Method for manufacturing acetaminophen

Abstract

A method, in which a solution containing p-nitrophenol, an acetylating agent, and hydrogen are introduced into a column filled with a catalyst, thereby performing an acetamidation reaction to produce acetaminophen. The method is characterized in that the catalyst is a metal-loaded catalyst in which a metal element is supported on a synthetic adsorbent, the reaction temperature of the acetamidation reaction is 0°C to 60°C, and the reaction pressure is 0.1 MPa to 1 MPa. By this method, acetaminophen can be continuously produced safely and inexpensively with high selectivity and good yield at a low reaction temperature and a low reaction pressure.

Description

Technical Field

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

[0002] Acetaminophen has been a commonly used antipyretic and analgesic drug, 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 reaction method has been known. For example, the following method is known: p-nitrophenol, 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).

[0004] However, in the method of Patent Document 1, the reaction temperature is high, and furthermore, there is intense heat generation when adding the catalyst, so the reaction is difficult to control.

[0005] Therefore, a safer and more productive industrial production method is needed.

[0006] As a method for improving productivity, a continuous reaction method is available.

[0007] For example, the following method is known: p-nitrophenol is added to an acetic anhydride / acetic acid solution to form a solution, and this 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°C to 140°C to carry out the reaction, thereby continuously producing acetaminophen (Patent Document 2).

[0008] However, in the method of Patent Document 2, equipment capable of withstanding very high pressure conditions is required, and the reaction temperature is also high. In addition, in the case of continuous long-term reaction under high temperature and high pressure, there is a possibility of accelerating the deterioration of the catalyst.

[0009] Therefore, as a continuous production method, a production method that can carry out the reaction under milder conditions, save energy, and has low costs for equipment, etc. is expected.

[0010] Patent Document 1: International Publication No. 2017 / 154024

[0011] Patent Document 2: Specification of Chinese Patent Application Publication No. 102060729 Summary of the Invention

[0012] An object of the present invention is to provide a method that can continuously produce acetaminophen safely and inexpensively with high selectivity and good yield at a low reaction temperature and a low reaction pressure.

[0013] The present inventors have found that when a solution containing p-nitrophenol is continuously introduced together with an acetylating agent and hydrogen into a column filled with a catalyst, which is a metal-supported catalyst having a metal element supported on a synthetic adsorbent, acetaminophen can be obtained safely and inexpensively with high selectivity and good yield even at low reaction pressures and reaction temperatures.

[0014] The present invention has the following features.

[0015] [1] A method for producing acetaminophen, which comprises introducing a solution containing p-nitrophenol together with an acetylating agent and hydrogen into a column filled with a catalyst to carry out an acetamidation reaction for producing acetaminophen, characterized in that the catalyst is a metal-supported catalyst having a metal element supported on a synthetic adsorbent, the reaction temperature of the acetamidation reaction is 0°C to 60°C, and the reaction pressure is 0.1 MPa to 1 MPa.

[0016] [2] The method for producing acetaminophen according to [1], characterized in that the synthetic adsorbent is a styrene / divinylbenzene copolymer.

[0017] [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.

[0018] [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.

[0019] [5] The method for producing acetaminophen according to any one of [1] to [4], characterized in that the synthetic adsorbent is a porous synthetic adsorbent having a BET specific surface area of 200 m 2 / g to 2000 m 2 / g.

[0020] [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 pore mode radius of 1 nm to 50 nm.

[0021] [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 relative to the metal-supported catalyst.

[0022] Effects of the Invention

[0023] The method for manufacturing acetaminophen according to the present invention can continuously manufacture acetaminophen safely and inexpensively with high selectivity and good yield at a low reaction temperature and a low reaction pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 FIG. is a system diagram of a flow synthesis system showing an example of an embodiment of the method for manufacturing acetaminophen according to the present invention.

[0025] Figure 2 FIG. is a system diagram of a flow synthesis system equipped with a back pressure valve showing another example of an embodiment of the method for manufacturing acetaminophen according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] Hereinafter, the present invention will be described in detail.

