction vessel 3 to the recovery tank 4, and the other configurations are the same. This flow synthesis system will be described later.

[0021] [P-nitrophenol solution] As the p-nitrophenol which is a raw material for producing acetaminophen, a commercially available product may be used, or one obtained by applying a known method may be used.

[0022] As the solvent used for the p-nitrophenol solution, there is no particular limitation as long as it can dissolve p-nitrophenol and does not inhibit the progress of the reaction. Examples of such solvents include alcohol solvents such as methanol, ethanol, and propanol; and carboxylic acid solvents such as formic acid, acetic acid, and propionic acid. From the viewpoints of cost, reactivity, etc., methanol and acetic acid are preferably used.

[0023] These solvents may be used alone or in any combination and ratio by mixing two or more of them.

[0024] The concentration of p-nitrophenol in the p-nitrophenol solution is not particularly limited as long as there is no hindrance to the flow through the column. From the viewpoints of productivity and reactivity, the concentration of p-nitrophenol in the p-nitrophenol solution is usually 0.1% by mass to 80% by mass, preferably 10% by mass to 70% by mass, and particularly preferably 20% by mass to 60% by mass.

[0025] <Hydrogen> The amount of hydrogen (hydrogen gas) used is not particularly limited as long as the reaction proceeds. The amount of hydrogen (hydrogen gas) used is usually 1 mol or more, preferably 3 mol or more, and usually 20 mol or less, preferably 10 mol or less, per 1 mol of p-nitrophenol.

[0026] There is no particular limitation on the method of supplying hydrogen. Hydrogen may be continuously injected and mixed into the p-nitrophenol solution or the p-nitrophenol solution containing an acetylating agent in the flow path before column 2, or may be directly pressed into column 2. Hydrogen may be used by dissolving a part or all of it in the solvent of the p-nitrophenol solution.

[0027] Hydrogen can also be used by mixing it with an inert gas such as nitrogen, helium, or argon.

[0028] <Acetylating agent> The acetylating agent is not particularly limited as long as it can acetylate an amino group. Usually, one or more of acetic anhydride, acetyl chloride, etc. are used as the acetylating agent. From the viewpoints of cost and reactivity, acetic anhydride is preferred.

[0029] The amount of the acetylating agent used is not particularly limited. From the viewpoint of reactivity, the amount of the acetylating agent used is usually 1 mol to 10 mol, preferably 1 mol to 5 mol, more preferably 1 mol to 2 mol, per 1 mol of p-nitrophenol.

[0030] The acetylating agent may be premixed in the solution containing p-nitrophenol, or may be injected into the feeding flow path of the p-nitrophenol solution before and / or after column 2 to be continuously mixed with the p-nitrophenol solution, or may be injected into column 2 separately from the p-nitrophenol solution to be continuously mixed with the p-nitrophenol solution in column 2. From the viewpoint of quickly converting the unstable intermediate into the target product, it is preferable that the acetylating agent is continuously mixed with the p-nitrophenol solution in the flow path before column 2.

[0031] <Metal-supported catalyst> The metal-supported catalyst of the present invention is a catalyst in which a metal element is supported on a synthetic adsorbent, and the metal is immobilized.

[0032] The metal element that can be used in the metal-supported catalyst of the present invention is not particularly limited as long as it has the activity to reduce a nitro group. Usually, palladium (Pd), platinum (Pt), rhodium (Rh), ruthenium (Ru), Ag (silver), and mixtures of two or more of these can be used. Among these metal elements, Pd alone, or a mixture of Pd and at least one selected from Pt, Rh, Ru, and Ag is preferred. From the viewpoint of catalyst performance, Pd and / or Pt, particularly Pd alone, is preferred.

[0033] From the viewpoints of catalyst performance and cost, the content of the metal element in the metal-supported catalyst of the present invention is usually 0.1% by mass or more, preferably 1% by mass or more, more preferably 3% by mass or more, particularly preferably 5% by mass or more as the lower limit, and usually 25% by mass or less, preferably 20% by mass or less, more preferably 15% by mass or less, particularly preferably 10% by mass or less as the upper limit.

