METHOD FOR THE PREPARATION OF AN N-ACETYLATED AROMATIC PRIMARY AMINE

Description

[0001] The present invention relates to a continuous preparation process for an N-acetylated aromatic primary amine, in particular an N-acetyl-aminophenol, preferably paracetamol, also called N-acetyl-p-aminophenol (APAP), N-(4-hydroxyphenyl)acetamide or acetaminophen.

[0002] N-acetylaminophenol comprises several regioisomers, including paracetamol. Paracetamol's analgesic and antipyretic properties have made it a preferred active ingredient for over a century.

[0003] The preparation of N-acetyl-aminophenol has been extensively studied. Numerous synthetic processes have been described, typically starting from phenol, chlorobenzene, or nitrobenzene.

[0004] Several processes have proven their effectiveness on an industrial scale. Among them, Celanese has developed a route whose final step is a Beckmann rearrangement of the p-hydroxyacetophenone oxime.

[0005] In other industrial processes, the final step is the N-monoacetylation of p-aminophenol (hereafter referred to as PAP). Monoacetylation of PAP can take place in the presence of acetic anhydride or acetic acid.

[0006] Using acetic acid in this reaction involves a high reaction temperature and a long residence time, which leads to the production of undesirable impurities in the final product.

[0007] Numerous prior art documents also indicate that the use of acetic anhydride presents certain drawbacks, notably insufficient purity and discoloration of the final product. Their purpose is therefore to remedy this problem. Examples include US patents 3,042,719; 3,748,358; 3,781,354; and 4,264,526.

[0008] US 2012 / 065423 aims at the continuous preparation of N-acetylated aromatic primary amines.

[0009] The presence of impurities, especially colored ones, leads to lengthy purification processes and the production of numerous wastes and effluents.

[0010] Furthermore, in the prior art, the monoacetylation reaction of PAP takes place in batches, which implies limited productivity at the industrial level.

[0011] In the current environmental context, it is necessary to develop a process for preparing N-acetylated aromatic primary amine, and preferably N-acetyl-aminophenol, with a greatly reduced ecological footprint while being industrially viable and with high productivity.

[0012] To this end, the invention relates to a process for preparing an N-acetylated aromatic primary amine comprising the steps of: b) contacting an aromatic primary amine with an acetylating agent selected from acetic anhydride, acetyl halide, and a mixture of these in equimolar or submolar amounts relative to the aromatic primary amine, thereby obtaining a reaction stream comprising an N-acetylated aromatic primary amine, said contacting being carried out in the absence of palladium, c) cooling the reaction stream, thereby crystallizing the N-acetylated aromatic primary amine, steps b) and c) being carried out continuously.

[0013] The inventors have developed a process for preparing N-acetyl-aminophenol with a minimized environmental impact.

[0014] Implementing steps b) and c) continuously reduces the amount of waste and effluent while increasing productivity. Not only the acetylation reaction (step b)), but also the crystallization (step c)), occur continuously.

[0015] The primary aromatic amine is preferably an aminophenol, in particular 2-aminophenol, 3-aminophenol, or 4-aminophenol, preferably 2-aminophenol or 4-aminophenol. Most preferably, the primary aromatic amine is 4-aminophenol (also called p-aminophenol (PAP)), and the process then allows the preparation of paracetamol (APAP).

[0016] The acetylation agent is chosen from acetic anhydride, an acetyl halide, and a mixture thereof. Specifically, the acetyl halide is acetyl chloride or acetyl bromide, most commonly acetyl chloride. Typically, the acetylation agent is acetic anhydride.

[0017] The process may include, before step b), a step a) of supplying the aromatic primary amine.

[0018] Preferably, the aromatic primary amine supplied in step a) is at a temperature of 0°C to 120°C, in particular 0°C to 110°C, and especially 5°C to 90°C. This temperature corresponds to that of the aromatic primary amine just before contact in step b). Higher temperatures are avoided so as not to degrade the aromatic primary amine.

[0019] The degree of purity of the aromatic primary amine is then typically at least 95%, preferably at least 97%, more preferably at least 98%.

[0020] In a first embodiment, the aromatic primary amine supplied in step a) is in essentially solvent-free form. Generally, the aromatic primary amine supplied is in solid form, typically as a powder.

[0021] In this embodiment, the temperature of the primary aromatic amine in step a) is generally from 0°C to 85°C, preferably from 5°C to 80°C, more preferably from 20°C to 70°C. This temperature corresponds to that of the primary aromatic amine just before contact in step b).