[0027] [Method for Manufacturing Acetaminophen]

[0028] In the method for manufacturing acetaminophen according to the present invention, a solution containing p-nitrophenol (hereinafter sometimes referred to as "p-nitrophenol solution"), an acetylating agent, and hydrogen are continuously introduced into a column filled with a catalyst, whereby an acetamidation reaction is carried out to continuously manufacture acetaminophen (hereinafter sometimes 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"). The reaction temperature of the acetamidation reaction is 0°C to 60°C, and the reaction pressure is 0.1 MPa to 1 MPa.

[0029] [Acetamidation Step]

[0030] The method for carrying out the acetamidation step of the present invention is not particularly limited.

[0031] For example, as Figure 1 , 2 shown, the following method based on a flow synthesis system can be cited: A p-nitrophenol solution, an acetylating agent, and hydrogen are continuously introduced into a reaction vessel 3 equipped with a column 2 filled with a metal-supported catalyst 1 of the present invention. In the column 2, in the presence of the metal-supported catalyst of the present invention, p-nitrophenol is continuously subjected to an acetamidation reaction with the acetylating agent and hydrogen, and the reaction product solution containing acetaminophen flowing out from the column 2 is received in a recovery tank 4.

[0032] Figure 2 The flow synthesis system of Figure 1 differs from the flow synthesis system of

[0033] Regarding the flow synthesis system, as described later.

[0034] <p-nitrophenol solution>

[0035] As the p-nitrophenol used as a raw material for manufacturing acetaminophen, commercially available products can be used, or p-nitrophenol obtained by applying known methods can be used.

[0036] As the solvent used in the p-nitrophenol solution, there is no particular limitation as long as it can dissolve p-nitrophenol and does not hinder the progress of the reaction. As such a solvent, for example, alcohol solvents such as methanol, ethanol, and propanol; carboxylic acid solvents such as formic acid, acetic acid, and propionic acid can be cited. From the viewpoints of cost, reactivity, etc., methanol and acetic acid are preferred.

[0037] These solvents can be used alone as one kind, or two or more kinds can be mixed and used in any combination and ratio.

[0038] Regarding the concentration of p-nitrophenol in the p-nitrophenol solution, there is no particular limitation as long as it does not affect 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 mass% to 80 mass%, preferably 10 mass% to 70 mass%, and particularly preferably 20 mass% to 60 mass%.

[0039] <Hydrogen>

[0040] Regarding the amount of hydrogen (hydrogen gas) used, there is no particular limitation as long as the reaction proceeds. The amount of hydrogen (hydrogen gas) used is usually 1 mol or more, preferably 3 mol or more, relative to 1 mol of p-nitrophenol, and usually 20 mol or less, preferably 10 mol or less.

[0041] There is no particular limitation on the method of supplying hydrogen. Hydrogen can be continuously injected into the flow path before column 2 and mixed into the p-nitrophenol solution or the p-nitrophenol solution containing an acetylating agent, or it can be directly pressed into column 2. Hydrogen can be used by dissolving a part or all of it in the solvent of the p-nitrophenol solution.

[0042] Hydrogen can also be used in mixture with inert gases such as nitrogen, helium, and argon.

[0043] <Acetylating agent>

[0044] As the acetylating agent, there is no particular limitation as long as it can acetylate an amino group. As the acetylating agent, usually one kind or two or more kinds such as acetic anhydride and acetyl chloride are used. From the viewpoints of cost and reactivity, acetic anhydride is preferred.

[0045] The amount of the acetylating agent is not particularly limited. From the aspect of reactivity, the amount of the acetylating agent is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, more preferably 1 mol to 2 mol, relative to 1 mol of p-nitrophenol.

[0046] The acetylating agent can be premixed into the solution containing p-nitrophenol, can be injected into the supply flow path of the p-nitrophenol solution before and / or after the column 2 to be continuously mixed with the p-nitrophenol solution, or can be separately injected into the column 2 from the p-nitrophenol solution and be continuously mixed with the p-nitrophenol solution in the column 2. From the aspect of being able to rapidly convert the unstable intermediate into the target substance, the acetylating agent is preferably continuously mixed with the p-nitrophenol solution in the flow path before the column 2.

[0047] <Metal-loaded catalyst>

[0048] The metal-loaded catalyst of the present invention is a catalyst in which a metal element is loaded on a synthetic adsorbent to immobilize the metal.

