OA21016A - Continuous paracetamol synthesis process - Google Patents

Abstract

The present invention relates to a process for the continuous preparation of paracetamol, comprising a nitration step or a nitrosation step to obtain p-nitrophenol or p-nitrosophenol respectively. p-nitrophenol or p-nitrosophenol can then be converted to paracetamol by hydrogenation, followed by acylation. The process according to the present invention makes it possible to obtain paracetamol with very good regioselectivity and excellent yields.

Description

Technical area

The present invention relates to a process for the continuous synthesis of paracetamol.

Prior art

Paracetamol, also called acetaminophen, corresponds to A-(4-hydroxyphenyl)0 acetamide. This compound is used as both an analgesic (painkiller) and an antipyretic (antifever), and is among the most common, used and prescribed medications in the world.

It is indicated in the treatment of mild to moderate pain and its great popularity is due to the fact that it has fewer contraindications than other analgesics and enjoys a good image among the public.

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

There are multiple paracetamol synthesis processes, such as those described in patents EP 0 435 263, US 6,969,775, and EP 2 266 949.

Figure 1 summarizes the main chemical pathways for paracetamol synthesis with their intermediates.

Essentially, these routes pass either through phenol (via cumene), or through chlorobenzene, or through nitrobenzene, all three of which are high-tonnage raw materials globally.

Starting from nitrobenzene, 3 chemical steps are necessary, which correspond to hydrogenation, followed by hydroxylation and acylation to obtain paracetamol.

Starting from chlorobenzene, 4 chemical steps are required. In this case, the synthesis begins with nitration, followed by hydrolysis, reduction and finally acylation to obtain paracetamol.

Finally, regarding phenol, two routes are possible, which involve two or three steps respectively. The two-step route involves hydroquinone, but is relatively complex (reaction lasting more than 12 hours at 200°C with purification between the two steps due to a change of solvent). As for the 3-step pathway, this goes through 4aminophenol.

This last route, which is among the most used, involves nitration of the phenol with the formation of para-nitrophenol and is followed by a reduction and acetylation of the latter to form paracetamol.

Now, this synthesis route suffers from a fundamental shortcoming which lies in the fact that the nitration step of the phenol to obtain the p-nitrophenol of interest - which is the precursor of paracetamol - presents a low yield. Indeed, the product of the reaction in the oitho position of the phenyl ring can present a proportion of up to 66%, this constituting the normal result of having two equivalent attachment positions resulting in onitrophenol for only one position. for the para position. In addition, o-nitrophenol is favored by the formation of a hydrogen bond between the hydroxyl group and one of the two oxygen atoms of the NO ₂ group.

As a result, different technologies have been developed to try to increase the yield of p-nitrophenol (two-step reaction giving a yield of 48% described in patent EP 0 626 366).

Now, whether it is this synthesis route or the others, it takes a production time of around one to two weeks to obtain purified paracetamol, and this with a significant quantity of waste.

Presentation of the invention

The inventors have now developed a new process for synthesizing paracetamol which is carried out continuously and which allows its production to be carried out in less than 3 hours, with simultaneously a considerable reduction in the quantity of associated waste due to its very high efficiency.

In the batch production process, the transition from one step to the next is carried out in series and therefore the overall process time is, in fact, the sum of the times required for the different steps.

In its general principle, this process consists of a continuous flow of integrated reactions in which a succession of reactors are interconnected. Each reactor allows a specific and essential step to be carried out to produce the final product.

In the continuous process, all steps are carried out simultaneously (although in different compartments of the system), and therefore the overall time required for the process is shortened. In addition, the volume required for the reactors is much lower for a continuous process which, in addition to facilitating the management of the safety of the installations, makes it possible to work in much more (astringent) restrictive conditions than for batch processes.

A first object of the present invention relates to a process for preparing paracetamol, in which the process comprises a step A of nitration, or nitrosation, of a compound of Formula 1 with a nitration agent, or a nitrosation agent suitable for obtain a compound of Formula 2:

2 in which R represents:

• a hydrogen atom, • a protective group chosen from a benzyl or an acetate, and in which X represents a nitro group or a nitroso group, said nitration step A being carried out continuously:

• either under microwaves, • either under ultrasound, • either under microwaves followed by ultrasound, • or, optionally under microwaves and/or under ultrasound, the nitration agent being sodium nitrite, in the presence of an oxidizing agent, particularly in the presence of HNO, said nitrosation step A being carried out continuously:

• the nitrosation agent being sodium nitrite.

The inventors have found that the continuous nitration or nitrosation reaction of phenol, optionally protected on the hydroxyl function by an acetate or benzyl group, leads respectively to the para-nitro, or para-nitroso compound, with excellent regioselectivity. The continuous flow reaction thus makes it possible to limit the formation of the ortho isomer, as well as that of other impurities such as polymerization products.

The inventors have also found that, in the context of nitration, the continuous process can be carried out in combination with microwave and/or ultrasound irradiation, allowing improved reaction efficiency in terms of reaction speed and the reduced formation of impurities such as the ortho isomer.

Furthermore, the use of a phenolic compound protected on the hydroxyl function makes it possible to introduce steric hindrance, which, in combination with the suppression of the hydroxyl function which plays a role in the nitration mechanism, further the suppression of the formation of the ortho isomer.

According to a particular embodiment, the present invention relates to a process as defined above, in which step A is a nitration step, R being as defined above, and X being a nitro group, to obtain a nitrate compound in which the compound of Formula 2 has the structure of a compound of Formula 2a:

According to another particular embodiment, the present invention relates to a process as defined above, in which step A is a nitrosation step, R being as defined above 1, and X being a nitroso group, to obtain a nitroso compound in which the compound of Formula 2 has the structure of a compound of Formula 2b:

b

In this embodiment, a nitroso compound is obtained, which represents an intermediate that can be used in the preparation of paracetamol. In this context, it is possible to reduce the nitroso function directly to an amine function, or to first convert the nitroso function to nitro, during an additional oxidation step, in particular with nitric acid.

The inventors have observed that the nitrosation reaction is very efficient in terms of kinetics, and typically leads to total conversion only after 10 minutes of reaction, and this with an excellent regioselectivity of 90% in favor of the para compound compared to the secondary product. ortho. This nitrosation route is particularly advantageous because the concomitant formation of polymers is very limited.

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A, or the nitrosation step A is carried out under an inert atmosphere, or in the open air.

By “inert atmosphere” we mean that the nitration or nitrosation is carried out in a reactor under nitrogen or under argon. Conversely, “in the open air” means that no precautions have been taken in this regard.

According to another particular embodiment, the present invention relates to a process as defined above, in which the compound of Formula 1 is phenol, R being a hydrogen atom, to obtain p-nitrophenol as a compound of Formula 2, X being a nitro group, or p-nitrosophenol as a compound of Formula 2, X being a nitroso group.

In this embodiment, the phenol is not protected on the hydroxyl function. This represents an advantage in terms of production costs, phenol being a commodity product.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitration step A is carried out with a nitration agent chosen from HNO3 and NaNO ₂ , to obtain a compound of Formula 2 in which X is a nitro group.

Nitric acid can be used in the presence of an acid such as sulfuric acid, but also in the absence of said acid. Preferably, the nitric acid is introduced into the reactor in the form of an aqueous solution.