[0022] In a second embodiment, the aromatic primary amine supplied in step a) is in the form of a mixture of the aromatic primary amine and a solvent. This mixture will be used in step b) as a source of aromatic primary amine.

[0023] Step a) may include a step a1) of mixing an aromatic primary amine and a solvent to obtain a mixture of an aromatic primary amine and a solvent, and optionally a step a2) of heating this mixture to a temperature ranging from 20°C to 120°C, in particular from 20°C to 110°C, and in particular from 40°C to 90°C. This temperature corresponds to that of the mixture just before contact in step b). Preferably, the temperature is below the boiling point of the solvent, in particular at least 5°C below the boiling point of the solvent.

[0024] A mixture of an aromatic primary amine and a solvent can be in the form of a solution or a suspension. The form of the mixture depends, in particular, on the mass concentration of the aromatic primary amine in the solvent and the temperature of the mixture. Specifically, it is a suspension. Alternatively, it is a solution.

[0025] The solvent can be water, acetic acid, or a mixture of these. The proportions of acetic acid to water can vary from 100 / 0 to 0 / 100, including from 90 / 10 to 10 / 90, for example, from 75 / 25 to 25 / 75. In particular, the solvent is water. Advantageously, the solvent is acetic acid.

[0026] The mass concentration of the aromatic primary amine in the mixture can be from 10% to 50%, i.e., from 0.10 kg to 0.50 kg of aromatic primary amine in 1 kg of the aromatic primary amine-solvent mixture. Preferably, it is from 15% to 45%, and more preferably from 20% to 45%.

[0027] Step a) can be carried out continuously. In particular, steps a1) and a2) are carried out continuously.

[0028] The process may include, before step b), a step a') of supplying an acetylating agent selected from acetic anhydride, an acetyl halide and a mixture thereof.

[0029] Preferably, the acetylation agent supplied in step a') is at a boiling point of -10°C, in particular 0°C, and more particularly 5°C. When the acetylation agent is a mixture, it is preferably supplied at a temperature lower than or equal to the lowest boiling point of the acetylation agents it contains. This temperature corresponds to that of the acetylation agent just before contact in step b). Higher temperatures are avoided to prevent degradation of the acetylation agent. As a first alternative, the acetylation agent is at ambient temperature, typically between -10 and 40°C. Indeed, the stock of acetylation agent is generally stored outdoors. As a second alternative, the acetylation agent is at the same temperature as the primary aromatic amine.

[0030] The degree of purity of the acetyling agent is typically at least 95%, preferably at least 97%, more preferably at least 98%.

[0031] In a first embodiment, the acetylation agent provided is in an essentially solvent-free form.

[0032] In a second embodiment, the acetyling agent provided is in the form of a mixture of acetyling agent and a solvent. This mixture of acetyling agent and a solvent will be used in step b) as the source of acetyling agent.

[0033] Step a') may include a step a1') of mixing an acetylation agent and a solvent to obtain a mixture of the acetylation agent and a solvent, and optionally a step a2') of heating this mixture to a temperature ranging from 20°C to 110°C, in particular from 40°C to 90°C. This temperature corresponds to that of the mixture of the acetylation agent and a solvent just before contact in step b). Preferably, the temperature is below the boiling point of the solvent, in particular at least 5°C below the boiling point of the solvent.

[0034] The mixture of acetylating agent and solvent is in solution form at the temperature at which it is used to carry out step b).

[0035] The solvent is preferably acetic acid.

[0036] The mass concentration of the acetylation agent in the mixture can be from 20% to 98%, i.e., from 0.20 kg to 1 kg of acetylation agent in 1 kg of the acetylation agent-solvent mixture. Preferably, it is from 30% to 95%, and more preferably from 40% to 90%.

[0037] Step a') can be carried out continuously. In particular, steps a1') and a2') are carried out continuously.

[0038] The process includes a step b) of contacting the aromatic primary amine with an acetylating agent in an equimolar or submolar amount relative to the aromatic primary amine, thereby obtaining a reaction stream comprising an N-acetylated aromatic primary amine, said contacting being carried out in the absence of palladium.

[0039] The process uses an equimolar or submolar amount of acetylation agent relative to the aromatic primary amine. Generally, the number of acetylation agent equivalents relative to the aromatic primary amine is less than or equal to 1.00, preferably from 0.80 to 1.00, for example from 0.90 to 1.00, and particularly from 0.95 to 1.00. Continuous control of the amount of acetylation agent results in a cleaner and less colored product. This simplifies the purification of the resulting N-acetylated aromatic primary N-amine.

