Continuous synthesis of paracetamol

Abstract

The present invention relates to a continuous process for the preparation of paracetamol, which comprises a nitration step or a nitrosation step to obtain p-nitrophenol or p-nitrosophenol, respectively, which can then be converted to paracetamol by hydrogenation followed by acylation. The process of the present invention allows for the preparation of paracetamol with good regioselectivity and in excellent yields.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a continuous process for the synthesis of paracetamol. [Background technology]

[0002] prior art Paracetamol, also known as acetaminophen, corresponds to N-(4-hydroxyphenyl)acetamide. This compound is used for pain relief (analgesic) and fever reduction (antipyretic) and is one of the most commonly used and prescribed medications worldwide.

[0003] Indicated for the treatment of mild to moderate pain, the compound's immense popularity is due to the fact that it has fewer contraindications than other analgesics and its favorable image among the general public.

[0004] The exact mechanism by which acetaminophen exerts its analgesic and antipyretic effects remains undefined. The primary mechanism of action is thought to be the inhibition of cyclooxygenase (COX), with a primary effect on COX-2.

[0005] There are several methods for synthesizing paracetamol, such as those described in EP 0,435,263, US 6,969,775 and EP 2,266,949.

[0006] Figure 1 summarizes the main chemical routes for the synthesis of paracetamol, along with the intermediates.

[0007] In most cases, such chemical routes go through phenol (via cumene), chlorobenzene, and nitrobenzene, all of which are abundant raw materials worldwide.

[0008] Starting from nitrobenzene, three chemical steps are required to obtain paracetamol, corresponding to a hydrogenation step, a hydroxylation step and an acylation step.

[0009] Starting from chlorobenzene, four chemical steps are carried out: in this case, the synthesis begins with nitration, followed by hydrolysis, reduction and finally acylation to give paracetamol.

[0010] Finally, for phenol, two routes are possible, each involving two or three steps: the two-step route via hydroquinone is relatively complex (reaction at 200 °C for more than 12 hours, with purification between the two steps by solvent change), and the three-step route via 4-aminophenol.

[0011] This last route, which is one of the most used, goes via the nitration of phenol with the formation of para-nitrophenol, followed by reduction and acetylation of the latter to form paracetamol.

[0012] However, this synthetic route suffers from the fundamental problem of low yields in the nitration step of phenol to obtain the interesting p-nitrophenol, a precursor of paracetamol. In fact, the reaction product at the ortho position of the phenyl ring can be up to 66% in proportion, which usually results in two equivalent attachment positions for the para position, resulting in o-nitrophenol at only one position. Furthermore, o-nitrophenol is supported by the formation of a hydrogen bond between the hydroxyl group and one of the two oxygen atoms of the NO group.

[0013] As a result, various techniques have been developed to improve the yield of p-nitrophenol (EP 0 626 366 describes a two-step reaction that produces a 48% yield).

[0014] Here, whether by synthetic method or other methods, the production time to obtain purified paracetamol is about one to two weeks, which is a huge waste of time. Summary of the Invention [Means for solving the problem]

[0015] Detailed Description of the Invention The inventors have developed a new method for the synthesis of paracetamol which can be carried out continuously and with production runs in less than three hours, while at the same time its high throughput performance significantly reduces the associated waste. In a batch manufacturing process, the transition from one step to the next is carried out continuously, so that the overall time of the process is actually the sum of the times required for the different steps. In general principle, such a process involves a continuous flow of integrated reactions in a series of interconnected reactors, each reactor allowing the realization of a specific and essential step leading to the final product. In a continuous process, all steps are carried out simultaneously (albeit in different compartments of the system), reducing the overall time required for the process, and the reactor volume required is much smaller in a continuous process, allowing for more restrictive (harsh) conditions to be operated compared to batch processes, in addition to facilitating plant safety.

[0016] A first object of the present invention relates to a method for preparing paracetamol, said method comprising a nitration or nitrosation step A involving a compound of formula 1 with a nitrating or nitrosating agent suitable to obtain a compound of formula 2; [ka] where R represents: Hydrogen atoms a protecting group selected from benzyl or acetate and X represents a nitro group or a nitroso group. The nitration step A is carried out sequentially as described below: Under microwave irradiation Under ultrasound irradiation Under microwave irradiation followed by ultrasound irradiation or optionally under microwave and / or ultrasonic irradiation and in the presence of an oxidizing agent, in particular HNO3, the nitrating agent consisting of sodium nitrite, The nitrosation step A is carried out sequentially: Nitrosating agents consist of sodium nitrite.

[0017] The present inventors have found that sequential nitration or nitrosation reactions of phenols, optionally protected on the hydroxyl functionality with acetate or benzyl groups, lead to the para-nitro or para-nitroso compounds with excellent regioselectivity. Thus, continuous flow reactions can limit the formation of ortho isomers as well as other impurities such as polymerization products.

[0018] The inventors have also found that in nitration, a continuous process can be carried out in combination with microwave and / or ultrasonic irradiation, which can improve the reaction efficiency in terms of reaction rate and reduce the formation of impurities such as ortho isomers.

[0019] Also, the use of phenolic compounds protected on the hydroxyl functionality allows for the introduction of steric hindrance, with the combined effect of suppressing the hydroxyl functionality that plays a role in the nitration mechanism, and further suppressing the formation of ortho isomers.

[0020] In a particular embodiment, the present invention relates to the method described above, wherein step A is a nitration step, R is as described above, and X is a nitro group, to obtain a nitro compound, wherein the compound of formula 2 has the structure of formula 2a: [ka]

[0021] In another particular embodiment, the present invention relates to the method described above, wherein step A is a nitrosation step, R is as described above, and X is a nitroso group, and the compound of formula 2 has the structure of formula 2b, to obtain a nitroso compound: [ka]

[0022] In such an embodiment, a nitroso compound is obtained which represents an intermediate that can be used in the preparation of paracetamol. In this context, the nitroso function can be reduced or pre-converted to a nitro function directly on the amine function during an additional oxidation step, in particular with nitric acid.

[0023] We observed that the nitrosation reaction was highly efficient from a kinetic standpoint, with excellent regioselectivity of 90% in favor of the Para compound over the ortho secondary product, typically reaching full conversion within 10 minutes of reaction. This nitrosation route is particularly advantageous because the concomitant formation of polymer is very limited.

[0024] In another particular embodiment, the present invention relates to the process described above, wherein the nitration step A or the nitrosation step A is carried out under an inert atmosphere or in open air. By "inert atmosphere" is meant that the nitration or nitrosation is carried out in a reactor under nitrogen or argon, whereas "in the open air" means that no precautions are taken for this purpose.

[0025] In another particular embodiment, the present invention relates to the method described above, wherein R is a hydrogen atom, the compound of formula 1 is a phenol, and X is a nitro group, resulting in p-nitrophenol as the compound of formula 2, or X is a nitroso group, resulting in p-nitrosophenol as the compound of formula 2. In such embodiments, the phenol is not protected on the hydroxyl functionality, which is advantageous from a production cost standpoint as phenol is a commodity product.