[0049] The metal element that can be used in the metal-loaded catalyst of the present invention is not particularly limited as long as it has the activity of reducing nitro groups. As such a metal element, palladium (Pd), platinum (Pt), rhodium (Rh), ruthenium (Ru), Ag (silver), and a mixture of two or more of them can generally 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 aspect of catalytic performance, Pd and / or Pt, especially Pd alone, is preferred.

[0050] Regarding the loading amount of the metal element, from the aspects of catalytic performance and cost, based on the content of the metal element in the metal-loaded catalyst of the present invention, the lower limit is generally 0.1% by mass or more, preferably 1% by mass or more, more preferably 3% by mass or more, and particularly preferably 5% by mass or more, and the upper limit is generally 25% by mass or less, preferably 20% by mass or less, more preferably 15% by mass or less, and particularly preferably 10% by mass or less.

[0051] In the present invention, the synthetic adsorbent refers to a porous synthetic adsorbent formed of a porous organic polymer manufactured by chemical synthesis.

[0052] As the synthetic adsorbent used in the present invention, aromatic, substituted aromatic, or acrylic polymers or copolymers (hereinafter sometimes referred to as “polymers or copolymers” as “(co)polymers”) can be cited.

[0053] As the aromatic (co)polymers, styrene / divinylbenzene copolymers and divinylbenzene polymers can be cited.

[0054] As the substituted aromatic (co)polymer, bromostyrene / divinylbenzene copolymer can be mentioned.

[0055] As the acrylic (co)polymer, methacrylate (co)polymers such as methyl methacrylate / bis(2-methyl-2-propenoic acid) ethylene glycol ester copolymer can be mentioned.

[0056] Among these, aromatic (co)polymers are preferred, styrene / divinylbenzene copolymers such as styrene / divinylbenzene copolymer and bromostyrene / divinylbenzene copolymer are more preferred, and styrene / divinylbenzene copolymer is particularly preferred. This copolymer has a crosslinked structure insoluble in organic solvents and is also stable in acidic or alkaline solutions.

[0057] Since the synthetic adsorbent used in the present invention has little influence on the reaction, substances that substantially do not have functional groups such as ion exchange groups, for example, substances with an ion exchange capacity of less than 1 meq / g or non-polar substances, are preferred.

[0058] For the purpose of improving reactivity, 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.

[0059] For the purpose of improving reactivity, 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, particularly preferably 500 m 2 / g to 700 m 2 / g.

[0060] For the purpose of improving reactivity, the modal 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.

[0061] The synthetic adsorbent used in the present invention is preferably a porous synthetic adsorbent having relatively large pores.

[0062] In the present invention, the pore volume, BET specific surface area, and modal pore radius of the porous synthetic adsorbent can be measured by the nitrogen adsorption method according to a conventional method.

[0063] The shape and size of the synthetic adsorbent are not particularly limited as long as it can be filled into the column without hindering the flow of the reaction solution. As the synthetic adsorbent, granular, pellet-like, film-like, or cylindrical substances can be used. From the perspective of packing properties, granular substances are more preferred.

[0064] The particle size of the granular synthetic adsorbent is generally in the range of 1 μm to 2000 μm, preferably in the range of 3 μm to 2000 μm. From the aspects of industrial processability, etc., the particle size of the synthetic adsorbent is preferably in the range of 4 μm to 1000 μm, and the mode particle size is preferably 50 μm or more, preferably 150 μm or more, and particularly preferably 250 μm or more.

[0065] The particle size of the synthetic adsorbent is the average particle size measured by the laser diffraction particle size distribution measurement method according to the conventional method.

[0066] As the synthetic adsorbent used in the present invention, for example, 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 perspective of reactivity, HP20SS, HP20, and SP20SS are preferred.

[0067] The details of these commercially available synthetic adsorbents are shown in Table 1 below.

[0068] [Table 1]

[0069]

[0070] As the metal-supported catalyst of the present invention, a catalyst in which Pd is supported on a synthetic adsorbent composed 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 composed of a styrene / divinylbenzene copolymer (hereinafter sometimes referred to as "Pt / PS-DVB") are preferred, and Pd / PS-DVB is particularly preferred.