[0040] In particular in step b), the amount of acetylating agent is equimolar with respect to the aromatic primary amine.

[0041] Step b) is carried out in the absence of palladium, preferably in the absence of a hydrogenation catalyst, or even in the absence of a metallic catalyst in the form of a metal or metal oxide. Thus, there is no hydrogenation reaction occurring simultaneously with acetylation, which distinguishes the process according to the invention from those employing the hydrogenation of a nitro-aromatic compound (in particular a nitrophenol, such as para-nitrophenol) to obtain an aromatic primary amine that is concomitantly acetylated. Preferably, step b) is carried out in the absence of hydrogen.

[0042] Preferably, step b) is carried out in a solvent. This solvent may be added during step b). The solvent is typically water, acetic acid, or a mixture thereof, particularly acetic acid. Preferably, when the aromatic primary amine supplied in step a) is in essentially solvent-free form, the process includes the addition of a solvent during step b). Preferably, when the aromatic primary amine supplied in step a) is in the form of a mixture of the aromatic primary amine and a solvent, no solvent is added during step b) (by "no solvent" means no solvent other than that of the aromatic primary amine / solvent mixture and the acetyling agent / solvent mixture if the acetyling agent is added as an acetyling agent / solvent mixture).

[0043] The contact between the aromatic primary amine and the acetylation agent in step b) allows the acetylation reaction to occur, and the formation of a reaction stream comprising an N-acetylated aromatic primary amine, which is the product of the acetylation of the aromatic primary amine. Generally, the acetylation is monoacetylation, and the N-acetylated aromatic primary amine is an N-monoacetylated aromatic primary amine.

[0044] Generally, step b) is carried out at a temperature of 25°C to 120°C, particularly 25°C to 110°C, preferably 30°C to 100°C, and more preferably 35°C to 95°C, for example, 40°C to 90°C. Below 25°C, the reaction flow is generally too viscous. Above 110°C, the level of impurities produced is often too high.

[0045] Generally, step b) lasts less than 2 hours, specifically less than 1 hour, and more preferably from 1 second to 45 minutes, and more preferably from 1 minute to 30 minutes. Typically, the higher the temperature, the shorter the duration of step b).

[0046] Step b) is usually carried out in a reactor. The reactor can be a tubular reactor or a continuous stirred tank reactor. Typically, the reactor is a continuous stirred tank reactor (commonly called a CSTR).

[0047] The aromatic primary amine (possibly in a mixture with a solvent), the acetylation agent (possibly in a mixture with a solvent), and the solvent (if present) are the reactor input streams. Within the reactor, these input streams are brought into contact, resulting in a reaction stream comprising an N-acetylated aromatic primary amine from the acetylation reaction. This reaction stream is then exited the reactor.

[0048] The duration of step b) described above is typically the residence time in the reactor.

[0049] The reaction stream within or exiting the reactor may be in the form of a solution or a suspension. When it is in the form of a suspension, the process may include, after step b), one or two additional steps b1) of heating the reaction stream to form a solution, and optionally a step b2) of filtering the reaction stream (it being understood that the filtrate is used for the remainder of the process). When the reaction stream is in the form of a solution, the process may include, after step b), an additional step b2) of filtering the reaction stream (it being understood that the filtrate is used for the remainder of the process).

[0050] During step b1), the reaction stream can be heated to a temperature ranging from 60°C to 120°C, preferably from 70°C to 110°C. In particular, the reaction stream is heated at least 10°C above the temperature of step b), more particularly at least 20°C above, notably between 10 and 50°C above, for example between 10 and 30°C above.

[0051] Generally, step b1) lasts less than 2 hours, specifically less than 1 hour, and more preferably from 1 second to 45 minutes, and more preferably from 1 minute to 30 minutes. Typically, the higher the temperature, the shorter the duration of step b1).

[0052] Step b1) is usually carried out in a reactor. The reactor can be a tubular reactor or a continuous stirred tank reactor. Typically, the reactor is a continuous stirred tank reactor (commonly called a CSTR).

[0053] The process includes a step (c) of cooling the reaction stream, by which the N-acetylated aromatic primary amine crystallizes. During this step (c), the reaction stream is generally cooled to a temperature of 15°C to 35°C, specifically 20°C to 30°C. Typically, this is room temperature.