[0026] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A is carried out using a nitrating agent selected from HNO3 and NaNO2, to obtain a compound of formula 2, with X as a nitro group. Nitric acid can be used in the presence of an acid such as sulfuric acid or in the absence of such an acid. Preferably, the nitric acid is introduced into the reactor as an aqueous solution. Sodium nitrite, when used in combination with oxidizing agents including nitric acid, leads to nitro compounds.

[0027] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A comprises the following: a) a feed system for the reactor with a solution of the compound of formula 1, in particular aqueous, in particular at a concentration of about 0.4 M, to obtain a reaction medium, and with a nitrating agent, in particular aqueous, in particular at a concentration of about 0.3 to 0.4 M; b) Formation of the compound of formula 2.

[0028] The compound of formula 1, which is a raw material in solution, and the nitrating agent, which is reactive in solution, are continuously introduced into the reactor through an inlet line. The nitration reaction then occurs in the reactor to form the compound of formula 2, where X represents a nitro group. The reaction mixture containing the nitro product (crude product) can then be discharged from the reactor through an outlet channel. The reactor is thoroughly stirred, allowing for uniform distribution of materials within the reactor. Preferably, the rate of introduction or injection of reactants is the same as the rate of discharge or extrusion of the reaction crude product, allowing for a constant volume within the reactor. During the nitration step A, the reactants are introduced into the reactor at a rate of 5 to 20 ml / min, in particular about 10 ml / min or 15 ml / min.

[0029] In another particular embodiment, the present invention relates to the process as described above, wherein the nitration step A is carried out at an initial ratio of nitrating agent / compound of formula 1 of 1.1 to 1.6, preferably 1.2 to 1.5. Here, "1.1 to 1.6" also means the following ranges: 1.1 to 1.5, 1.1 to 1.4, 1.1 to 1.3, 1.1 to 1.2, 1.2 to 1.6, 1.3 to 1.6, 1.4 to 1.6, 1.5 to 1.6, 1.2 to 1.5, 1.3 to 1.4. The "initial rate" refers to the rate at which the nitrating agent and the compound of formula 1 are introduced into the reactor. At this stage, the reagents and raw materials have not yet participated in the nitration reaction.

[0030] In another particular embodiment, the present invention relates to the method described above, wherein the nitration or nitrosation step A is carried out at an initial concentration of the compound of formula 1, in particular phenol, of 0.2 to 0.6 M, more particularly 0.25 to 0.5 M.

[0031] In another particular embodiment, the present invention relates to the method described above, wherein the nitration or nitrosation step A is carried out at an initial concentration of the nitrating agent, in particular HNO3 or NaNO2, respectively, of 0.25 to 0.8 M, more particularly 0.3 to 0.7 M.

[0032] In another particular embodiment, the present invention relates to the process described above, wherein the nitration step A is carried out at a temperature of 70-110°C, preferably 80-100°C. Below 70°C, the reaction kinetics may be too slow to be compatible with an industrially viable process. Above 110°C, secondary products such as polymers or polynitro products may form. When phenol is used as the raw material, the hydroxyl functionality may also be nitrated, forming o-nitrophenol as a by-product. Here, "70-110°C" also means the following ranges: 70-100°C, 70-90°C, 70-80°C, 80-110°C, 90-110°C, 100-110°C, 80-100°C.

[0033] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A is carried out under microwave irradiation, and the nitration under microwave irradiation is carried out in a continuous microwave by a 2.45 GHz or 915 MHz wave generator. Commercially available microwaves are equipped with wave generators at 2.45 GHz or 915 Hz. For industrial processes, the 915 Hz frequency is preferred.

[0034] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A is carried out under microwave irradiation, and the nitration under microwave irradiation is carried out in a continuous microwave with a power in the range of 200-1000 W. Commercially available microwaves range in power from 200 to 1000 W. Here, "200-1000W" also means the following ranges: 200-800W, 200-600W, 200-400W, 400-1000W, 600-1000W, 800-1000W, 400-800W. In particular, the power is about 450W or about 850W.

[0035] In another particular embodiment, the present invention relates to the process described above, wherein the nitration step A is carried out in the presence of a temperature-controlled cooling means. The nitration reaction is exothermic. The exothermic reaction can be controlled by providing the reactor with a cooling means. For example, the reactor may be equipped with a double jacket that allows for the circulation of a cooling liquid. Thus, the term "temperature control" contemplates that the temperature of the reaction medium is kept sufficiently low, below 110°C, preferably below 90°C, to avoid the formation of by-products such as ortho isomers and polymers.

[0036] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A is carried out in a reactor equipped with a wave oscillator integrated with a cooling system. In such an embodiment, a microwave reactor equipped with cooling means is used: typically, a tube is integrated into the microwave reactor for circulating a heat transfer fluid, which is maintained at the desired temperature thanks to a cryostat. For example, a cooling tube continuous reactor: SAIREM's cavity "DOWNSTREAM" can be used.

[0037] In another particular embodiment, the present invention relates to the method described above, wherein the nitration step A is carried out in at least two microwave reactors in series, preferably in at least three microwave reactors in series, preferably in at least four microwave reactors in series. In such an embodiment, multiple reactors are configured in series. The starting compound of Formula 1 and the reactive nitrating agent in solution are introduced into a first reactor, where the nitration reaction occurs with incomplete conversion. The reaction medium continuously exits the first reactor and is injected into a subsequent reactor, where the nitration reaction continues. For example, in a system containing three reactors in series, 60% conversion is possible at the end of the first reactor, 90% conversion is possible at the end of the second reactor, and full conversion can be observed in the third reactor.

[0038] In another particular embodiment, the present invention relates to the process as described above, comprising reactors in series and a cooling step to adjust the temperature to 20-40°C, preferably 20-30°C. In such an embodiment, the reaction medium is cooled between the two reactors in series, which allows for the injection of cooled medium into the subsequent reactor, leading to better control of the exothermic phenomena of the reaction. FIG. 3 illustrates a configuration consisting of multiple microwave reactors in series, each of which is interconnected by a cooling circuit.

[0039] In another particular embodiment, the present invention relates to the process described above, wherein the nitrosation step A is carried out in an acidic medium, in particular in an aqueous solution of hydrochloric acid or sulfuric acid. In such an embodiment, the aqueous solution of the nitrosating agent, sodium nitrite, is pre-acidified by addition of an acid, in particular to a pH of less than 4. The mixture thus obtained is injected into the reactor.

[0040] In another particular embodiment, the present invention relates to the method described above, wherein the nitrosation step A comprises the following: a) a feed system for the reactor with a solution of the compound of formula 1, in particular in aqueous form, and a solution of NaNO2, in particular an aqueous acid solution, especially aqueous hydrochloric acid, to obtain a reaction medium b) Formation of the compound of formula 2. During the nitrosation step A, the reagent NaNO2 in solution and the starting compound of formula 1 in solution are introduced into the reactor at a rate of 5 to 20 ml / min, in particular about 10 ml / min or about 15 ml / min.