[0071] By using such a metal-supported catalyst of the present invention, acetaminophen can be obtained efficiently, safely, and inexpensively with high selectivity and good yield even at low pressure and low temperature.

[0072] The metal supported catalyst of the present invention can be produced by a conventionally known method such as the method described in Japanese Patent Application Laid-Open No. 2008-114164. For example, a synthetic adsorbent and a metal salt are added to an organic solvent, stirred sufficiently, and then the generated metal salt adsorbed synthetic adsorbent is filtered, washed with water and methanol, and dried.

[0073] <Flow Synthesis System>

[0074] The flow synthesis system suitable for implementing the method for producing acetaminophen of the present invention refers to a system in which a reaction vessel having an inlet and an outlet is used to simultaneously perform "input of raw materials from the inlet", "reaction" and "recovery of products from the outlet", and this concept is well known to those skilled in the art (for example, "Flow Microsynthesis" (Chemistry Co., Ltd., 2014, p. 9). In the flow synthesis system, the column filled with the metal-supported catalyst of the present invention is in a thin tubular shape.

[0075] The material of the column of the present invention is not particularly limited, and examples of the material of the column include glass, stainless steel (SUS), Hastelloy alloy, and Teflon (registered trademark).

[0076] The size of the column is not particularly limited as long as it is suitable for the reaction, and as the column, for example, a column with a diameter of 10 mm and a length of 100 mm, a column with a diameter of 10 mm and a length of 250 mm, etc. can be used.

[0077] As an example of a catalyst-packed column, there can be mentioned a column 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 densely packed in a 10 mm×100 mm SUS column, and a column 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 densely packed in a 10 mm×250 mm SUS column.

[0078] The tube used for the flow path for introducing and discharging the substrate etc. into the column is not particularly limited. A specific example of the tube is a Teflon (registered trademark) tube having an inner diameter of 1 mm.

[0079] The introduction and discharge of the substrate and the like into and from the column can be performed by liquid transport using a syringe pump, a diaphragm pump, a mass controller, or the like.

[0080] A back pressure valve or an online analysis device may be installed in the flow path on the side where the reaction product liquid flows out of the column.

[0081] <Reaction Conditions>

[0082] The reaction temperature of the acetylation reaction of the present invention refers to the external 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 generally 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 sometimes decrease. When the reaction temperature is higher than the above upper limit, the yield and purity may decrease due to side reactions, and the metal-supported catalyst of the present invention may deteriorate.

[0083] The lower limit of the reaction stress of the acetylation reaction of the present invention is generally 0.1 MPa or more, preferably 0.2 MPa or more, and the upper limit is generally 1 MPa or less, preferably 0.8 MPa or less, and particularly preferably 0.6 MPa or less. By carrying out the reaction under the reaction pressure within the above range, the hydrogen concentration in the p-nitrophenol solution increases, and the reaction can be carried out efficiently.

[0084] The reaction pressure can be adjusted by applying back pressure to the flow path after passing through the column filled with the metal-supported catalyst of the present invention by using a back pressure valve or the like.

[0085] The reaction time of the acetylation reaction of the present invention refers to the time (residence time) for the reaction solution to stay in the column filled with the metal-supported catalyst of the present invention, and varies depending on the reaction temperature and reaction pressure, and is generally 0.1 second to 60 seconds, preferably 0.1 second to 30 seconds.

[0086] <Post-treatment>

[0087] Regarding the separation of acetaminophen as the target substance from the reaction product solution obtained in the acetylation process of the present invention, it can be carried out by treatments such as neutralization, liquid separation, concentration, and filtration of the reaction product solution, or by known purification means such as crystallization and column chromatography.

[0088] Examples

[0089] The present invention will be described in more detail by way of examples. The scope of the present invention is not limited to the following examples.

[0090] In the following examples and comparative examples, unless otherwise specified, the supply rate (mL / min) ratio of p-nitrophenol, acetic anhydride, and hydrogen is 1:0.9:67. The reaction time is the time for the mixed solution to stay in the column.

[0091] [Abbreviation symbols]

[0092] In the examples, each abbreviation symbol represents the following compound.