[0054] Preferably, when in step b) the acetylation agent is present in a submolar quantity relative to the aromatic primary amine, in step c) more acetylation agent is added to the reaction stream. This addition minimizes the formation of undesirable byproducts and thus improves the purity of the N-acetylated aromatic primary amine obtained by the process. It also improves the final conversion and limits discoloration.

[0055] The amount of acetyling agent added in step c) is preferably such that the total amount of acetyling agent added in steps b) and c) is at least 1.00 molar equivalent, in particular 1.00 to 1.15 molar equivalents, preferably 1.00 to 1.08 molar equivalents, particularly preferably 1.00 molar equivalent, relative to the aromatic primary amine used in step b).

[0056] In step c), the acetylation agent is preferably added to the reaction stream when the temperature of said reaction stream is below 70°C, in particular below 60°C, preferably below 55°C, and more preferably below or equal to 40°C. Typically, the acetylation agent is added to the reaction stream when the temperature of the reaction stream is above 15°C. These temperature ranges advantageously minimize the formation of undesirable byproducts. Step c) then typically involves cooling the reaction stream from step b) to a temperature below 80°C, in particular below 60°C, preferably below 55°C, and more preferably below or equal to 40°C, and then adding the acetylation agent to the reaction stream.

[0057] Preferably, the acetylation agent added in step c) is at a temperature of 0°C to 90°C, more specifically 5 to 50°C. Higher temperatures are avoided to prevent degradation of the acetylation agent and / or the formation of undesirable products.

[0058] According to one alternative, the acetylation agent is at ambient temperature, typically between -10 and 40°C. Indeed, the stock of acetylation agent is generally kept outdoors.

[0059] According to a second alternative, the acetylation agent is at the same temperature as the reaction flow at the outlet of step b).

[0060] According to a third alternative, the acetylation agent is at the same temperature as the reaction stream when it is added. For example, the acetylation agent is at a temperature between 15 and 60°C when it is added to the reaction stream, which itself is at a temperature between 15 and 60°C.

[0061] The degree of purity of the acetyling agent is typically at least 95%, preferably at least 97%, more preferably at least 98%.

[0062] In a first embodiment, the acetylation agent added in step c) is in an essentially solvent-free form. Generally, the acetylation agent is in liquid form.

[0063] In a second embodiment, the acetylation agent added in step c) is in the form of a mixture of the acetylation agent and a solvent. This mixture is then added in step c) as the source of the acetylation agent.

[0064] Step c) may include a step c1) of mixing the acetyling agent and a solvent to obtain a mixture of the acetyling agent and a solvent, and then optionally a step c2) of bringing this mixture to the temperature at which it is added in step c). The mixture of the acetyling agent and the solvent may be in solution at the temperature at which it is added in step c).

[0065] The solvent is preferably acetic acid.

[0066] The mass concentration of the acetylation agent in the mixture can be from 20% to 98%, i.e., from 0.20 kg to 1 kg of acetylation agent in 1 kg of the acetylation agent-solvent mixture. Preferably, it is from 30% to 95%, and more preferably from 40% to 90%.

[0067] In a first embodiment, step c) comprises transferring the reaction stream through a series of continuously stirred tank reactors (CSTRs), in particular at least two CSTRs, and more particularly at least three CSTRs. Preferably, the series of CSTRs ranges from two to ten CSTRs, and more preferably from three to eight CSTRs. A series of CSTRs is defined as CSTRs connected in series.

[0068] The residence time of the reaction flow in each CSTR is typically 15 minutes to 1 hour.

[0069] In a second embodiment, step c) includes transferring the reaction flow into at least one tubular heat exchanger, preferably from one to thirty tubular heat exchangers in series. The tubular heat exchanger, or each tubular heat exchanger independently of the others when there are several, may be a tubular heat exchanger with or without a transport system.

[0070] The residence time in the tubular exchanger or series of tubular exchangers is typically 15 minutes to 1 hour.

[0071] In a third embodiment, step c) includes transferring the reaction flow into at least one shell and tube heat exchanger and at least one CSTR, in particular at least one shell and tube heat exchanger followed by at least one CSTR in series. More specifically, step c) includes transferring the reaction flow into a series of one to thirty shell and tube heat exchangers and then into a series of one to ten CSTRs. The shell and tube heat exchanger, or each shell and tube heat exchanger independently when there are several, may be a shell and tube heat exchanger with or without a transport system. The residence time in the shell and tube heat exchanger or in the series of shell and tube heat exchangers is typically 15 minutes to 1 hour, and / or the residence time in each CSTR is typically 15 minutes to 1 hour.