[0041] In another particular embodiment, the present invention relates to the method described above, wherein the reactor is driven with an aqueous solution of the compound of formula 1 and comprises a nitrosation step A driven with NaNO in an acidic, in particular hydrochloric, aqueous solution.

[0042] In another particular embodiment, the present invention relates to the process described above, wherein the nitrosation step A is carried out at a temperature below 10°C, in particular in the range of -5 to 5°C, especially at about 0°C. Above 10°C, there can be fast kinetics that can lead to a runaway exothermic reaction. Also, under these conditions, secondary products such as polynitrosation products can form.

[0043] In another particular embodiment, the present invention relates to the method described above, wherein the nitrosation step A is carried out in the presence of air cooling means to control the temperature. The nitrosation reaction is exothermic. The exothermic reaction can be controlled by providing the reactor with a cooling means. For example, the reactor may be equipped with a double jacket that allows for the circulation of a cooling liquid.

[0044] In another particular embodiment, the present invention relates to the process described above, wherein the nitration or nitrosation step A leads to the formation of compounds of formula 2, in particular p-nitrophenol or p-nitrosophenol, and with a regioselectivity of more than 60%, in particular more than 80%, and in particular with a ratio of ortho isomer / compound of formula 2 of less than 2 / 8, in particular about 1 / 9. Here, "greater than 60% regioselectivity" also means greater than 70%, greater than 80%, or greater than 90%. For example, such regioselectivity can be measured using NMR or HPLC. At the end of the nitration or nitrosation step A, the crude reaction product can be directly transferred to the reactor of the next step, i.e., the hydrogenation step. However, it is advantageous to purify such crude reaction product by aqueous washing or crystallization. If the compound of formula 2 is O-acetyl-4-nitrophenol or O-acetyl-4-nitrosophenol, purification in aqueous medium hydrolyzes the acetate group, leading to 4-nitrophenol or 4-nitrosophenol, respectively.

[0045] The inventors have found that the continuous process of the present invention has excellent regioselectivity in favor of para compounds, particularly greater than 80% compared to batch production processes.

[0046] In another particular embodiment, the present invention relates to the process described above, wherein after step A of nitration or nitrosation, such process further comprises step B of hydrogenation of the compound of formula 2 to obtain the compound described below: 4-aminophenol, where R is a benzyl group or a hydrogen atom, or O-acetyl-4-aminophenol, where R is an acetate group [ka] R and X are as defined above The hydrogenation step B is carried out in the presence of hydrogen, a solvent and a catalyst, either continuously or batchwise, preferably continuously.

[0047] The hydrogenation step reduces the nitro or nitroso group to an amine. When R represents a benzyl group, the reaction involves hydrogenolysis of the benzyl group to give p-aminophenol. On the other hand, when R represents an acetate group, O-acetyl-4-aminophenol is obtained because the acetate group is inert and not inhibited under the hydrogenation conditions. Step B of the hydrogenation is carried out in the presence of a catalyst that catalyzes the reduction of the nitro or nitroso compounds to amines. Preferably, the catalyst is a heterogeneous catalyst that can be maintained within the reactor. For this purpose, the reactor may be equipped with a filtering device, for example, a sintered filter at the outlet, to prevent the nitro or nitroso compounds from being discharged with the flow of crude reaction product leaving the reactor. The sintered filter has a porosity of 2 to 50 μm.

[0048] In another particular embodiment, the present invention relates to the method described above, wherein X is a nitro group, the compound of formula 2 is formula 2a, and the hydrogenation step B is carried out from the compound of formula 2: [ka] .

[0049] In another particular embodiment, the present invention relates to the method described above, wherein X is a nitroso group, the compound of formula 2 is formula 2b, and the hydrogenation step B is carried out from the compound of formula 2: [ka] .

[0050] In another particular embodiment, the present invention relates to the method described above, wherein R is a hydrogen atom and X is a nitro group and the compound of formula 2 is p-nitrophenol.

[0051] In another particular embodiment, the present invention relates to the method described above, wherein R is a hydrogen atom and X is a nitroso group and the compound of formula 2 is a p-nitrosophenol.

[0052] In another particular embodiment, the present invention relates in particular to the method described above, wherein the ratio of ortho isomer / compound of formula 2 is less than 2 / 8, in particular about 1 / 9, and the compound of formula 2 is mixed with the ortho isomer.

[0053] In another particular embodiment, the present invention relates to the process described above, wherein step B of the hydrogenation is carried out in the presence of a catalyst selected from Pd / C, Pt / C, Fe / HCl.

[0054] In another particular embodiment, the present invention relates to the process described above, wherein step B of the hydrogenation is carried out in the presence of Silicat Pd(0) as catalyst.

[0055] Thus, the preferred catalyst type for Siliacat Pd(0) is Siliacat®. In particular, Siliacat Pd(0) is a catalyst consisting of Pd trapped in a sol-gel system. Specifically, highly dispersed Pd nanoparticles (uniformly ranging from 4.0 to 6.0 nm) are encapsulated in an organosilice matrix. The catalyst structure is shown below. [ka] Such catalysts are sold by several companies, including Dichrom GmbH of Germany and Silicycle of Canada.

[0056] In another particular embodiment, the present invention relates to the process described above, wherein step B of the hydrogenation is carried out in the presence of a solvent selected from ethanol or methanol, in particular ethanol.

[0057] In another particular embodiment, the present invention relates to the process described above, wherein step B of the hydrogenation is carried out at a temperature of 50 to 130°C, in particular 80 to 100°C. Below 50°C, the reaction kinetics may be too low to be compatible with an industrially viable process, and above 100°C there is a risk of over-reduction, including reduction of the aromatic ring. Here, "50-130°C" also means the following ranges: 60-130°C, 70-130°C, 80-130°C, 90-130°C, 110-130°C, 60-110°C, 80-100°C, 70-90°C.

[0058] In another particular embodiment, the present invention relates to the process as described above, wherein step B of the hydrogenation is carried out at a hydrogen pressure of 10 to 50 bar, in particular 15 to 30 bar, especially about 20 bar. Below 10 bar, the reaction kinetics may be too low to be compatible with an industrially viable process, and above 50 bar there is a risk of over-reduction, especially of the aromatic ring. Here, "10-50 bar" also means the following ranges: 15-50 bar, 25-50 bar, 35-50 bar, 10-40 bar, 10-30 bar, 15-30 bar.

[0059] In another particular embodiment, the present invention relates to the method described above, wherein the compound of formula 2 is introduced into the reactor at a concentration of 0.5 to 1.5 M, in particular about 1 M, and at a rate of 5 to 20 ml / min, in particular 10 to 15 ml / min. In another particular embodiment, the present invention relates to the method described above, wherein the hydrogenation step B is carried out in at least two reactors in series, preferably in at least three reactors in series, particularly preferably in at least three or five reactors in series.

[0060] In another particular embodiment, the present invention relates to the method described above, wherein at least two of the reactors in series are of different sizes.