Sodium nitrite leads to the nitro compound when used in combination with an oxidizing agent, notably nitric acid.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitration step A comprises:

a) feeding a reactor with a solution, in particular aqueous, of the compound of Formula 1, in particular at a concentration of approximately 0.4 M, and with the nitrating agent, in solution, in particular aqueous, in particular at a concentration approximately 0.3 to 0.4 M, to obtain a reaction medium,

b) the formation of the compound of Formula 2.

The raw materials, namely the compound of Formula 1, in solution, and reagents, namely the nitrating agent, in solution, are continuously introduced into a reactor, via inlet channels. The nitration reaction then takes place within the reactor, resulting in the formation of the product of Formula 2, in which X represents a nitro group.

The reaction mixture, including the nitrated product (crude product) can then be discharged from the reactor via an outlet route.

The reactor is perfectly stirred, allowing homogeneous distribution of materials within the reactor. Preferably, the speed of introduction or injection of the reagents is identical to the speed of evacuation or extrusion of the reaction crude, thus allowing a constant volume within the reactor.

During nitration step A, the reagents are in particular introduced into the reactor at a rate of 5 to 20 ml/minute, in particular approximately 10 ml/minute or approximately 15 ml/minute.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitration step A is carried out with an initial ratio of nitration agent/compound of Formula 1 comprised of 1.1 to 1.6, preferably 1.2 to 1.5.

By “from 1.1 to 1.6” we also mean the following ranges: from 1.1 to 1.5, from 1.1 to 1.4, from 1.1 to 1.3, from 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.

“Initial ratio” refers to the ratio with which the nitrating agent and the compound of Formula 1 are introduced into the reactor. At this stage, the reagent and raw material have not yet been involved in the nitration reaction.

According to another particular embodiment, the present invention relates to a process as defined above, in which step A of nitration, or nitrosation is carried out with an initial concentration of compound of Formula 1, in particular of phenol, included from 0.2 to 0.6M, in particular from 0.25 to 0.5M.

According to another particular embodiment, the present invention relates to a process as defined above, in which step A of nitration, or nitrosation is carried out with an initial concentration of nitration agent, in particular HNOs, or NaNCh respectively, ranging from 0.25 to 0.8M, in particular between 0.3 to 0.7M.

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A is carried out at a temperature of 70 to 110°C, preferably 80 to 100°C. .

Below 70°C, the reaction kinetics may be too low to be compatible with an industrially viable process. Above 110°C, secondary products, such as polymers or polynitrated products can be formed. In the case where phenol is used as a raw material, the hydroxyl function can also be nitrated, to form Onitrophenol as a by-product.

By “70 to 110°C” we also mean the following ranges: from 70 to 100°C, from 70 to 90°C, from 70 to 80°C, from 80 to 110°C, from 90 to 110°C, from 100 to 110°C, from 80 to 100°C.

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A is carried out under microwaves, the nitration under microwaves being carried out in a microwave continuously with a generator waves of 2.45 GHz, or 915 MHz.

Commercially available microwaves are notably equipped with a 2.45 GHz or 915 MHz wave generator. In the context of an industrial process, a frequency of 915 MHz is desirable.

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A is carried out under microwaves, the nitration under microwaves being carried out in a microwave continuously with a power comprised from 200 to 1000 W.

Commercially available microwaves have a power ranging from 200 to 1000 W.

By “from 200 to 1000 W”, we also mean the following ranges: from 200 to 800 W, from 200 to 600 W, from 200 to 400 W, from 400 to 1000 W, from 600 to 1000 W, from 800 to 1000 W, from 400 to 800 W. The power being in particular approximately 450 W, or approximately 850 W.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitration step A is carried out in the presence of a cooling means making it possible to control the temperature.

Nitration reactions are exothermic. Equipping the reactor with a cooling means makes it possible to control this exotherm. The reactor can, for example, be equipped with a double jacket allowing the circulation of a cooling liquid.

Therefore the expression “control the temperature” means ensuring that the temperature of the reaction medium remains sufficiently low, below 110°C, preferably below 90°C, to avoid the formation of by-products, such as for example the ortho isomer, and polymers

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A is carried out in a reactor equipped with a wave generator with integration of a cooling system .

In this embodiment, a microwave reactor equipped with a cooling means is used. Typically, a tube is integrated into the microwave reactor, in order to circulate a heat transfer fluid, maintained at the desired temperature using a cryostat.

As an example, a cooled tubular continuous reactor: DOWNSTREAM cavity from the company SAIREM can be used.

According to another particular embodiment, the present invention relates to a process as defined above, in which the nitration step A is carried out in at least two microwave reactors in series, preferably at least three microwave reactors. microwaves in series and particularly preferably at least four microwave reactors in series.

In this embodiment, several reactors are configured in series. The raw materials, namely the compound of Formula 1, in solution, and reagents, namely the nitrating agent, in solution, are introduced into the first reactor, in which the nitration reaction takes place, with non-conversion. total. The reaction medium leaves the first reactor continuously, and is injected into the next reactor, in which the nitration reaction continues to take place.

For example, for a system comprising 3 reactors in series, the conversion at the end of the first reactor can be 60%, the conversion at the end of the second reactor can be 90%, and a total conversion can be be observed in the third reactor.

According to another particular embodiment, the present invention relates to a process as defined above, comprising, between each reactor in series, a cooling step so as to adjust the temperature to a temperature between 20 and 40°C, preferably 20 to 30°C.

In this embodiment, the reaction medium is cooled between 2 reactors in series. This operation makes it possible to inject a cooled mixture into the next reactor, which leads to better control of the exothermic phenomena of the reaction.

Figure 3 schematically shows this configuration with several microwave reactors in series, where each pair of microwave reactors is interconnected by a cooling circuit.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitrosation step A is carried out in an acidic medium, in particular in an aqueous solution of hydrochloric acid or sulfuric acid. .

In this embodiment, an aqueous solution of the nitrosation agent, i.e. sodium nitrite, is previously acidified, in particular to a pH lower than 4, by adding an acid. The mixture thus obtained is injected into the reactor.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitrosation step A comprises:

a) feeding a reactor with a solution of the compound of Formula 1, in particular aqueous, and with NaNCh in solution, in particular aqueous in an acid, in particular in hydrochloric acid, to obtain a reaction medium,

b) the formation of the compound of Formula 2.

During nitrosation step A, the reagent, namely NaNCh, in solution, and the raw material, namely the compound of Formula 1, in solution, are notably introduced into the reactor at a rate of 5 to 20 ml/ minute, in particular around 10 ml/minute or around 15 ml/minute.

According to another particular embodiment, the present invention relates to a process as defined above, comprising a nitrosation step A, in which a reactor is supplied with an aqueous solution of the compound of Formula 1, and with NaNCL in solution. aqueous in an acid, in particular in hydrochloric acid.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitrosation step A is carried out at a temperature below 10°C, in particular between -5 to 5°C, especially at a temperature of around 0°C.

Above 10°C, the reaction can exhibit high kinetics, which can lead to a runaway exothermic reaction. In addition, under these conditions, secondary products such as poly-nitroso products can be formed.

According to another particular embodiment, the present invention relates to a process as defined above, in which nitrosation step A is carried out in the presence of a cooling means making it possible to control the temperature.

Nitrosation reactions are exothermic. Equipping the reactor with a cooling means makes it possible to control this exotherm. The reactor can, for example, be equipped with a double jacket allowing the circulation of a cooling liquid.