[0072] The process generally includes, after step c), a step for recovering the N-acetylated aromatic primary amine. This recovery step may include a step c3) for filtering the reaction stream and optionally a step c4) for washing the N-acetylated aromatic primary amine with the same solvent as in steps b) and c) or with another solvent. Typically, the other solvent is chosen from acetic acid, water, or a mixture thereof.

[0073] The process may or may be exempt from an additional step of purification of the N-acetylated aromatic primary amine after step c). For example, the process may include, after step c), a step d) of recrystallization of the N-acetylated aromatic primary amine, in particular recrystallization in water, in acetic acid or in a mixture thereof, in particular in water.

[0074] Generally, the process involves only a single recrystallization of the N-acetylated aromatic primary amine. Alternatively, recrystallization step d) can be repeated.

[0075] Typically, step d) is performed continuously.

[0076] The process generally includes, after step d), a step for recovering the recrystallized N-acetylated aromatic primary amine. This recovery step may include a filtration step d1 and optionally a washing step d2 of the N-acetylated aromatic primary amine with the same solvent as in step d) or with another solvent. Typically, the other solvent is chosen from acetic acid, water, or a mixture thereof.

[0077] The process may include, after step c), in particular after step c3) or c4) or after step d), in particular after step d1) or d2) if it / they is / are present, a step e) of evaporating the remaining solvents in the N-acetylated aromatic primary amine.

[0078] The N-acetylated aromatic primary amine obtained at the end of the process is in the form of crystals. In the case of APAP, the crystal structure obtained is the type I polymorph.

[0079] Typically, in the case of APAP, at the end of step e), the size of the crystals is such that the D90 is greater than 200 µm, in particular greater than 250 µm, more particularly between 250 and 700 µm (determined by laser granulometry).

[0080] The process may include, after step e), a step f1) of grinding the N-acetylated aromatic primary amine and / or a step f2) of sieving the N-acetylated aromatic primary amine.

[0081] The N-acetylated aromatic primary amine obtained as a result of step c), in particular after step c3) or c4), or as a result of step d), in particular after step d1) or d2), is such that the amount of impurities is less than 0.5% by weight, in particular less than 0.2% by weight. When the aromatic primary amine is an aminophenol, the principal impurities are aminophenol (unreacted starting material) and N-acetylated and O-acetylated aminophenol. The amount of aminophenol (starting material) is preferably less than 100 ppm, more preferably less than 50 ppm. Advantageously, the percentage of N-acetylated and O-acetylated aminophenol is less than 0.1%, for example less than 0.05%.

[0082] When the primary aromatic N-acetylated amine is APAP, its color is white to off-white.

[0083] The invention is illustrated by the following examples. EXAMPLE 1 (invention):

[0084] 4-Aminophenol, acetic anhydride and acetic acid are added concomitantly by separate streams in a first CSTR reactor.

[0085] 4-Aminophenol (PAP) is added at room temperature at a rate of 3980 g / h.

[0086] Acetic acid is added at room temperature (20°C) at a rate of 7039 g / h.

[0087] 0.96 eq. of acetic anhydride (AA) is added with a rate of 3556 g / h (step b)), whereby acetylation occurs to form paracetamol (APAP).

[0088] The first CSTR reactor is at a temperature of 80°C with a residence time of the reaction stream of 1 minute.

[0089] The reaction stream is then transferred to a second CSTR reactor which is at a temperature of 100°C with a residence time of the reaction stream of 10 minutes (step b1).

[0090] The reaction flow is filtered (step b2).

[0091] It is then transferred to a COBR type tubular exchanger (oscillating counter-blade tubular exchanger) with a residence time of 20 minutes and an outlet temperature of 25°C (step c).

[0092] The reaction stream is transferred to a third CSTR reactor.

[0093] 0.06 eq. of AA is added in the third CSTR reactor.

[0094] The third CSTR reactor is at a temperature of 25°C with an additional reaction stream residence time of 4 hours.

[0095] The APAP is then filtered (step c3), washed with at least 0.3 vol. of acetic acid and optionally at least 0.5 vol. of water (step c4).

[0096] The yield obtained is 70%. The total impurity rate is less than 0.2% by weight. EXAMPLE 2 (invention):

[0097] 4-Aminophenol, acetic anhydride and acetic acid are added concomitantly by separate streams in a first CSTR reactor.

[0098] 4-Aminophenol (PAP) is added at room temperature (20°C) at a rate of 4218 g / h.

[0099] Acetic acid is added at room temperature at a rate of 6390 g / h.