[0061] In another particular embodiment, the present invention relates to the method described above, wherein at least two of the reactors in series are of different sizes and of increasing size. In such particular embodiments, at least one of the reactors is larger in size than the preceding reactor and at least one of the reactors is the size of the subsequent reactor. In this configuration, the fluid flow rate is constant and identical between each reactor. The fluid outlets for the reactors are located at the top of the reactors, as shown diagrammatically in Figure 4, and fluid will not exit a reactor unless the previous reactor is filled to the outlet height. The outflow rate is equal to the inflow rate. Such configuration of reactors of increasing size allows better control of exothermic phenomena and allows for higher productivity in the process.

[0062] Preferably, the size ratio between the preceding reactor and the succeeding reactor is from 1.1 to 3, including from 1.5 to 3. In a particularly preferred embodiment, the present invention relates to a process in which step B of the hydrogenation is carried out in three successive reactors of increasing size, in particular in a size ratio of about 1:1.5:3. For example, it can be carried out in a cascade of reactors with increasing volumes in the ratios 1, 1.5, 4.

[0063] In another particular embodiment, the present invention relates to the method described above, wherein at least two of the reactors in series are of different sizes and of decreasing size. In such a particular embodiment, at least one of the reactors is smaller than the size of the preceding reactor, and in the subsequent reactor, which is smaller than the size of the preceding reactor, the concentration of the feedstock, i.e., the compound of formula 2, is lower than in the preceding reactor, and some of the compound of formula 2 has already been converted. Subsequent smaller reactors allow for a lower cost increase in catalyst loading to compensate for the lower feedstock concentration. Small reactors can also be more easily agitated than larger reactors, facilitating dispersion of the catalyst in the reaction medium, which is important when catalyst charges are high. Preferably, when the first reactor has a volume R1, the second reactor has a volume R2 in the range of R1 to 0.5R1, and the third reactor has a volume R3 in the range of 0.8R1 to 0.5R1. For example, it can be carried out in a cascade of reactors of decreasing volume in the ratio 1:0.75:0.5.

[0064] In another particular embodiment, the present invention relates to the method described above, wherein step B of the hydrogenation is carried out under the conditions described below: p-Nitrophenol in the presence of catalyst Siliacat Pd(0) or Pt / C In the presence of Silicat Pd(0) or Pt / C as catalyst, Along with ethanol as a solvent In three reactors in series p-Aminophenol is obtained.

[0065] Advantageously, the three reactors in series are of increasing size as described above, such an embodiment allowing the amine compound to be obtained in high yield, in particular in excess of 80%, and especially in excess of 95%.

[0066] In another particular embodiment, the present invention relates to the method described above, wherein step B of the hydrogenation is carried out under the conditions described below: From p-nitrosophenol in the presence of catalyst Siliacat Pd(0) or Pt / C In the presence of Silicat Pd(0) or Pt / C as catalyst, Along with ethanol as a solvent In three reactors in series p-Aminophenol is obtained.

[0067] Advantageously, the three reactors in series are of increasing size as described above, such an embodiment allowing the amine compound to be obtained in high yield, in particular in a yield of more than 80%, in particular in a yield of more than 95%, and especially in a yield of more than 98%. During hydrogenation step B, it has been observed that when R represents an acetate group and a compound of formula 2 is used, the acetate group is transferred to the amine function formed. Thus, hydrogenation of O-acetyl-4-nitrophenol or O-acetyl-4-nitrosophenol leads directly to paracetamol.

[0068] In another particular embodiment, the present invention relates to the process described above, wherein said process further comprises, after the hydrogenation step B, a step C of acylation of p-aminophenol to obtain paracetamol: [ka] The acylation step C is carried out continuously or batchwise, preferably continuously.

[0069] In another particular embodiment, the present invention relates to the method described above, wherein the acylation step C is carried out using acetic anhydride as the organosilice acylating agent.

[0070] In another particular embodiment, the present invention relates to the method described above, wherein acylation step C is carried out using acetic acid as the acylating agent, and wherein such acylation step C is carried out under microwave irradiation in a batch or continuous system.

[0071] In another particular embodiment, the present invention relates to the process described above, wherein the acylation step C is carried out at an initial ratio of acetic anhydride / p-aminophenol of 1.0 to 1.6, preferably 1.1 to 1.4. Using too much acetic anhydride causes purification difficulties compared to suppressing excess acetic anhydride.

[0072] In another particular embodiment, the present invention relates to the process described above, wherein the acylation step C is carried out at a temperature of 60-100°C, preferably about 80°C. Here, "60-100°C" also means the following ranges: 60-90°C, 60-80°C, 60-70°C, 70-100°C, 80-100°C, 90-100°C, 70-80°C. Preferably, the acylation step C is carried out at the same temperature as the hydrogenation step B. For example, if the hydrogenation reaction is carried out at 80°C, the fluid leaving the hydrogenation reactor can be injected directly into the acylation reactor at an elevated temperature. In this way, the acylation reaction can be completed within a few minutes, in particular within 10 minutes or even within 5 minutes. Under these conditions, the temperature of the fluid is sufficiently high that no further heating of the medium is necessary.

[0073] In another particular embodiment, the present invention relates to the method described above, comprising the steps described below: [ka] Step A: Nitration or nitrosation of a compound of formula 1 to give a compound of formula 2 Nitration Step A is carried out as described below ■ Continuously, or continuously and under microwave irradiation, or continuously and under ultrasonic irradiation, or continuously and under microwave irradiation and ultrasonic irradiation. ■ The nitrating agent consists of sodium nitrite, optionally under microwave and / or ultrasonic irradiation and in the presence of an oxidizing agent, in particular HNO3; Nitrosation Step A is carried out continuously, the nitrosating agent comprises sodium nitrite, and R and X are as defined above. Step B of hydrogenation of the compound of formula 2 to obtain the compound shown below: ■ 4-aminophenol, in which R is a benzyl group or a hydrogen atom; or ■ Paracetamol, where R is an acetate group; or The hydrogenation step B is carried out continuously or batchwise, preferably continuously, and Step C of acylation of 4-aminophenol to obtain paracetamol The acylation step C is carried out continuously or batchwise, preferably continuously.

[0074] Preferably, all three steps A, B and C are carried out consecutively. It is understood that step C is carried out only if paracetamol has not been obtained at the end of step B of the hydrogenation.

[0075] In another particular embodiment, the present invention relates to the method described above, comprising the steps described below: Phenol nitration step A to obtain p-nitrophenol This step A of nitration is carried out continuously and under microwave irradiation. Step B: Hydrogenation of p-nitrophenol compounds to obtain p-aminophenol This step B of hydrogenation is carried out continuously in three reactors in series. Step C of acylation of 4-aminophenol to obtain paracetamol The acylation step C is carried out sequentially.

[0076] Such a preferred embodiment corresponds to the diagram shown below: [ka]

[0077] In another particular embodiment, the present invention relates to the method described above, comprising the steps described below: Nitrosation of phenol to give p-nitrosophenol, step A This step A of nitrosation is carried out continuously at a temperature below 10°C. Step B: Hydrogenation of p-nitrosophenol compounds to obtain p-aminophenols This step B of hydrogenation is carried out continuously in three reactors in series. Step C of acylation of 4-aminophenol to obtain paracetamol The acylation step C is carried out sequentially.