According to another particular embodiment, the present invention relates to a process as defined above, in which step A of nitration, or nitrosation leads to the formation of the compound of Formula 2, in particular p-nitrophenol or p-nitrosophenol, in particular p-nitrosophenol, with a regioselectivity greater than 60%, in particular greater than 80%, in particular in which the ortho isomer/compound ratio of Formula 2 is less than 2/8, and is in particular d 'approximately 1/9.

By “regioselectivity greater than 60%” we also mean a regioselectivity greater than 70%, greater than 80%, and greater than 90%. Said regioselectivity can for example be determined by NMR, or by HPLC.

At the end of step A of nitration, or nitrosation, the crude reaction product can be directly carried into the reactor of the next step, i.e. the hydrogenation step. However, it is more advantageous to purify said crude reaction product, for example by aqueous washing or by crystallization. In the case where the compound of Formula 2 is O-acetyl-4nitrophenol, or O-acetyl-4-nitrosophenol, purification in an aqueous medium makes it possible to hydrolyze the acetate group to yield 4-nitrophenol, or 4-nitrosophenol respectively.

The inventors have found that the continuous process according to the present invention leads to excellent regioselectivity in favor of the para compound, in particular greater than 80%, compared to a process in batch condition.

According to another particular embodiment, the present invention relates to a process as defined above, in which said process further comprises, after step A of nitration or nitrosation, a step B of hydrogenation of the compound of Formula 2, to obtain:

• either 4-aminophenol, in the case where R is a benzyl group or a hydrogen atom, • or O-acetyl-4-aminophenol, in the case where R is an acetate group,

X NHj NH2 • R and X being as defined above, said hydrogenation step B being carried out continuously or in batches, preferably continuously, in the presence of hydrogen, a solvent and a catalyst.

The hydrogenation step makes it possible to reduce the nitro group, or the nitroso group to amine. In the case where R represents a benzyl group, this reaction is accompanied by hydrogenolysis of said benzyl group, to obtain p-aminophenol. On the other hand, in the case where R represents an acetate group, O-acetyl-4-aminophenol is obtained, since the acetate group is inert, and is not removed under the hydrogenation conditions.

Hydrogenation step B is carried out in the presence of a catalyst capable of catalyzing a reduction of a nitro or nitroso compound to amine. The catalyst is preferably a heterogeneous catalyst which makes it possible to keep said catalyst within the reactor. The reactor can, for this purpose, be equipped with a filtration system, for example a frit, at the outlet, to prevent the catalyst from being evacuated with the flow of reaction crude leaving the reactor. The sinter notably has a porosity of 2 to 50 μm.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out from a compound of Formula 2 in which X is a nitro group, the compound of Formula 2 being a compound of Formula 2a:

A JL φ φ or φ

NO _a HHU HH2a

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out from a compound of Formula 2 in which X is a nitroso group, the compound of Formula 2 being a compound of Formula 2b:

According to another particular embodiment, the present invention relates to a process as defined above, in which the compound of Formula 2 is p-nitrophenol, R being a hydrogen atom, and X being a nitro group.

According to another particular embodiment, the present invention relates to a process as defined above, in which the compound of Formula 2 is p-nitrosophenol, R being a hydrogen atom, and X being a nitroso group.

According to another particular embodiment, the present invention relates to a process as defined above, in which the compound of Formula 2 is mixed with the ortho isomer, in particular in which the ortho isomer/compound of Formula 2 ratio is less than 2/8, and is in particular approximately 1/9.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out in the presence of a catalyst chosen from Pd/C, Pt/C and Fe/HCl ,

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out in the presence of Siliacat Pd(0) as catalyst.

Thus, a Siliacat® type catalyst is preferably used, in particular Siliacat Pd(O). Siliacat Pd(O) is a catalyst consisting of Pd trapped in a sol-gel system. Specifically, highly dispersed Pd nanoparticles (uniformly in the range of 4.0–6.0 nm), encapsulated in an organosilica matrix. The structure of the catalyst is shown below.

This catalyst is marketed by several companies, including Dichrom GmbH in Germany and Silicycle in Canada.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out in the presence of a solvent chosen from ethanol or methanol, in particular ethanol.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out at a temperature of 50 to 130°C, in particular of 80°C to 130°C. 100°C.

Below 50°C, the reaction kinetics may be too low to be compatible with an industrially viable process. Above 100°C, there is a risk of over-reduction, in particular reduction of the aromatic cycle.

By “50 to 130°C” we also mean the following ranges: 60 to 130°C, 70 to 130°C, 80 to 130°C, 90 to 130°C, 110 to 130°C , 60 to 110°C, 80 to 100°C, 70 to 90°C.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out at a hydrogen pressure of 10 to 50 bars, in particular of 15 at 30 bars, in particular around 20 bars.

Below 10 bars, the reaction kinetics may be too low to be compatible with an industrially viable process. Above 50 bars, there is a risk of over-reduction, in particular reduction of the aromatic cycle

By “from 10 to 50 bars” we also mean the following ranges: from 15 to 50 bars, from 25 to 50 bars, from 35 to 50 bars, from 10 to 40 bars, from 10 to 30 bars from 15 to 30 bars.

According to another particular embodiment, the present invention relates to a process as defined above, in which the starting compound of Formula 2 is introduced into the reactor at a concentration of 0.5 to 1.5 M, in particular of approximately 1 M, and at a rate of 5 to 20 ml/minute, in particular 10 or 15 ml/minute.

According to another particular embodiment, the present invention relates to a process as defined above, in which the hydrogenation step B is carried out in at least two reactors in series, preferably at least three reactors in series and particularly preferred manner three or five reactors in series.

According to another particular embodiment, the present invention relates to a process as defined above, in which at least two of the consecutive reactors are of different sizes.

According to another particular embodiment, the present invention relates to a process as defined above, in which at least two of the consecutive reactors are of different sizes, and are of increasing size.

According to this particular embodiment, at least one of the reactors is larger than the size of the previous reactor, at least one of the reactors being the following reactor.

In this configuration, the flow rate of fluids is constant and identical between each reactor. The reactor fluid outlet is located at the top of the reactor, as shown schematically in Figure

4, and as long as the previous reactor is not filled to the height of the outlet, the liquid does not leave the reactor. Then the outgoing flow is equal to the incoming flow.

This configuration of reactors of increasing size allows good control of exothermic phenomena, and leads to very good productivity of the process.

Preferably, the size ratio between the previous reactor and the following reactor being comprised from 1.1 to 3, in particular from 1.5 to 3.

Particularly preferably, the present invention relates to a process in which hydrogenation step B is carried out in 3 consecutive reactors, of increasing size, in particular with a size ratio of approximately 1:1.5:3.

For example, we can operate with a cascade of reactors of increasing volumes in the following proportions: 1, 1.5, 4.

According to another particular embodiment, the present invention relates to a process as defined above, in which at least two of the consecutive reactors are of different sizes, and are of decreasing size.

According to this particular embodiment, at least one of the reactors is smaller than the size of the previous reactor. In the next reactor, smaller in size than the next reactor, the concentration of raw material, namely the compound of Formula 2, is lower than in the previous reactor, a part of said compound of Formula 2 having already been converted.