[0034] In the present invention, the synthetic adsorbent is a porous synthetic adsorbent composed of a porous organic polymer produced by chemical synthesis.

[0035] Examples of the synthetic adsorbent used in the present invention include polymers or copolymers of aromatic, substituted aromatic, or acrylic systems (hereinafter, the "polymer or copolymer" may be referred to as "(co)polymer" in some cases).

[0036] Examples of the aromatic (co)polymer include styrene / divinylbenzene copolymer and divinylbenzene polymer. Examples of the substituted aromatic (co)polymer include bromostyrene / divinylbenzene copolymer. Examples of the acrylic (co)polymer include methacrylate-based (co)polymers such as methyl methacrylate / ethylene glycol bis(methacrylate) copolymer.

[0037] Among these, aromatic (co)polymers are preferred, styrene / divinylbenzene-based copolymers such as styrene / divinylbenzene copolymer and bromostyrene / divinylbenzene copolymer are more preferred, and styrene / divinylbenzene copolymer is particularly preferred. The copolymer has a cross-linked structure insoluble in organic solvents and is stable in acidic or alkaline solutions.

[0038] Since the synthetic adsorbent used in the present invention has little influence on the reaction, those having substantially no functional groups such as ion exchange groups, for example, those having an ion exchange capacity of less than 1 meq / g or non-polar ones are preferred.

[0039] The pore volume of the porous 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.

[0040] The BET specific surface area of the porous synthetic adsorbent is usually 200 m 2 / g to 2000 m 2 / g, preferably 300 m 2 / g to 1500 m 2 / g, more preferably 400 m 2 / g to 1000 m 2 / g, and particularly preferably 500 m 2 / g to 700 m 2 / g for the purpose of improving reactivity.

[0041] The most frequent pore radius of the porous 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.

[0042] The synthetic adsorbent used in the present invention is preferably a porous synthetic adsorbent having relatively large pores.

[0043] In the present invention, the pore volume, BET specific surface area, and most frequent pore radius of the porous synthetic adsorbent can be measured according to a conventional method by the nitrogen gas adsorption method.

[0044] The shape and size of the synthetic adsorbent are not particularly limited as long as it can be filled in a column and does not hinder the flow of the reaction solution. As the synthetic adsorbent, particulate, pellet, membrane, and columnar forms can be used, but from the viewpoint of packing properties, particulate forms are more preferable.

[0045] 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 and the like, 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 50 μm or more, preferably 150 μm or more, particularly preferably 250 μm or more.

[0046] The particle size of the synthetic adsorbent is the average particle size measured according to a conventional method by a laser diffraction particle size distribution measurement method.

[0047] Examples of the synthetic adsorbent used in the present invention include Diaion (registered trademark) HP20SS, HP20, HP21, Sepabeads (registered trademark) SP20SS manufactured by Mitsubishi Chemical Corporation; Amberlite (registered trademark) XAD TM -2, XAD TM 4, XAD TM 7HP and other commercially available products can be used. Among these, from the viewpoint of reactivity, HP20SS, HP20, and SP20SS are preferable.

[0048] Details of these commercially available synthetic adsorbents are shown in Table 1 below.

[0049]

Table 1

[0050] Examples of the metal-supported catalyst of the present invention include a catalyst in which Pd is supported on a synthetic adsorbent made of a styrene / divinylbenzene copolymer (hereinafter sometimes referred to as "Pd / PS-DVB"), and a catalyst in which Pt is supported on a synthetic adsorbent made of a styrene / divinylbenzene copolymer (hereinafter sometimes referred to as "Pt / PS-DVB"). Among them, Pd / PS-DVB is particularly preferable.

[0051] By using such a metal-supported catalyst of the present invention, acetaminophen can be obtained with high selectivity, good yield, high efficiency, safety, and low cost even at low pressure and low temperature.