[0078] Such a preferred embodiment corresponds to the diagram shown below: [ka]

[0079] In another particular embodiment, the present invention relates to the method described above, which comprises at least one purification step between A and B or B and C, in particular, such purification step is an aqueous wash. The synthetic intermediates obtained at the end of nitration / nitrosation step A and / or hydrogenation step B, as well as the final product obtained at the end of acylation step C, can be purified. For example, this can be by aqueous washing to remove acid and salt residues at the end of step A or C, or by filtration, a charcoal layer or a zeolite layer to remove catalyst residues at the end of step B. Alternatively, further purification can be carried out by crystallization, distillation or successive liquid / liquid extractions, etc.

[0080] In another particular embodiment, the present invention relates to the process as described above, comprising step D of purification of paracetamol, in particular by continuous distillation, continuous liquid / liquid extraction and / or crystallization, in particular continuous crystallization.

[0081] The final product of the process of the present invention, paracetamol, may be purified by methods well known to those skilled in the art to a purity compatible with therapeutic use, with the aim in particular of removing any residual ortho-isomers that may be present in the crude product.

[0082] Finally, the present invention relates to a method for preparing paracetamol, comprising the following successive steps: 1) Synthesis of p-nitrophenol from phenol [ka] 2) Synthesis of p-aminophenol from p-nitrophenol [ka] 3) Synthesis of paracetamol from p-aminophenol [ka] The method is characterized in that steps 1, 2, and 3 are carried out consecutively, and step 1 is carried out under microwave irradiation. In fact, the inventors were able to obtain a regioselectivity for the nitration of phenols at the para position of greater than 60%.

[0083] The present invention also relates to a method for preparing paracetamol, comprising the following successive steps: 1) Synthesis of p-nitrosophenol from phenol [ka] 2) Synthesis of p-aminophenol from p-nitrophenol [ka] 3) Synthesis of paracetamol from p-aminophenol [ka] [Brief explanation of the drawings]

[0084] [Figure 1] Figure 1 shows the different chemical pathways for paracetamol production. [Figure 2] FIG. 2 shows the temperature change of the reaction mixture over time as it passes through a circuit formed by multiple microwave reactors in series, each of which is interconnected by a cooling circuit. [Figure 3] FIG. 3 shows a schematic diagram of an installation for carrying out the first step, in which the phenol / HNO3 mixture is introduced into an installation with multiple microwave reactors in series, each of which is interconnected by a cooling circuit. [Figure 4]FIG. 4 shows an installation for carrying out the second hydrogenation step, in which several hydrogenation reactors are arranged in series. [Figure 5] FIG. 5 shows a flow chart of the continuous synthesis of paracetamol, including the nitration step. [Figure 6] FIG. 6 shows a flow chart of the continuous synthesis of paracetamol, including the nitrosation step. [Figure 7] FIG. 7 shows the conversion of the hydrogenation reaction in a three reactor system in series according to Example 5.2. DETAILED DESCRIPTION OF THE INVENTION

[0085] The nitration reaction is carried out with a mixture of phenol and nitric acid. Such reactions are carried out in the presence of a strong acid such as sulfuric acid, hydrofluoric acid, perchloric acid, or boron trifluoride. Preferably, such reactions are carried out in the presence of sulfuric acid. Here, in addition to the microwave step, the inventors also found that the concentration ratio of phenol to nitric acid has a strong influence on the regioselectivity and on the formation of p-nitrophenol over o-nitrophenol. Thus, the use of excess nitric acid promotes the formation of o-nitrophenol. Under these conditions, the inventors were able to obtain up to 82% p-nitrophenol (in this case, 18% o-nitrophenol).

[0086] Advantageously, the HNO3 / phenol ratio in the starting mixture is between 1.1 and 1.6, preferably between 1.2 and 1.5. Preferably, it is 0.25 to 0.5M.

[0087] The concentration of the starting mixture in HNO3 is 0.25-0.8M, preferably 0.3-0.7M. The water ratio of the starting mixture is 40 to 95% (volume relative to the volume of the mixture at this stage), preferably 50 to 90%. For step 1, the residence time of the mixture in the microwave reactor is increased to 70-110° C., preferably 80-100° C. A change to a higher temperature tends to affect regioselectivity and increase the proportion of o-nitrophenol.

[0088] The inventors were able to further increase the regioselectivity by increasing the residence time of the mixture in the microwave reactor without increasing the temperature. To achieve this, the inventors set up a series of microwave reactors incorporating a cooling circuit.

[0089] In a preferred embodiment, step 1 is carried out in at least two consecutive microwave reactors, preferably at least three consecutive microwave reactors, particularly preferably at least four consecutive microwave reactors, with cooling circuits between the microwave reactors allowing the temperature of the mixture to be between 20 and 40°C, preferably between 20 and 30°C. Typically, the residence time in all microwave reactors is from 2 to 20 minutes, preferably from 2 to 15 minutes. Preferably, each of the microwave reactors includes a nitric acid supply system. In this way, during the nitration reaction (in different microwave reactors), the ratio of HNO3 / phenol in the mixture can be maintained at 1.1-1.6, preferably 1.2-1.5.

[0090] FIG. 2 shows the temperature (° C.) evolution over time (in minutes) of the reaction mixture as it passes through a circuit formed by microwave reactors (MO) interconnected by cooling circuits. FIG. 3 shows a schematic diagram of the equipment for carrying out the first step, in which the phenol / HNO3 mixture is introduced into the first microwave reactor (MO), passes through the first cooling circuit before circulating in the second, third, and fourth microwave reactors, with the cooling circuit passing between the microwave reactors, primarily forming p-nitrophenol.

[0091] To optimize the balance of the reaction, cooling should be carried out quickly, typically within 0.5 to 3 minutes, preferably 1 to 2 minutes. At the end of step 1), the two isomers, o-nitrophenol and p-nitrophenol, can be easily separated. Such purification can be carried out by an intermediate step of steam distillation of o-nitrophenol (between step 1 and step 2) (see US Patent 3,933,929), filtration and washing with 70% sulfuric acid solution followed by water (see EP Patent 0626366), solubilization (n-pentane to remove o-nitrophenol using the difference in solubility of the two isomers in different solvents), ultrafiltration (see Yudiarto et al., Separation and Purification Technology, vol. 19, p:103-112, 2000), HPLC (SMB type (simulated moving bed) or VARICOL).

[0092] In a preferred embodiment, p-nitrophenol is purified at the end of step 2) and before step 3). Here, it is also possible to start step 2) without purification and separate p-aminophenol from o-aminophenol at the end of step 2).

[0093] Regarding the second step of the reduction of p-nitrophenol to p-aminophenol, the following methods can be selected and carried out: A) Addition of dihydrogen in the presence of catalyst type Pd / C, Pt / C, Fe / HCl or equivalent catalysts and under pressure B) Addition of a hydrogen donor (e.g., NaBH4) in the presence of a solid catalyst (e.g., gold nanoparticles).