[0100] 0.98 eq of acetic anhydride (AA) is added with a rate of 3822 g / h (step b)), whereby acetylation occurs to form paracetamol (APAP).

[0101] The first CSTR reactor is at a temperature of 80°C with a residence time of the reaction stream of 18 minutes.

[0102] The reaction stream is then transferred to a second CSTR reactor which is at a temperature of 105°C with a residence time of the reaction stream of 10 minutes (step b1).

[0103] The reaction flow is filtered (step b2).

[0104] It is then transferred to a scraped surface tubular heat exchanger with a residence time of 20 minutes and an outlet temperature of 45°C (step c).

[0105] The APAP is then filtered (step c3), washed with at least 0.3 vol. of acetic acid (step c4).

[0106] The yield obtained is 65%. The total impurity rate is less than 0.2% by weight.

[0107] The APAP is then recrystallized in water (step d).

[0108] The recrystallization yield is 93%. The total impurity rate is less than 0.2% by weight. EXAMPLE 3 (comparison with the acetylating agent in excess relative to the aromatic primary amine):

[0109] 4-Aminophenol, which is dissolved in acetic acid at 70°C, and acetic anhydride are added concomitantly by separate streams in a CSTR.

[0110] 1.05 eq of acetic anhydride (AA) is added (step b)), whereby acetylation occurs to form paracetamol (APAP).

[0111] The CSTR reactor is at a temperature of 80°C with a residence time of the reaction stream of 20 minutes.

[0112] The reaction stream is then transferred to another CSTR reactor which is at a temperature of 105°C with a residence time of the reaction stream of 20 minutes (step b1).

[0113] The reaction flow is filtered (step b2).

[0114] It is then transferred to a scraped surface tubular heat exchanger with a residence time of 20 minutes and an outlet temperature of 70°C (step c).

[0115] The reaction stream is transferred to a CSTR reactor and cooled to 20°C. The APAP is then filtered (step c3), washed with at least 0.3 vol. of acetic acid (step c4).

[0116] The yield obtained is 72%. The total impurity rate is 0.4% by weight, therefore twice as high as those of examples 1 and 2 according to the invention.

Claims

1. A method for the preparation of an N-acetylated aromatic primary amine comprising the steps of: b) bringing in contact an aromatic primary amine with an acetylating agent selected from acetic anhydride, an acetyl halide and a mixture thereof in an equimolar or sub-molar amount relative to the aromatic primary amine, whereby a reaction stream comprising an N-acetylated aromatic primary amine is obtained, the bringing in contact taking place in the absence of palladium, c) cooling the reaction stream, whereby the N-acetylated aromatic primary amine crystallizes, steps b) and c) being carried out continuously.

2. The method according to claim 1, wherein the aromatic primary amine is an aminophenol, preferably 2-aminophenol, 3-aminophenol, or 4-aminophenol.

3. The method according to claim 2, wherein the aromatic primary amine is 4-aminophenol.

4. The method according to any of claims 1 to 3, wherein in step b) the acetylating agent is in a sub-molar amount relative to the aromatic primary amine, and, during step c), acetylating agent is added to the reaction stream.

5. The method according to claim 4, wherein the amount of acetylating agent added in step c) is such that the total amount of acetylating agent added in steps b) and c) is at least 1.00 molar equivalents, in particular 1.00 to 1.15 molar equivalents, preferably 1.00 to 1.08 molar equivalents, particularly preferably 1.00 molar equivalents, with respect to the aromatic primary amine used in step b).

6. The method according to claim 4 or 5, wherein during step c) the acetylating agent is added to the reaction stream when the temperature of said reaction stream is less than 70°C, preferably less than 55°C.

7. The method according to any of claims 1 to 6 comprising, after step c), a step d) of recrystallization of a N-acetylated aromatic primary amine in water, in acetic acid or in a mixture thereof.

8. The method according to any of claims 1 to 7, wherein step b): - is carried out at a temperature from 25°C to 120°C, in particular from 25°C to 110°C, preferably from 30°C to 100°C, more preferentially from 40°C to 90°C, and / or - lasts less than 2 hours, in particular less than 1 hour, more particularly from 10 seconds to 45 minutes, more preferentially from 1 minute to 30 minutes.

9. The method according to any of claims 1 to 8, wherein step b) is carried out in a solvent, preferably acetic acid, water or a mixture thereof.

10. The method according to any of claims 1 to 9, wherein step b) takes place in a continuous stirred-tank reactor.