A subsequent smaller reactor makes it possible to increase the catalyst load, at lower cost, in order to compensate for this lower concentration of raw material. In addition, the smaller reactor can be stirred more easily than a larger reactor. This facilitates the dispersion of the catalyst in the reaction medium, which is important when the load of said catalyst is higher.

Preferably, if the first reactor has a volume RI, the second reactor has a volume R2 between RI and 0.5 RI and the third reactor has a volume R3 between 0.8 RI and 0.4 RI.

For example, we can operate with a cascade of reactors of decreasing volumes in the following proportions: 1:0.75:0.5.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out:

• from p-nitrophenol, in the presence of the catalyst SiliaCat Pd(0), or Pt/C • in the presence of SiliaCat Pd(0) or Pt/C as catalyst, • with ethanol as solvent, • in three reactors in series, to obtain p-aminophenol.

Advantageously, the 3 reactors in series are of increasing sizes, as defined above. This embodiment makes it possible to obtain the amine compound with a good yield, in particular with a yield greater than 80%, in particular greater than 95%.

According to another particular embodiment, the present invention relates to a process as defined above, in which hydrogenation step B is carried out:

• from p-nitrosophenol, in the presence of the catalyst SiliaCat Pd(0), or Pt/C • in the presence of SiliaCat Pd(0) or Pt/C as catalyst, • with ethanol as solvent, • in three reactors in series, to obtain p-aminophenol.

Advantageously, the 3 reactors in series are of increasing sizes, as defined above. This embodiment makes it possible to obtain the amine compound with a good yield, in particular with a yield greater than 80%, in particular greater than 95%, in particular greater than 98%.

It has been observed that during hydrogenation step B, in the case of using a compound of Formula 2 in which R represents an acetate group, said acetate group migrates towards the amine function formed. Thus, the hydrogenation of O-acetyl-4-nitrophenol, or Oacetyl-4-nitrosophenol leads directly to paracetamol.

According to another particular embodiment, the present invention relates to a process as defined above, in which said process further comprises, after hydrogenation step B, a step C of acylation of p-aminophenol to obtain paracetamol:

OH OH φ — δ κ Ύ^ ⁴ said acylation step C being carried out continuously or in batches, preferably continuously.

According to another particular embodiment, the present invention relates to a process as defined above, in which acylation step C is carried out with acetic anhydride as acylating agent.

According to another particular embodiment, the present invention relates to a process as defined above, in which acylation step C is carried out with acetic acid as acylation agent, said acylation step C being carried out in microwaves, in batches, or continuously.

According to another particular embodiment, the present invention relates to a process as defined above, in which the acylation step C is carried out with an initial ratio of acetic anhydride/p-aminophenol comprised from 1.0 to 1.6, preferably 1.1 to 1.4.

Using too much acetic anhydride results in purification difficulties, compared to removing excess acetic anhydride.

According to another particular embodiment, the present invention relates to a process as defined above, in which the acylation step C is carried out at a temperature of 60 to 100°C, preferably at around 80°C. .

By “from 60 to 100°C”, we also mean the following ranges: from 60 to 90°C, from 60 to 80°C, from 60 to 70°C, from 70 to 100°C, from 80 to 100° C, from 90 to 100 °C, and from 70 to 80 °C.

Acylation step C is preferably carried out at the same temperature as hydrogenation step B. For example, if the hydrogenation reaction is carried out at 80°C, the fluid leaving the hydrogenation reactor can be directly injected, hot, into the acylation reactor. Thus, the acylation reaction can be completed in a few minutes, in particular in less than 10 minutes, or 5 minutes. In these conditions it is not necessary to heat the medium further, the temperature of the fluid being sufficiently high.

According to another particular embodiment, the present invention relates to a method as defined above, comprising:

• a step A of nitration or nitrosation of a compound of Formula 1, to obtain a compound of Formula 2, said step A of nitration being carried out, either continuously, or continuously and under microwaves, or continuously and under ultrasound , either continuously and under microwaves and under ultrasound, or continuously and optionally under microwaves and/or under ultrasound, the nitration agent being sodium nitrite, in the presence of an oxidizing agent, in particular in the presence of said HNCh nitrosation step A being carried out continuously, the nitrosation agent being sodium nitrite, R and X being as defined above, • a hydrogenation step B of the compound of Formula 2, to obtain:

either 4-aminophenol, in the case where R is a benzyl group or a hydrogen atom, or paracetamol, in the case where R is an acetate group, said hydrogenation step B being carried out continuously or in batches, preferably continuously, and • an acylation step C of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously or in batches, preferably continuously.

The three steps A, B and C are preferably all carried out continuously.

It is understood that step C is to be implemented only if paracetamol is not already obtained at the end of hydrogenation step B.

According to another particular embodiment, the present invention relates to a process as defined above, comprising:

• a nitration step A of the phenol, to obtain p-nitrophenol, said nitration step A being carried out continuously and under microwaves, • a step B of hydrogenation of the p-nitrophenol compound, to obtain paminophenol:

said hydrogenation step B being carried out continuously in three reactors in series, and • a step C of acylation of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously.

This preferred embodiment corresponds to the following diagram:

According to another particular embodiment, the present invention relates to a process as defined above, comprising:

• a step A of nitrosation of the phenol, to obtain p-nitrosophenol, said step A of nitrosation being carried out continuously, at a temperature below 10 ° C, • a step B of hydrogenation of the p-nitrosophenol compound, to obtain p-aminophenol:

said hydrogenation step B being carried out continuously in three reactors in series, and • a step C of acylation of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously.

This preferred embodiment corresponds to the following diagram:

O

According to another particular embodiment, the present invention relates to a process as defined above, comprising, between at least one step A, B, or C, a purification step, in particular by aqueous washing.

The synthesis intermediates, obtained from steps A of nitration/nitrosation and/or B of hydrogenation, as well as the final product, obtained from step C of acylation can be purified, in order to improve the impurity profile of the process. It may be, for example, a simple aqueous wash, to remove acid and salt residues at the end of step A or C, or filtration or a bed of carbon or zeolite to remove catalyst residues at the end of step B. Alternatively, more purifying purifications can be implemented such as for example crystallizations or distillations or continuous liquid/liquid extraction.

According to another particular embodiment, the present invention relates to a process as defined above, further comprising a step D of purification of paracetamol, in particular by continuous distillation, continuous liquid-liquid extraction and/or by crystallization, in particular by continuous crystallization.

The final product of the process of the present invention, paracetamol, can be purified by techniques known to those skilled in the art, in order to allow a purity compatible with therapeutic use. The purification aims in particular to remove residues of the ortho isomer that may be present in the crude product.

Finally, the subject of the invention is a process for preparing paracetamol comprising the successive steps:

1) synthesis of p-nitrophenol from phenol

OH + HNO3

OH

2) synthesis of p-aminophenol from p-nitrophenol

+ hydrogen

3) synthesis of paracetamol from p-aminophenol

OH + acylating agent

Characterized in that steps 1, 2 and 3 are carried out continuously and in that step 1) is carried out under microwaves.

Indeed, the inventors were able to obtain a nitration regioselectivity of phenol 10 in the para position greater than 60%.

The invention also relates to a process for preparing paracetamol comprising the successive steps:

1) synthesis of p-nitrosophenol from phenol

2) synthesis of p-aminophenol from p-nitrophenol

3) synthesis of paracetamol from p-aminophenol

OH + ^OH acylating agent

Brief description of the drawings

Figure 1 shows different chemical routes for the production of Paracetamol.