[0052] The metal-supported catalyst of the present invention can be produced by a conventionally known method such as the method described in JP-A-2008-114164. For example, it can be produced by adding a synthetic adsorbent and a metal salt to an organic solvent, stirring well, filtering the produced metal salt-adsorbed synthetic adsorbent, washing with water and methanol, and drying.

[0053] <Flow synthesis system> A flow synthesis system suitable for carrying out the method for producing acetaminophen of the present invention means a system that uses a reaction vessel having an inlet and an outlet and simultaneously performs "input of raw materials from the inlet", "reaction", and "recovery of products from the outlet", and the concept is well known to those skilled in the art (for example, "Flow Micro Synthesis" (Kagaku Dojin), published in 2014, page 9). In this flow synthesis system, the column filled with the metal-supported catalyst of the present invention is a thin tube.

[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). The size of the column is not particularly limited as long as it is suitable for the reaction. As the column, for example, a column having a diameter of 10 mm and a length of 100 mm, a column having a diameter of 10 mm and a length of 250 mm, etc. can be used.

[0055] As an example of the catalyst-filled column, there is one in which Pd / PS-DVB (Pd: 2.55 g, 0.9 mmol / g, styrene / divinylbenzene copolymer: Diaion (registered trademark) HP20, manufactured by Mitsubishi Chemical Corporation) is packed to the maximum density in a SUS column having a size of 10 mm × 100 mm, or one in which Pd / PS-DVB (Pd: 2.55 g, 0.9 mmol / g, styrene / divinylbenzene copolymer: Diaion (registered trademark) HP20, manufactured by Mitsubishi Chemical Corporation) is packed to the maximum density in a SUS column having a size of 10 mm × 250 mm.

[0056] The tube used for the flow path for introducing and discharging the substrate and the like into the column is not particularly limited. Specific examples of the tube include a Teflon (registered trademark) tube with an inner diameter of 1 mm.

[0057] The introduction and discharge of the substrate and the like into the column can be carried out by liquid feeding using a syringe pump, a diaphragm pump, a mass controller, or the like.

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

[0059] <Reaction conditions> The reaction temperature of the acetaminoation reaction of the present invention means the outer temperature of the column filled with the metal-supported catalyst of the present invention. From the viewpoints of reactivity and productivity, etc., the reaction temperature is usually 0°C to 60°C, preferably 5°C to 50°C, and particularly preferably 10°C to 40°C. When the reaction temperature is lower than the above lower limit, the reactivity may decrease. When the reaction temperature is higher than the above upper limit, there is a risk of a decrease in yield and purity due to side reactions and deterioration of the metal-supported catalyst of the present invention.

[0060] The lower limit of the reaction stress of the acetaminoation reaction of the present invention is usually 0.1 MPa or more, preferably 0.2 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 reaction at the reaction pressure within the above range, the hydrogen concentration in the p-nitrophenol solution increases, and the reaction can be carried out efficiently. The reaction pressure can be adjusted by applying back pressure using a back pressure valve or the like in the flow path after passing through the column filled with the metal-supported catalyst of the present invention.

[0061] The reaction time of the acetaminoation reaction of the present invention means the residence time (residence time) of the reaction solution in the column filled with the metal-supported catalyst of the present invention, and although it varies depending on the reaction temperature and reaction pressure, it is usually 0.1 second to 60 seconds, preferably 0.1 second to 30 seconds.

[0062] <Post-treatment> The isolation of acetaminophen, which is the target product from the reaction product solution obtained in the acetamination step of the present invention, may be carried out by treating the reaction product solution such as neutralization, liquid separation, concentration, filtration, etc., or may be carried out by known purification means such as crystallization, column chromatography, etc.

Examples

[0063] The present invention will be described in more detail with reference to examples. The scope of the present invention is not limited to the following examples. In the following examples and comparative examples, unless otherwise specified, the ratio of the supply rates (mL / min) of paranitrophenol, acetic anhydride, and hydrogen gas is 1:0.9:67. The reaction time is the residence time of the mixed solution in the column.