[0093] PAP: p-aminophenol

[0094] APAP: acetaminophen

[0095] PAAPA: 4-Acetamidophenyl acetate

[0096] PNP: p-Nitrophenol

[0097] PNPA: 4-Nitrophenyl acetate

[0098] MeOH: Methanol

[0099] AcOH: Acetic acid

[0100] [Flow synthesis apparatus]

[0101] In the following Examples and Comparative Examples, the following flow synthesis apparatus was used.

[0102] "Asia Flow Chemistry System" manufactured by Syriss Co., Ltd.

[0103] [Analysis method 1 (HPLC)]

[0104] The apparatus and conditions used for the analysis of the reaction product solutions in the following Examples and Comparative Examples are shown in Table 2 below.

[0105] [Table 2]

[0106]

[0107] [Synthesis Example 1]

[0108] Using the synthetic adsorbent Diaion (registered trademark) HP20 (styrene / divinylbenzene copolymer, manufactured by Mitsubishi Chemical Corporation) and palladium acetate, a metal-supported catalyst was produced by the method of Example 1 of JP-A-2008-114164. The resulting metal-supported catalyst had Pd element supported on the synthetic adsorbent (Pd / HP20), and the loading amount of Pd was 9.5 mass% of the whole metal-supported catalyst.

[0109] [Example 1]

[0110] 2.55 g of Pd / HP20 (produced in Synthesis Example 1) (Pd loading amount: 0.24 g (2.3 mmol)) was packed into a SUS column having a diameter of 10 mm and a length of 100 mm to serve as a reaction vessel, and acetaminophen was synthesized using the Figure 2 flow synthesis system shown.

[0111] The column temperature was maintained at 35 °C using a water bath. Under this condition, 1 L of a methanol solution of p-nitrophenol with a concentration of 0.84 mol / L (13.9% by mass), 500 mL of acetic anhydride as an acetylating agent, and hydrogen were slowly mixed and fed through the column for 20 minutes. At this time, using a diaphragm pump and a cylinder pump, the feeding rate of the methanol solution of p-nitrophenol was maintained at 3.6 mL / minute, the feeding rate of acetic anhydride was maintained at 0.336 mL / minute, and using a mass controller, the feeding rate of hydrogen was maintained at 240 mL / minute. This condition corresponds to a hydrogen supply amount of 3.6 mol and an acetic anhydride supply amount of 1.2 mol relative to 1 mol of p-nitrophenol. In addition, a Teflon tube and a back pressure valve were installed at the outlet of the reaction vessel, and the back pressure was set to 0.5 MPa. The feeding rate of the methanol solution of p-nitrophenol, the reaction time, the reaction pressure, and the reaction temperature are shown in Table 3.

[0112] The resulting reaction product solution was analyzed by Analytical Method 1, and the result contained 8.8 g of acetaminophen (yield 96.0%).

[0113] [Examples 2 - 5]

[0114] In Example 1, as shown in Table 3, the solvent of the p-nitrophenol solution, the reaction pressure, the feeding rate, and the reaction time were changed, and the reaction was carried out in the same manner as in Example 1 except for this. The resulting reaction product solution was analyzed in the same manner as in Example 1, and the results are summarized in Table 3.

[0115] [Comparative Examples 1 - 3]

[0116] In Example 1, 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 instead of Pd / HP20. As shown in Table 3, the feeding rate of the methanol solution of p-nitrophenol and the reaction time were changed, and the reaction was carried out in the same manner as in Example 1 except for this. The resulting reaction product solution was analyzed in the same manner as in Example 1, and the results are summarized in Table 3.

[0117] It should be noted that as a comparative example, using Pd / carbon (powder) instead of Pd / HP20 was also studied. However, the particle size of Pd / carbon (powder) is very small and the pressure loss is very large. Therefore, it was speculated that the solution of p-nitrophenol could not be passed into the reaction vessel without high pressure and the reaction would not proceed. Therefore, Pd / C (beads) was used in this comparative example.

[0118]

[0119] As can be seen from Example 1 and Comparative Examples 1 to 3 in Table 3, by using Pd / HP20, compared with Pd / C used in the prior art, acetaminophen can be efficiently obtained with a short reaction time, high selectivity and good yield.