Figure 2 illustrates the evolution of the temperature of the mixture with time of the reaction mixture when it passes through the circuit formed by several microwave reactors in series, of which each pair of microwave reactors is interconnected by a circuit cooling.

Figure 3 schematically shows an installation for carrying out the first step where the phenol/HNO3 mixture is introduced into an installation with several microwave reactors in series, where each pair of microwave reactors is interconnected by a cooling circuit.

Figure 4 schematically shows an installation for carrying out the second hydrogenation stage where several hydrogenation reactors are connected in series.

Figure 5 presents a flowchart of the process for the continuous synthesis of paracetamol, including a nitration step.

Figure 6 presents a flowchart of the continuous synthesis process for paracetamol, including a nitrosation step.

Figure 7 represents the conversion of a hydrogenation reaction in a system of 3 reactors in series, according to example 5.2.

The nitration reaction is carried out by mixing phenol and nitric acid.

This reaction is carried out in the presence of a strong acid such as sulfuric acid, hydrofluoric acid, perchloric acid or even boron trifluoride. Preferably, this reaction is carried out in the presence of sulfuric acid.

Now, in addition to the microwave step, the inventors have demonstrated that the ratio between the concentration of nitric acid and phenol also had a strong influence on the regioselectivity and the obtaining of p-nitrophenol rather than o-nitrophenol. . Thus, the use of excess nitric acid promotes the formation of o-nitrophenol. Under such conditions, the inventors were able to obtain up to 82% p-nitrophenol (for 18% o-nitrophenol).

Advantageously, the ratio between HNO3/Phenol ratio within the starting mixture is between 1.1 and 1.6, preferably between 1.2 and 1.5.

The concentration of the starting mixture in phenol is between 0.2 and 0.6M, preferably between 0.25 and 0.5M.

The HNO3 concentration of the starting mixture is between 0.25 and 0.8M, preferably between 0.3 and 0.7M.

The proportion of water in the starting mixture is between 40 and 95% (by volume relative to the volume of the mixture at this point), preferably between 50 and 90%.

As for step 1, the residence time of the mixture within the microwave reactor is such that the mixture is brought to a temperature between 70 and 110°C, preferably between 80 and 100°C. . Moving to a higher temperature affects the regioselectivity and tends to increase the proportion of o-nitrophenol.

The inventors were able to show that it is possible to further increase the regioselectivity by increasing the residence time of the mixture in the microwave reactor, but without increasing the temperature.

To do this, the inventors put microwave reactors in series between which cooling circuits are inserted.

According to a preferred embodiment, step 1) is carried out in at least two consecutive microwave reactors, preferably at least three consecutive microwave reactors and particularly preferably at least four consecutive microwave reactors , with a cooling circuit between each microwave reactor so as to bring the mixture to a temperature between 20 and 40°C, preferably between 20 and 30°C.

Typically, the residence time within all of the microwave reactors is between 2 and 20 minutes, preferably between 2 and 15 minutes.

Preferably, each of the microwave reactors (possibly apart from the first) comprises a nitric acid supply.

In this way, it is possible to maintain the HNO3/Phenol ratio within the mixture between 1.1 and 1.6, preferably between 1.2 and 1.5, throughout the nitration reaction (within of the different microwave reactors).

Figure 2 illustrates the evolution of the temperature (°C) over time (minutes) of the reaction mixture as it passes through the circuit formed by the microwave reactors (MO) interconnected via a cooling circuit.

Figure 3 schematically shows an installation for carrying out the first step where the phenol/HNO3 mixture is introduced into a first microwave reactor (MO) in which it passes before passing into a first cooling circuit before circulating in a second, third then fourth microwave reactor to form the vast majority of pnitrophenol with, each time, a passage via a cooling circuit between each microwave reactor.

To optimize the reaction balance, cooling should be carried out as quickly as possible, typically between 0.5 and 3 minutes, preferably between 1 and 2 minutes.

At the end of step 1), it is possible to simply separate the two isomers o-nitrophenol and pnitrophenol.

Such purification can be carried out by an intermediate step (between steps 1 and 2) of steam stripping of the o-nitrophenol (see US patent 3,933,929), filtration and washing with an aqueous solution of sulfuric acid at 70 % then with water (see patent EP 0626366), solubilization (using the difference in solubility in various solvents of the two isomers, N-pentane to remove O-Nitrophenol), ultrafiltration (Yudiarto et al. , Separation and Purification Technology, vol. 19, p: 103-112, 2000), HPLC (SMB (Simulated Moving Bed) or VARICOL type)

According to a preferred embodiment, the p-nitrophenol is purified at the end of step 1) and before step 2).

Now, it is also possible to start step 2) without purification and to separate the paminophenol from the o-aminophenol at the end of step 2).

Concerning the second step of reduction of p-nitrophenol to p-aminophenol, it can be carried out as desired by:

A) addition of dihydrogen under pressure in the presence of a catalyst such as Pd/C, Pt/C, Fe/HCl or equivalent.

B) addition of a hydrogen donor (e.g. NaBH4) in the presence of a solid catalyst (gold nanoparticles, etc.).

According to a preferred embodiment, step 2) is carried out by adding dihydrogen under pressure in the presence of Pd/C, Pt/C, Fe/HCl or equivalent catalyst.

Advantageously, the mixture corresponds to the choice of p-nitrophenol in an aqueous medium in the presence of an acid (preferably sulfuric acid because it gives better yields than hydrochloric acid in particular) or to p-nitrophenol in solution in alcohol, preferably ethanol or methanol.

Advantageously, the hydrogenation of p-nitrophenol is carried out in alcohol solution, preferably in ethanol.

The alcohol concentration of the mixture is advantageously between 70% and 95% (by volume relative to the volume of the mixture upstream of the hydrogenation reactor), preferably between 80% and 90%.

Preferably, the catalyst used is Pt/C. It is in fact this which gives the best returns. The catalyst load within the hydrogenation reactor is greater than or equal to 1% (by weight relative to the weight of the mixture within the reactor), preferably greater than or equal to 2% and, particularly preferably, it is equal to 5%.

The pressure within the hydrogenation reactor is advantageously greater than 20 bars.

Preferably, the pressure within the hydrogenation reactor is between 20 and 100 bars, preferably between 20 and 50 bars.

The temperature of the mixture within the hydrogenation reactor is advantageously greater than 80°C.

Preferably, the temperature of the mixture within the hydrogenation reactor is between 80 and 180°C, preferably between 100 and 150°C.

To increase the conversion efficiency, the inventors put several hydrogenation reactors in series.

According to a preferred embodiment, step 2) is carried out in at least two consecutive hydrogenation reactors, preferably at least three consecutive hydrogenation reactors and particularly preferably at least four consecutive hydrogenation reactors.

Preferably, an online analysis of the mixture is carried out between each hydrogenation reactor in order to control the kinetics of the reaction and, consequently, to control the possible deactivation of the catalyst in order to change it when necessary.

Figure 4 schematically shows an installation for carrying out the second step where the mixture comprising p-nitrophenol in solution in ethanol is introduced into a first hydrogenation reactor comprising solid catalyst (Pt/C) and into which is injected dihydrogen under pressure before passing into a second, third then fourth hydrogenation reactor to form the vast majority of p-aminophenol.

Finally, the inventors were able to obtain a conversion yield of pnitrophenol into p-aminophenol of around 97%.