[0094] In a preferred embodiment, step 2) is carried out by addition of dihydrogen in the presence of a catalyst of the type Pd / C, Pt / C, Fe / HCl or equivalent, and under pressure. Advantageously, the mixture corresponds to a selection of p-nitrophenol in aqueous medium in the presence of an acid (preferably sulfuric acid, since it gives a higher yield than hydrochloric acid), or p-nitrophenol in alcoholic solution, preferably ethanolic or methanolic solution. Advantageously, the hydrogenation of p-nitrophenol is carried out in an alcoholic solution, preferably an ethanolic solution. Advantageously, the concentration of the mixture in alcohol is between 70 and 95% (comparison of said volume with the volume of the mixture upstream of the hydrogenation reactor), preferably between 80 and 90%.

[0095] Preferably, the catalyst used is Pt / C, which in fact maximizes the yield. The catalyst charge in the hydrogenation reactor is greater than or equal to 1% (ratio of the weight of the mixture in the reactor to the weight of the mixture in the reactor), preferably greater than or equal to 2%, particularly preferably equal to 5%. Advantageously, the pressure in the hydrogenation reactor is greater than 20 bar. Preferably, the pressure in the hydrogenation reactor is between 20 and 100 bar, preferably between 20 and 50 bar. Advantageously, the temperature of the mixture in the hydrogenation reactor is greater than 80°C. Preferably, the temperature of the mixture in the hydrogenation reactor is 80 to 180°C, preferably 100 to 150°C.

[0096] To improve the conversion yield, the inventors installed multiple hydrogenation reactors in series. In a preferred embodiment, step 2) is carried out in at least two hydrogenation reactors in series, preferably in three hydrogenation reactors in series, particularly preferably in at least four hydrogenation reactors in series. Preferably, an online analysis of the mixture is carried out between each of the hydrogenation reactors to control the reaction kinetics and, if necessary, to modify this, to control possible deactivation of the catalyst.

[0097] FIG. 4 illustrates an installation for carrying out the second step in which a mixture containing p-nitrophenol in ethanol solution is introduced into a first hydrogenation reactor containing a solid catalyst (Pt / C), and dihydrogen is injected under pressure before passing to the second, third, and fourth hydrogenation reactors to form primarily p-aminophenol.

[0098] Finally, the inventors were able to obtain a conversion yield of p-nitrophenol to p-aminophenol of the order of 97%. It is worth noting that such a second step also offers numerous advantages over conventional processes: in fact, it is a continuous operation, which guarantees high productivity even at a compact size, it is safer due to the small volume required for the reactor, and it maximizes the useful life of the catalyst used. At the end of step 2), and preferably at the end of step 2), if p-nitrophenol is not purified in step 3).

[0099] In another embodiment, p-aminophenol is purified at the end of step 2. Such a separation can be easily achieved by one of ordinary skill in the art using the solubility differences between the two isomers. Regarding the third step, which is the acylation of p-aminophenol to paracetamol, this is carried out at the outlet of the (final) hydrogenation reactor by addition of an acylating agent to the mixture. As for the acylating agent, both acetic acid and acetic anhydride are worthy of consideration. Advantageously, the acylating agent / p-aminophenol ratio in the mixture and after addition of the acylating agent is between 1 and 10, preferably between 1 and 4. When the acylating agent is acetic anhydride, the mixture contains an alcohol as the solvent, preferably ethanol or methanol.

[0100] The acylation reaction is then carried out by heating the mixture preferably to a temperature of 20 to 90°C for 0.5 to 10 minutes, particularly preferably to a temperature of 20 to 60°C for 1 to 4 minutes. If the acylation reaction is with acetic acid, such acylation can be carried out in a similar manner to acetic anhydride, but without the presence of alcohol and acetic acid. Then, the temperature and reaction time used must be increased. Typically, the acylation reaction is carried out by heating at a temperature of 50 to 130°C for 1 to 40 minutes, and particularly preferably by heating at a temperature of 60 to 100°C for 10 to 20 minutes.

[0101] The inventors have now discovered that the acylation reaction can be carried out extremely rapidly using acetic acid in a microwave reactor. It is noteworthy that in this case, acetic acid is used as a solvent, which greatly simplifies the process, since the solvent can be reused by simple distillation of the mixture from the microwave reactor. In addition to the high cost of acetic anhydride, its use requires the removal of the solvent (ethanol or methanol) used.

[0102] In a preferred embodiment, step 3 uses acetic acid and is carried out under microwave irradiation. Preferably, no additional solvent (in addition to acetic acid) is used in such step 3. Typically, the ratio of p-aminophenol to acetic acid is 1 / 5 to 10, preferably 1 / 6 to 1 / 9. To achieve this, the residence time of the mixture in the microwave reactor is the time until the temperature is raised to 80 to 120°C, preferably 90 to 110°C. Typically, the residence time in all microwave reactors is from 1 to 60 minutes, preferably from 10 to 30 minutes.

[0103] At the end of the acylation reaction, the paracetamol is continuously purified. Typically, such a purification step can be carried out by simple distillation to remove the solvent. Advantageously, such a purification step may comprise a washing step with purified water, in particular under an inert gas, argon or equivalent gas.

[0104] The process of the present invention, the flow chart of which is shown in Figure 5, allows the synthesis of paracetamol in excellent (more than 70%) yield. The examples set forth below are offered for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0105] Example 1) Phenol nitration: In a microwave reactor of 6 ml volume, 50 mg of phenol are introduced with 0.7 ml of nitric acid 6% by weight together with 1.07 ml of H2O. The reactor is then set to start a heating step at a temperature of 160°C for 1 minute 30 seconds followed by cooling to 55°C, followed by heating at 120°C for 1 minute 30 seconds followed by cooling to 55°C. The results of HPLC analysis showed that the conversion of phenol to nitrophenol was obtained in an overall yield of 99.35%, specifically, the ratio was about 60% p-nitrophenol (and about 40% o-nitrophenol). Subsequent tests show that the faster the cooling step, the greater the regioselectivity and therefore the greater the proportion of p-nitrophenol. For the continuous nitration reaction, tests were carried out in a continuous microwave (SAIREM) with a 2.45 GHz wave generator and a coaxial transition / waveguide with a cooler at a power of 450 W.