[0120] As can be seen from Examples 2 to 3, even at a lower reaction pressure, acetaminophen can be efficiently obtained with high selectivity and good yield.

[0121] As can be seen from Examples 1, 4 and 5, by changing the solvent from methanol to acetic acid, the formation of PAAPA can be inhibited.

[0122] [Examples 6 to 15]

[0123] In Example 1, the column size was changed from a diameter of 10 mm × a length of 100 mm to a diameter of 10 mm × a length of 250 mm, and the amount of Pd / HP20 was changed from 2.55 g to 6.38 g (the ratio of the amount of Pd / HP20 to the column volume was the same). As shown in Table 4, the reaction temperature, reaction pressure and the supply rate of the methanol solution of p-nitrophenol were changed, and the reaction was carried out in the same manner as in Example 1 except for this. The resulting reaction product solution was analyzed in the same manner as in Example 1, and the results are summarized in Table 4.

[0124]

[0125] As can be seen from Examples 6 to 13 in Table 4, even when the reaction pressure is around atmospheric pressure, by selecting appropriate reaction temperature and reaction time, acetaminophen can be efficiently obtained with high selectivity and good yield.

[0126] Example 15 changed the column length compared with Example 3. As can be seen from Example 15 and Example 3, even when the column length was changed, the same result was obtained, that is, there was no influence due to the column length.

[0127] Example 14 increased the reaction pressure compared with Example 12. From these results, it can be seen that if the pressure is increased, the reactivity is improved.

[0128] Industrial Applicability

[0129] The method for manufacturing acetaminophen of the present invention does not require high-pressure reaction equipment, and can continuously manufacture acetaminophen useful as a medicine from p-nitrophenol safely and inexpensively with high selectivity and good yield under mild conditions such as low reaction temperature and low reaction pressure, and is industrially useful.

[0130] The present invention has been described in detail using a specific method, but it is obvious to those skilled in the art that various modifications can be made without departing from the intention and scope of the present invention.

[0131] This application is based on Japanese Patent Application No. 2020-086766 filed on May 18, 2020, and incorporates the entire contents thereof by reference.

[0132] Symbol Explanation

[0133] 1 Metal-supported catalyst of the present invention

[0134] 2 Column

[0135] 3 Reaction vessel

[0136] 4 Recovery tank

[0137] 5 Back pressure valve

Claims

1. A method for manufacturing acetaminophen, which method involves passing a solution containing p-nitrophenol, an acetylating agent, and hydrogen through a column filled with a catalyst, thereby performing an acetamidation reaction to manufacture acetaminophen. The method is characterized in that the catalyst is a metal-loaded catalyst in which a metal element is loaded on a synthetic adsorbent, the metal element being palladium, platinum, rhodium, ruthenium, silver, or a mixture of two or more of them, the reaction temperature of the acetamidation reaction is 0°C to 60°C, the reaction pressure is 0.1 MPa to 1 MPa, and the synthetic adsorbent is a styrene / divinylbenzene-based copolymer and is a substance with an ion exchange capacity of less than 1 meq / g or a non-polar substance.

2. The method for manufacturing acetaminophen according to claim 1, characterized in that, the styrene / divinylbenzene-based copolymer is a styrene / divinylbenzene copolymer, and the metal element is palladium and / or platinum.

3. The method for manufacturing acetaminophen according to claim 1 or 2, characterized in that, the synthetic adsorbent is a porous synthetic adsorbent with a pore volume of 0.1 mL / g to 3.0 mL / g.

4. The method for manufacturing acetaminophen according to claim 1 or 2, characterized in that, The synthetic adsorbent is a porous synthetic adsorbent with a BET specific surface area of 200 m 2 / g to 2000 m 2 / g.

5. The method for manufacturing acetaminophen according to claim 1 or 2, characterized in that, the synthetic adsorbent is a porous synthetic adsorbent with a pore mode radius of 1 nm to 50 nm.

6. The method for manufacturing acetaminophen according to claim 1 or 2, characterized in that, the metal element loading amount of the metal-loaded catalyst is 1% by mass to 25% by mass relative to the metal-loaded catalyst.

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