Note that this second step also presents a large number of advantages compared to conventional processes. Indeed, it guarantees high productivity with a small size due to its continuous operation, it offers great safety due to the low volume required for the reactors, it allows the use of catalysts to the maximum of their lifespan.

At the end of step 2), and preferably in the case where the p-nitrophenol has not been purified at the end of step 1) and before step 2).

According to another preferred embodiment, the p-aminophenol is purified at the end of step 2). Such a separation can be carried out simply by those skilled in the art with regard to their general knowledge, for example by using the differences in solubility between these 2 isomers.

Concerning the third step of acylation of p-aminophenol to paracetamol, it is carried out by the addition to the mixture, and at the end of the (last) hydrogenation reactor, of an acylation agent.

By acylating agent, we are considering both acetic acid and acetic anhydride.

Advantageously, the acylating agent/p-aminophenol ratio within the mixture, and after the addition of the acylating agent, is between 1 and 10, preferably between 1 and 4.

In the case where the acylating agent is acetic anhydride, the mixture comprises alcohol as solvent, preferably ethanol or methanol.

The acylation reaction is then carried out by heating, preferably heating the mixture at a temperature of between 20 and 90°C and for a time of between 0.5 and 10 minutes, and particularly preferably by heating the mixture. at a temperature between 20 and 60°C and for a time between 1 and 4 minutes.

In the case where the acylating agent is acetic acid, it is possible to carry out this acylation as with acetic anhydride, but without the presence of alcohol and with acetic acid. The temperatures used and the reaction time must then be increased

Typically, the acylation reaction carried out by heating a temperature between 50 and 130°C and for a time between 1 and 40 minutes, and particularly preferably by heating at a temperature between 60 and 100°C and for a time of between 10 and 20 minutes.

Now the inventors have also demonstrated that this acylation reaction can be carried out very quickly with acetic acid in a microwave reactor. Note also that, in this case, acetic acid can be used as a solvent which considerably simplifies the process since the solvent can be reused by simple distillation of the mixture leaving the microwave reactor. For acetic anhydride, in addition to the higher cost, its use then requires the elimination of the solvent used (ethanol or methanol)

According to a preferred embodiment, step 3 uses acetic acid and is carried out under microwaves.

Preferably, this step 3 does not use any additional solvent (in addition to acetic acid).

Typically, the p-aminophenol/acetic acid ratio is between 1/5 and 1/10, preferably between 1/6 and 1/9.

To do this, the residence time of the mixture within the microwave reactor is such that the mixture is brought to a temperature between 80 and 120°C, preferably between 90 and 110°C.

Typically, the residence time within all microwave reactors is between 1 and 60 minutes, preferably between 10 and 30 minutes.

At the end of the acylation reaction, paracetamol is continuously purified.

Typically, this purification step can be carried out by a simple distillation aimed at removing the solvent.

Advantageously, this purification step can include a washing step, with purified water, in particular under inert gas, argon or equivalent.

The process according to the invention, a flowchart of which is presented in Figure 5, makes it possible to synthesize paracetamol with excellent yield (greater than 70%).

The examples which follow are provided for illustration purposes and cannot limit the scope of the present invention.

Examples

1) Nitration of phenol:

In a microwave reactor with a volume of 6 ml, 50 mg of phenol are introduced with 0.7 ml of nitric acid 6% by weight with 1.07 ml of HzO.

The reactor is then adjusted so as to obtain a temperature of 160°C for one minute and 30 seconds before cooling to 55°C, before initiating a new heating step at 120°C for one minute and 30 seconds followed by further cooling to 55°C.

The results of HPLC analyzes showed that a conversion of phenol into nitrophenol was obtained with a yield of 99.35% overall, but above all with a proportion of nearly 60% of p-nitrophenol (and approximately 40% of o-nitrophenol).

The tests carried out subsequently showed that the faster the cooling step, the more the regioselectivity, and therefore the proportion of p-nitrophenol, increases.

For the continuous nitration reaction, the experiments are carried out in a continuous microwave (SAIREM) with a 2.45GHz wave generator and 450W power with coaxial transition/waveguide equipped with a cooler.

2) Hydrogenation of p-nitrophenol to p-aminophenol

In a continuous hydrogenation reactor (total volume 400ml), separated into different zones each equipped with stirrers, the pure solvent is introduced with the Pt/C catalyst. The temperature in the reactor is controlled and maintained at the desired temperature by several thermostatically controlled baths which heat or cool the different zones of the continuous reactor. The hydrogen pressure is kept constant at the desired pressure in each zone.

The p-nitrophenol is then introduced continuously into the solvent at a certain flow rate and concentration.

Samples are taken at the output to measure conversion and selectivity.

For a flow rate of 800ml/h composed of a solution of 0.5M p-nitrophenol in ethanol, i.e. 13.3ml/min, the Pt/C catalyst load was 2% (weight/weight of the mixture at within the reactor) at a constant temperature of 80°C in each zone.

The results showed a conversion of 99% with a selectivity of 98% for a residence time of 3Omn within the reactor.

Optimization is in progress concerning the reaction parameters (reaction volume in each zone, catalyst load in each zone, temperature and H2 pressure in each zone and overall flow rate).

The results have already shown that the Pt/C catalyst provides the best results (around 1% w/w). Now, for a hydrogenation reactor capable of withstanding a hydrogen pressure of 100 bar and a temperature of 150°C, it is possible to increase the catalyst loading up to 5% (w/w) which induces a strong increase in productivity by reducing the residence time which can be reduced between 15 to 30 minutes, while maintaining good catalyst activity.

3) Acylation of p-aminophenol to paracetamol:

3.1) temperature conversion tests

The tests are carried out in the VAPOURTEC R2+ and R3 type reactor with a volume of 10ml, which is powered by peristaltic pumps. The samples are then collected at the VAPOURTEC outlet to be analyzed by HPLC.

In a first test, the solution of p-aminophenol (0.3M in methanol) is injected into the VAPOURTEC at a flow rate of 5ml/min and at room temperature. Simultaneously, the acetic anhydride solution (0.3M in methanol) is injected into the VAPOURTEC at a flow rate of 5ml/min at room temperature. The total flow rate is lOml/min with a passage time of Imn in the VAPOURTEC.

The analyzes showed a conversion of p-aminophenol of 99.9%, with a selectivity of 98.7% for paracetamol.

In a second test, the solution of p-aminophenol (0.14M in ethanol) is injected into the VAPOURTEC at a flow rate of 5ml/min and at a temperature of 60°C. Simultaneously, the acetic anhydride solution (0.14M in ethanol) is injected into the VAPOURTEC at a flow rate of 5ml/min at 60°C. The total flow rate is lOml/min with a passage time of Imn in the VAPOURTEC.

The analyzes showed a conversion of p-aminophenol of 99.9%, with a selectivity of 98.9% for paracetamol.

In a third test, the p-aminophenol solution (0.14M in ethanol) is injected into the VAPOURTEC at a flow rate of 3.3ml/min and room temperature. Simultaneously, the acetic anhydride solution (0.14M in ethanol) is injected into the VAPOURTEC at a flow rate of 3.3ml/min at room temperature. The total flow rate is 6.6 ml/min with a passage time of 1.5 min in the VAPOURTEC.

The analyzes showed a conversion of p-aminophenol of 99.9%, with a selectivity of 98.9% for paracetamol.