[0106] 2) Hydrogenation of p-nitrophenol to p-aminophenol In a continuous hydrogenation reactor (total volume 400 ml), the reactor is divided into different zones, each equipped with a stirrer, and the pure solvent is introduced together with the catalyst Pt / C. The temperature in the reactor is controlled by a thermostatic bath that heats or cools different parts of the continuous reactor, and is maintained at the desired temperature. The hydrogen pressure is maintained constant at each part. p-Nitrophenol is then continuously introduced into the solvent at a predetermined rate and concentration. The output samples are taken for conversion and selectivity measurements. The catalyst charge Pt / C was 2% (wt / wt percent of the mixture in the reactor) in each zone, at a constant temperature of 80°C, for a flow rate of 800 / h or 13.3 ml / min consisting of a 0.5 M solution of p-nitrophenol in ethanol. The results obtained showed a conversion of 99% with a selectivity of 98% at a residence time in the reactor of 30 minutes. Optimization is performed with respect to the reaction parameters (reaction volume in each zone, catalyst loading in each zone, temperature and pressure H2 in each zone, and total flow rate). Previously, Pt / C catalysts have shown the best results (at about 1% w / w), where an increase in catalyst charge of up to 5% (w / w) is possible in a hydrogenation reactor capable of withstanding a hydrogen pressure of 100 bar and a temperature of 150°C, thereby reducing the residence time to 15-30 minutes and significantly increasing productivity while maintaining good catalytic activity.

[0107] 3) Acylation of p-aminophenol to paracetamol 3.1) Temperature conversion test The test is carried out in vapourtec R2+ and R3 types with a volume of 10 ml, filled by a peristaltic pump. The sample is then collected at the outlet of the vapourtec and analyzed by HPLC. In the first test, a solution of p-aminophenol (0.3 M in ethanol) is injected into the vapourtec at a rate of 5 ml / min and at room temperature. Simultaneously, a solution of acetic anhydride (0.3 M in ethanol) is injected into the vapourtec at a rate of 5 ml / min and at room temperature. The total flow rate is 10 ml / min with a transit time in the vapourtec of 1 minute. Analysis showed a p-aminophenol conversion of 99.9% with a selectivity of 98.7% for paracetamol. In the second test, a solution of p-aminophenol (0.14 M in ethanol) is injected into the vapourtec at a rate of 5 ml / min and at a temperature of 60° C. Simultaneously, a solution of acetic anhydride (0.14 M in ethanol) is injected into the vapourtec at a rate of 5 ml / min and at a temperature of 60° C. The total flow rate is 10 ml / min with a transit time in the vapourtec of 1 minute. Analysis showed 99.9% conversion of p-aminophenol with 98.9% selectivity for paracetamol. In the third test, a p-aminophenol solution (0.14 M in ethanol) was injected into the vapourtec at a rate of 3.3 ml / min and at room temperature. Simultaneously, an acetic anhydride solution (0.14 M in ethanol) was injected into the vapourtec at a rate of 3.3 ml / min and at room temperature. The total flow rate was 6.6 ml / min with a transit time through the vapourtec of 1.5 min. Analysis showed 99.9% conversion of p-aminophenol with 98.9% selectivity with respect to paracetamol.

[0108] 3.2) Microwave conversion test The microwave used is a MONOWAVE 300 (ANTON PAAR) with a magnetron power of 850 watts, where the power is adapted to the desired temperature. The various reagents are delivered to a stirred 10 mL reactor placed inside a microwave containment chamber. Upon completion of the cycle, the reactor is allowed to cool before samples are removed and analyzed by HPLC. In the first test, p-aminophenol is introduced into a solution of acetic anhydride in water (30 / 70) at a concentration of 7.77 M. The reactor is then introduced into a microwave at a temperature of 40° C. for 10 seconds. The results obtained showed a 99.9% conversion of p-aminophenol with a selectivity of 98.9% with respect to paracetamol. In a second test, p-aminophenol is introduced into an acetic acid solution at a concentration of 5 M. The reactor is then placed in a microwave at a temperature of 100° C. for 20 minutes. The results obtained showed 95% conversion of p-aminophenol with 93.5% selectivity with respect to paracetamol.

[0109] 4) Continuous nitration of phenol with nitric acid 4.1) Uncooled tubular continuous reactor: SAIREM "AVOCADO" cavity The reaction was carried out in a 500 mL borosilicate tubular reactor inserted into the cavity of an "AVOCAT" type (SAIREM) and connected to a microwave generator GMS450 with a maximum power transmission of 450 W thanks to the quartz window transmission. The total irradiation volume was 160 mL. 350 mL of a 0.4 M phenol solution and 0.375 M nitric acid (1.25 eq) was injected into the cavity at a rate of 16 mL / min, thus resulting in a transit time in the irradiation zone of 10 min. The reaction is carried out by microwave irradiation using a microwave generator operating at 2.45 GHz with a 250 W power supply. In this way, paracetamol was obtained in a ratio of 20 / 80 with a productivity of 25 g / h.

[0110] 4.2) Cooled-tube continuous reactor: SAIREM "DOWNSTREAM" cavity The device consists of a borosilicate tubular reactor (60 mL, internal diameter 12 mm) equipped with coolant inlet and outlet channels and inserted into a second borosilicate tube (double envelope, internal diameter 23 mm). The assembly is inserted into a cavity mold "DOWNSTREAM" (company name: SAIREM) and is connected to a microwave generator GMS1000 with a maximum power transmission of 1000 W thanks to a quartz window transmission. The total irradiation volume is approximately 10 mL. The device also includes a temperature probe (fiber optic) immersed in the reactor. A specific oil with a zero dielectric constant (and therefore microwave transparent) is used to cool the inner reactor. The coolant can be maintained at temperatures between -10 °C and 0 °C thanks to a cryostat. An aqueous solution of 0.4 phenol and 0.375 M nitric acid (1.25 eq) was injected into the cavity at a rate of 10 ml / min. Thus, the transit time in the irradiation zone was 6 minutes. Tests have shown that microwave heating with cooling allows for perfect control and stable temperatures in such a process.

[0111] 5) Hydrogenation of p-nitrophenol using Silicat as catalyst 5.1) Batch Testing Batch reactions were carried out in a single sealed reactor. The reactor was preloaded with a solution of 6.95 g of p-nitrophenol in 100 mL of EtOH and 0.208 mg of SiliaCat Pd(0) (reagent purchased from Aldrich and catalyst purchased from SiliCycle). The reactor was then purged with dinitrogen (3 purges, 5-7 bar) and pressurized with hydrogen (H2Alphagaz, Air Liquide) under 15 bar. Agitation was set at 1000 rpm (revolutions per minute). When the reactor was heated to T=80° C., 86% conversion was obtained in 80 minutes, and when the reactor was at 100° C., 88% conversion was obtained in 60 minutes.

[0112] 5.2) Continuous Test The same conditions as used in Example 2 were employed and tested using the catalyst Siliacat Pd(0) (SiliCycle, Quebec Canada, Ref RD-R815-SiliaCat® Pd0) at a rate of 0.5 mol%. Complete conversion was achieved in 90 minutes.

[0113] 5.3) Three consecutive reactors in series - Tests with reactors of increasing size The hydrogenation reaction is carried out using three reactors in series. The results shown below were obtained. [Table 1]

[0114] In the table above, the amount of catalyst "Mcata" is expressed in mol %. A productivity of 3.7 kg / L / day of p-aminophenol was achieved with three reactors in series. Figure 7 shows the conversion of each reactor.