[0064] [Abbreviations] In the examples, each abbreviation represents the following compound. PAP: p-Aminophenol APAP: Acetaminophen PAAPA: 4-Acetamidophenyl acetate PNP: Paranitrophenol PNPA: 4-Nitrophenyl acetate MeOH: Methanol AcOH: Acetic acid

[0065] [Flow synthesis apparatus] In the following examples and comparative examples, the following flow synthesis apparatus was used. 「Asia Flow Chemistry System」 manufactured by Syriss

[0066] [Analysis method 1 (HPLC)] The apparatus and conditions used for the analysis of the reaction product solution in the following examples and comparative examples are as shown in Table 2 below.

[0067]

Table 2

[0068] [Synthesis Example 1] Using synthetic adsorbent Diaion (registered trademark) HP20 (styrene / divinylbenzene copolymer, manufactured by Mitsubishi Chemical Corporation) and palladium acetate, a metal-supported catalyst was produced according to the method of Example 1 in JP-A-2008-114164. The obtained metal-supported catalyst was one in which Pd element was supported on the synthetic adsorbent (Pd / HP20), and the supported amount of Pd was 9.5% by mass of the whole metal catalyst support medium.

[0069] [Example 1] A reaction vessel was prepared by filling a SUS column with a diameter of 10 mm and a length of 100 mm with 2.55 g of Pd / HP20 (produced in Synthesis Example 1) (Pd supported amount: 0.24 g (2.3 mmol)), and acetaminophen was synthesized using the flow synthesis system shown in Figure 2.

[0070] While maintaining the column temperature at 35 °C in a water bath, 1 L of a methanol solution of paranitrophenol with a concentration of 0.84 mol / L (13.9% by mass), 500 mL of acetic anhydride as an acetylating agent, and hydrogen gas were gradually mixed and supplied to the column for 20 minutes to circulate. At this time, using a diaphragm pump and a cylinder pump, the supply rate of the methanol solution of paranitrophenol was maintained at 3.6 mL / min, the supply rate of acetic anhydride was maintained at 0.336 mL / min, and using a mass controller, the supply rate of hydrogen gas was maintained at 240 mL / min. This condition corresponds to a supply amount of 3.6 mol of hydrogen gas and 1.2 mol of acetic anhydride per 1 mol of paranitrophenol. Also, a Teflon tube and a back pressure valve were attached to the outlet of the reaction vessel, and the back pressure was set to 0.5 MPa. The supply rate of the methanol solution of paranitrophenol, the reaction time, the reaction pressure, and the reaction temperature are shown in Table 3.

[0071] As a result of analyzing the obtained reaction product solution by Analysis Method 1, 8.8 g (yield 96.0%) of acetaminophen was contained.

[0072] [Examples 2 to 5] In Example 1, the reaction was carried out in the same manner as in Example 1, except that the solvent, reaction pressure, feed rate, and reaction time of the p-nitrophenol solution were changed as shown in Table 3. The results of analyzing the obtained reaction product solution in the same manner as in Example 1 are summarized in Table 3.

[0073] [Comparative Examples 1 to 3] In Example 1, instead of Pd / HP20, 4.4 g of a catalyst in which Pd was supported on carbon (beads) (Pd / C (beads), manufactured by N.E. Chemcat Corporation) (Pd loading amount: 0.24 g (2.3 mmol)) was used, and the reaction was carried out in the same manner as in Example 1, except that the feed rate and reaction time of the methanol solution of p-nitrophenol were changed as shown in Table 3. The results of analyzing the obtained reaction product solution in the same manner as in Example 1 are summarized in Table 3.

[0074] As a comparative example, using Pd / carbon (powder) instead of Pd / HP20 was also considered. However, since Pd / carbon (powder) has a very small particle size and a very large pressure loss, it is presumed that the solution of p-nitrophenol cannot be passed through the reaction vessel under non-high pressure and the reaction does not proceed. Therefore, Pd / carbon (beads) was used in this comparative example.