3.2) Microwave conversion test

The microwave used was the MONOWAVE 300 (ANTON PAAR) with a magnetron power of 850 watts. For this, the power is adapted to the desired temperature.

The various reagents are introduced into a 10 mL reactor with stirring which is placed in the microwave enclosure. Once the cycle is complete, the reactor is cooled before taking a sample and performing HPLC analysis.

In a 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 the microwave for 10 seconds and at a temperature of 40°C.

The results showed that a conversion of 99.9% of p-aminophenol was obtained with a selectivity of 97% for paracetamol.

In a second test, p-aminophenol is introduced into an acetic acid solution at a concentration of 5M. The reactor is then introduced into the microwave for 20 minutes and at a temperature of 100°C.

The results showed that a conversion of 95% of p-aminophenol was obtained with a selectivity of 93.5% for paracetamol.

4) nitration of phenol with nitric acid, continuously

4.1) Uncooled continuous tubular reactor: AVOCAT SAIREM cavity

The reactions were carried out in a 500 mL tubular borosilicate reactor inserted in an AVOCAT type cavity (SAIREM company) and coupled to a GMS 450 microwave generator capable of delivering a maximum power of 450 W thanks to transmission via quartz window. . The total irradiated volume is 160 mL.

350 ml of a solution containing 0.4 M phenol and 0.375 M nitric acid (1.25 eq.) were injected into the cavity at a rate of 16 ml/min. Thus, the passage time in the irradiated zone was 10 minutes.

The reaction is carried out by microwave irradiation with a power of 250 W, with a microwave generator operating at 2.45 GHz.

Thus, para-nitrophenol was obtained with a productivity of 25 g/h, and an o/p ratio of 20/80.

4.2) Cooled tubular continuous reactor: DOWNSTREAM SAIREM cavity

This device consists of a tubular borosilicate reactor (60 mL, internal diameter 12 mm) inserted in a second borosilicate tube (double jacket, internal diameter 23 mm) provided with a coolant inlet and outlet route. The assembly is inserted in a DOWNSTREAM type cavity (SAIREM company) and coupled to a GMS 1000 microwave generator capable of delivering a maximum power of 1000 W thanks to transmission via quartz window. The total volume irradiated is around 10 mL. This device was also equipped with a temperature probe (optical fiber) immersed in the reactor. To cool the internal reactor, a specific oil, with zero dielectric permittivity (therefore transparent to microwaves), was used. The heat carrier can be maintained between -10°C and 0°C using a cryostat.

An aqueous solution of 0.4 M phenol and 0.375 M nitric acid (1.25 eq.) was injected into the cavity at a rate of 10 ml/min. Thus, the passage time in the irradiated zone was 6 minutes.

The test demonstrated that microwave heating with cooling allows perfect control and a stable temperature throughout the process.

5) hydrogenation of p-nitrophenol with Siliacat Pd(0) as catalyst

5.1) batch test

The reaction in batch mode was carried out on a single closed reactor. The reactor is preloaded with a solution of 6.95 g of β-nitrophenol in 100 mL of EtOH and 0.208 mg of SiliaCat P(0) (reagents purchased from Aldrich and catalyst from SiliCycle). The reactor was then purged with dinitrogen (3 purges, 5-7 bar) then pressurized with hydrogen (H ₂ Alphagaz, Air Liquide) under 15 bar. Agitation is set at 1000 rpm or rpm (revolutions per minute rotation per minute).

When the reactor is heated to T=80°C, a conversion of 86% is obtained in 80 minutes and when the reaction is carried out at 100°C, a conversion of 88% is obtained in 60 minutes

5.2) continuous test

The same conditions as those used in Example 2 were used, using the Siliacat Pd(0) catalyst (SiliCycle, Quebec Canada, Ref RD-R815-SiliaCat® PdO), at a rate of 0.5 mol%.

Full conversion was achieved in 90 minutes.

5.3) Test on 3 reactors in series and continuously - reactors of increasing size

The hydrogenation reaction was carried out using 3 reactors in series. The following results were obtained.

Settings RI operating conditions Operating conditions R2 Operating conditions R3 (Modeling) Volume 0.1 L 0.15 L 0.4 L Speed 12 ml/min 12 ml/min 12 ml/min Pressure 20 bar 12 Bar 5 Bar Temperature 100 °C 110 °C 130 °C Mcata Siliacat Pd 0.70% 1.70% 2% Con p-Nitrophenol entry 1 mol/l 0.64 mol/l 0.163 mol/l Conc p-Nitro Output 0.64 mol/l 0.16 mol/l 0.011 mol/l Conversion 0.36 0.73 0.93 Overall conversion (%) 35.95 83.62 98.85

In the table above, the quantity of “Mcata” catalyst is expressed in mol%.

A productivity of 3.7 kg/L/day of p-aminophenol was obtained with 3 reactors in series.

Figure 7 shows the conversions for each reactor.

5) Hydrogenation of p-nitrophenol in a cascade of two or three perfectly stirred continuous reactors

5.1) Debugging in batch mode

The reaction in batch mode is carried out on a single closed reactor. The reactor is preloaded 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 is then purged of dinitrogen (3 purges, 5-7 bar) then pressurized with hydrogen (EL Alphagaz, Air Liquide) under 15 bar. Stirring is set at 1000 rpm and the reactor is heated to 80°C by its double jacket for 1h20. At the end of the reaction, the reactor is inerted by purging the dinitrogen and the reaction medium is analyzed by HPLC (reverse phase, Cl8 column). The analysis demonstrates a conversion of 92% of /2-nitrophenol to /?-aminophenol without trace of reaction co-product.

5.2) Cascade reaction

The same device used in Example 5.1 is reused to carry out the reaction on a cascade of two perfectly stirred continuous reactors. The outlet channel of the first reactor, always equipped with a 5 μm filter candle in order to keep the catalytic load of the autoclave constant, is connected to the inlet of a second reactor in every respect similar to the first. The two reactors are loaded with 20 mg of Pt/C 10% w/w (Sigma Aldrich). A conversion of 50% is simulated in the first reactor (2.72 g of p-aminophenol for 3.48 g of p-nitrophenol) and a conversion of 75% is simulated in the second reactor (4 g of paminophenol for 1.8 g of p-nitrophenol) . Under the conditions previously described, but with a slightly decreasing pressure (80 °C, 15 bar, 1000 rpm in the first reactor; 80 °C, 12 bar, 1000 rpm in the second reactor), the cascade is supplied with a solution of p-nitrophenol in ethanol (0.3 M) at a flow rate of 3 mL/min (passage time, 30 minutes per reactor) for 5 hours. The withdrawal valve of the second reactor is adjusted so as to have an outlet flow approximately equal to the inlet flow. No events occur during the 5 hours of reaction. Samples are taken every 4 minutes. HPLC analyzes show that the conversion oscillates between 70 and 83% for 20 minutes before stabilizing around 80% without formation of co-product.

In another scenario, a third reactor is connected to the cascade. Similarly, this reactor is loaded with 20 mg of Pt/C, and an initial conversion of 90% is simulated (4.9 g of p-aminophenol for 695 mg of p-nitrophenol). Under the conditions described above (80 °C, 1000 rpm, 15 bar; 12 bar; 10 bar), the waterfall is supplied for 4 hours at a flow rate of 4 mL/min (throughput time 25 minutes). No event occurs. At the reactor outlet, samples are taken every 4 minutes. HPLC analyzes show that the conversion oscillates between 80 and 96% for 20 minutes before stabilizing at 95% for 4 hours.