[0115] 5) Hydrogenation of p-nitrophenol in a cascade of two or three fully stirred continuous reactors 5.1) Batch Focus The reaction in batch mode was carried out in a single sealed reactor. The reactor was precharged with a solution of 6.95 g of p-nitrophenol in 100 mL of EtOH and 9.75 mg of Pt / C (Sigma-Aldrich). The reactor was then purged with dinitrogen (3 purges, 5-7 bar) and then pressurized with hydrogen (H2Alphagaz, Air Liquide) under 15 bar. The stirring was fixed at 1000 rpm and the mixture was heated to 80 °C with a double envelope for 1 h 20 min. At the end of the reaction, the mixture was inactivated with a dinitrogen purge and the reaction medium was analyzed by HPLC (reverse phase, column C18). Analysis showed a 92% conversion of p-nitrophenol to p-aminophenol without any reaction by-products.

[0116] 5.2) Cascade Reactions The same equipment used in Example 5.1 was reused to carry out the reaction in a cascade of three fully stirred continuous reactors. The outlet piping of the first reactor, always equipped with a 5 μm filtering candle to maintain a constant catalyst load in the autoclave, was connected to the inlet of the second reactor at a similar point to the first reactor. Both reactors were charged with 20 mg of Pt / c 10% w / w (Sigma-Aldrich). 50% conversion was simulated in the first reactor (3.48 g of p-nitrophenol vs. 2.72 g of p-aminophenol) and 75% conversion was simulated in the second reactor (1.8 g of p-nitrophenol vs. 4 g of p-aminophenol). Under the conditions described above (80 °C, 15 bar, 1000 rpm for the first reactor and 80 °C, 12 bar, 1000 rpm for the second reactor), but with a slightly reduced pressure, the cascade was fed with a solution of p-nitrophenol in ethanol (0.3 M) at a flow rate of 3 mL / min (passage time: 30 min per reactor). The outlet valve of the second reactor was set so that the outflow was approximately equal to the inflow. No events occurred during the reaction for 5 h. Samples were taken every 4 min. HPLC analysis showed that the conversion fluctuated between 70% and 83% and then stabilized at around 80% without the formation of by-products. In another example, a third reactor is connected in cascade. Similarly, this reactor is loaded with 20 mg Pt / C, and an initial conversion of 90% is simulated (4.9 g of p-aminophenol for 695 g of p-nitrophenol). Under the conditions described above (80 °C, 15 bar, 1000 rpm, 15 bar, 12 bar, 10 bar), waterfall is fed at a flow rate of 4 mL / min for 4 hours (pass time: 25 min). No events occur. Samples are taken at the reactor outlet every 4 minutes. HPLC analysis shows that the conversion fluctuates between 80% and 96%, then stabilizes at around 95% for 4 hours.

[0117] 6) Phenol nitrosation and hydrogenation - batch protocol 6.1) Nitrosation A solution of NaNO2 (42% in water, 2 eq.) was added dropwise to a solution of HCl 35% (40 ml) under air with stirring at T = 0 °C. The solution turned orange and released a small amount of orange gas. A solution of phenol in water (80% in water, 1 g, 1 eq.) was added dropwise to the solution (final phenol concentration = 0.3 M). The solution gradually turned black and the mixture became thick. After 30 min, HPLC analysis showed that the phenol was completely consumed. The mixture was diluted with 500 mL of H2O and extracted with AcOEt (3 * 250 mL). The organic layer was collected, dried over Na2SO4, filtered, and evaporated to dryness to give a mixture of 2-nitrosophenol and 4-nitrosophenol.

[0118] 6.2) Hydrogenation of pure p-nitrosophenols and para- and ortho-nitrosophenols The crude mixture obtained in Example 6.1 was solubilized in MeOH, and Pt / (C) (mass%) was suspended. The mixture was stirred and placed under hydrogen pressure (1 atm). After 2 hours, no traces of 2-nitrosophenol and 4-nitrosophenol remained. The solution was filtered through Celite to obtain a mixture of 2-aminophenol and 4-aminophenol in an o / p ratio of 10 / 90. Two further hydrogenation experiments on pure p-nitrosophenol were carried out using catalysts Pt / C and SiliaCat Pd(0) under pressure (P = 15 bar) at T = 80 °C. Conversions on the order of 99% were obtained (HPLC control) with an excellent yield of 99.8%.

[0119] 7) Phenol nitrosation - sequential protocol The same ratio as used in Example 6.1 was used for the continuous test. However, after a residence time of 5 minutes in the continuous reactor, an aqueous solution of phenol was added, and after a residence time of 5 minutes, nitrosophenol was continuously obtained. According to the conditions of Example 6.2, the extraction was carried out in batch, and batch hydrogenation was carried out to obtain a mixture of 2-aminophenol and 4-aminophenol in an o / p ratio of 10 / 90.

Claims

1. 1. A process for the preparation of paracetamol, comprising step A: nitration or nitrosation of a compound of formula 1 using a nitrating or nitrosating agent to obtain a compound of formula 2: 【Chemistry 1】 where R represents: Hydrogen atoms a protecting group selected from benzyl or acetate and X represents a nitro group or a nitroso group. The nitration step A is carried out sequentially as described below: Using at least two microwave reactors in series, including a temperature-controlled cooling means selected from a double jacket allowing the circulation of a cooling fluid between the reactors in series or a tube integrated in the microwave reactor for circulating a heat transfer fluid maintained at a desired temperature by virtue of a cryostat, under microwave irradiation. using at least two microwave reactors in series, including a temperature-controlled cooling means selected from a tube integrated into the microwave reactor for circulating a heat transfer fluid maintained at a desired temperature by virtue of a double jacket or a cryostat allowing circulation of a cooling fluid between the reactors in series, under microwave irradiation and subsequent ultrasonic irradiation; - Sodium nitrite is used as the nitrating agent, and the nitration is carried out in the presence of an oxidizing agent or HNO 3 In the presence of Under microwave irradiation, in the presence of an oxidizing agent or HNO 3 In the presence of a nitrating agent consisting of sodium nitrite, the nitroso functionality is converted to a nitro functionality during an additional oxidation step. Under ultrasonic irradiation, in the presence of an oxidizing agent or HNO 3 in the presence of a nitrating agent consisting of sodium nitrite, which converts the nitroso functionality to a nitro functionality during an additional oxidation step, or Under microwave and ultrasonic irradiation, in the presence of an oxidizing agent or HNO 3 In the presence of a nitrating agent consisting of sodium nitrite, the nitroso functionality is converted to a nitro functionality during an additional oxidation step. The nitrosation step A is carried out sequentially: The nitrosating agent consists of sodium nitrite, The nitrosation step A is carried out in an aqueous solution of hydrochloric acid in the absence of an oxidizing agent.

2. 2. The method of claim 1, wherein step A is a nitration step, R is as defined in claim 1, and X is a nitro group, to obtain a nitro compound: 【Chemistry 2】 。

3. The method of claim 1, wherein step A is a nitrosation step, R is as defined in claim 1, and X is a nitroso group, to obtain a nitroso compound, wherein the compound of formula 2 has the structure of formula 2b: 【Transformation 3】 。

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