[0075]

Table 3

[0076] As is clear from Example 1 and Comparative Examples 1 to 3 in Table 3, by using Pd / HP20, acetaminophen can be efficiently obtained with a short reaction time, high selectivity, and good yield, compared to Pd / C used in the prior art. As is clear from Examples 2 to 3, even at a lower reaction pressure, acetaminophen can be efficiently obtained with high selectivity and good yield. As is clear from Examples 1, 4, and 5, the formation of PAAPA can be suppressed by changing the solvent from methanol to acetic acid.

[0077] [Examples 6 - 15] In Example 1, the column size was changed from a diameter of 10 mm × length of 100 mm to a diameter of 10 mm × length of 250 mm, and the amount of Pd / HP20 used was changed from 2.55 g to 6.38 g (the ratio of the amount of Pd / HP20 used to the column volume was the same). The reaction was carried out in the same manner as in Example 1, except that the reaction temperature, reaction pressure, and the supply rate of the methanol solution of p - nitrophenol were changed as shown in Table 4. The results of analyzing the obtained reaction product solution in the same manner as in Example 1 are summarized in Table 4.

[0078] [Table 4]

[0079] As is clear from Examples 6 - 13 in Table 4, even when the reaction pressure is near atmospheric pressure, by selecting an appropriate reaction temperature and reaction time, acetaminophen can be efficiently obtained with high selectivity and good yield. Example 15 is obtained by changing the column length with respect to Example 3. From Example 15 and Example 3, it can be seen that equivalent results are obtained even when the column length is changed, that is, there is no influence due to the column length. Example 14 is obtained by increasing the reaction pressure with respect to Example 12. From these results, it can be seen that increasing the pressure increases the reactivity. [Industrial Applicability]

[0080] The method for producing acetaminophen of the present invention can continuously produce acetaminophen useful as a pharmaceutical from p - nitrophenol with high selectivity and good yield, safely and inexpensively, under mild conditions of low reaction temperature and low reaction pressure, without the need for high - pressure reaction equipment, and is industrially useful.

[0081] Although the present invention has been described in detail using specific embodiments, it is obvious to those skilled in the art that various changes can be made without departing from the intention and scope of the present invention. This application is based on Japanese Patent Application No. 2020-086766 filed on May 18, 2020, the entire disclosure of which is incorporated herein by reference.

Explanation of Reference Numerals

[0082] 1 Metal-supported catalyst of the present invention 2 Column 3 Reaction vessel 4 Recovery tank 5 Back pressure valve

Claims

1. A method for producing acetaminophen by subjecting a solution containing paranitrophenol to an acetamidation reaction by passing it through a column filled with a catalyst together with an acetylating agent and hydrogen, wherein the catalyst is a metal-supported catalyst in which a metal element is supported on a synthetic adsorbent, the synthetic adsorbent is a styrene / divinylbenzene copolymer, and the metal element is palladium, the reaction temperature of the acetamidation reaction is 0°C to 60°C and the reaction pressure is 0.1 MPa to 1 MPa. A method for producing acetaminophen, characterized by this.

2. The method for producing acetaminophen according to claim 1, wherein the synthetic adsorbent is a porous synthetic adsorbent having a pore volume of 0.1 mL / g to 3.0 mL / g.

3. The synthetic adsorbent has a BET specific surface area of 200 m ２ / g to 2000 m ２ / g, and is a porous synthetic adsorbent, and the method for producing acetaminophen according to claim 1 or 2 is characterized thereby.

4. The method for producing acetaminophen according to any one of claims 1 to 3, wherein the synthetic adsorbent is a porous synthetic adsorbent having a most frequent pore radius of 1 nm to 50 nm.

5. The method for producing acetaminophen according to any one of claims 1 to 4, wherein the metal element supported amount of the metal-supported catalyst is 1% by mass to 25% by mass based on the metal-supported catalyst.

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