6) nitrosation of phenol then hydrogenation — batch protocol

6.1) nitrosation

To a 35% HCl solution (40 ml) under air, with stirring at T=0°C, a solution of NaNCE (42% in water, 2 eq.) was added dropwise. 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 = 0.3M). The solution gradually became black and the mixture became denser. After 30 minutes, an HPLC analysis shows that the phenol has been completely consumed. The mixture was diluted in 500 mL of H2O and extracted with AcOEt (3*250 mL). The organic phases were combined, dried over NaiSCh, filtered and evaporated to dryness to obtain a mixture of 2nitrosophenol and 4-nitrosophenol.

6.2) Hydrogenation of pure p-nitrosophenol and a mixture of para- and ortho-nitrosophenol

The dry crude mixture, obtained in Example 6.1, was dissolved in MeOH, Pt/(C) (% by weight) was suspended, the mixture was then placed under hydrogen (latm) with stirring. After 2 hours, the mixture no longer showed traces of 2-nitrosophenol and 4nitrosophenol. The solution was filtered through Celite, and evaporated to dryness to obtain a mixture of 2-aminophenol and 4-aminophenol in a ratio of o/p=10/90.

Two other hydrogenation tests of pure p-nitrosophenol were carried out under pressure (P=15bar) at T=80°C, using the Pt/C catalyst and the SiliaCat Pd(0) catalyst. A conversion of around 99.9% was obtained with an excellent yield of 99.8% (control by HPLC)

7) nitrosation of phenol - continuous protocol

The same ratios as used in example 6.1 were tested continuously. However, after 5 minutes of residence time in the continuous reactor, the aqueous solution of phenol was added, and after a residence time of 5 minutes, nitrosophenol was obtained continuously. The extraction was carried out in batch to carry out the hydrogenation in batch, according to the conditions of example 6.2, to obtain a mixture of 2-aminophenol and 4-aminophenol in a ratio of o/p=10/90.

Claims (15)

1 2 1 2b 1 2a or in which step A is a nitrosation step, R being as defined in claim 1, and X being a nitroso group, to obtain a nitroso compound in which the compound of Formula 2 has the structure of a composed of Formula 2b: 1 2 in which R represents: • a hydrogen atom, • a protective group chosen from a benzyl or an acetate, and in which X represents a nitro group or a nitroso group, said nitration step A being carried out continuously: • either under microwaves, • either under ultrasound, • either under microwaves followed by ultrasound, • or, optionally under microwaves and/or under ultrasound, the nitration agent being sodium nitrite, in the presence of an oxidizing agent, particularly in the presence of HNOs, said nitrosation step A being carried out continuously: • the nitrosation agent being sodium nitrite. 1. Process for preparing paracetamol, in which the process comprises a step A of nitration, or nitrosation, of a compound of Formula 1 with a nitration agent, or an appropriate nitrosation agent to obtain a compound of Formula 2: 2. Method according to claim 1, in which step A is a nitration step, R being as defined in claim 1, and X being a nitro group, to obtain a nitro compound in which the compound of Formula 2 has the structure of a compound of Formula 2a: 3. Method according to one of claims 1 to 2, in which the nitration step A is carried out in at least two microwave reactors in series, preferably at least three microwave reactors in series and in a manner particularly preferred at least four microwave reactors in series, in particular comprising, between each reactor in series, a cooling step so as to adjust the temperature to a temperature of 20 to 40°C, preferably 20 to 30 °C. 4. Method according to one of claims 1 or 2 in which nitrosation step A is carried out in an acidic medium, in particular in an aqueous solution of hydrochloric acid or sulfuric acid, 5. Method according to one of claims 1,2 or 4, in which a reactor is supplied with an aqueous solution of the compound of Formula 1, and with NaNO2 in aqueous solution in an acid, in particular in hydrochloric acid. 6. Method according to one of claims 1, 2, 4 or 5, in which nitrosation step A is carried out at a temperature below 10 °C, in particular between -5 to 5 °C, in particular at a temperature approximately 0°C, 7. Method according to one of claims 1 to 6 in which step A of nitration or nitrosation leads to the formation of the compound of Formula 2, in particular p-nitrophenol or p-nitrosophenol, in particular pnitrosophenol, with a regioselectivity greater than 60%, in particular greater than 80%, in particular in which the ortho isomer/compound of Formula 2 ratio is less than 2/8, and is in particular approximately 1/9. 8. Method according to one of claims 1 to 7, in which said method further comprises, after step A of nitration or nitrosation, a step B of hydrogenation of the compound of Formula 2, to obtain: • either 4-aminophenol, in the case where R is a benzyl group or a hydrogen atom, • or O-acetyl-4-aminophenol, in the case where R is an acetate group said hydrogenation step B being carried out continuously or in batches, preferably continuously, in the presence of hydrogen, a solvent and a catalyst. 9. Process according to claim 8, in which hydrogenation step B is carried out in the presence of a catalyst chosen from Pd/C, Pt/C and Fe/HCl, in particular in which hydrogenation step B is carried out in the presence of Siliacat Pd(0) as catalyst, in particular in which hydrogenation step B is carried out in the presence of a solvent chosen from ethanol or methanol, in particular ethanol, in particular in which the hydrogenation step B is carried out at a temperature between 50 and 130°C, in particular between 80°C and 100°C, in particular in which the hydrogenation step B is carried out at a hydrogen pressure between 10 and 50 bars, in particular between 15 and 30 bars, in particular around 20 bars. in particular in which the hydrogenation step B is carried out in at least two reactors in series, preferably at least three reactors in series and particularly preferably three or five reactors in series. 10. Method according to one of claims 8 or 9, in which said method further comprises, after hydrogenation step B, a step C of acylation of p-aminophenol to obtain paracetamol: said acylation step C being carried out continuously or in batches, preferably continuously. 11. Method according to claim 10, in which acylation step C is carried out with acetic anhydride as acylating agent, in particular in which acylation step C is carried out at a temperature between 60 and 100°C. 12. Method according to one of claims 10 or 11, comprising: 13. • a step A of nitration or nitrosation of a compound of Formula 1, to obtain a compound of Formula 2, said step A of nitration being carried out, either continuously, or continuously and under microwaves, or continuously and under ultrasound , either continuously and under microwaves and under ultrasound, or continuously and optionally under microwaves and/or under ultrasound, the nitration agent being sodium nitrite, in the presence of an oxidizing agent, in particular in the presence of HNO ₃ said nitrosation step A being carried out continuously, the nitrosation agent being sodium nitrite, R and X being as defined in claim 1, • a hydrogenation step B of the compound of Formula 2, to obtain: either 4-aminophenol, in the case where R is a benzyl group or a hydrogen atom, or paracetamol, in the case where R is an acetate group, said hydrogenation step B being carried out continuously or in batches, preferably continuously, and • an acylation step C of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously or in batches, preferably continuously. Method according to one of claims 10 to 12, comprising: • a nitration step A of the phenol, to obtain p-nitrophenol, said nitration step A being carried out continuously and under microwaves, • a step B of hydrogenation of the p-nitrophenol compound, to obtain paminophenol: said hydrogenation step B being carried out continuously in three reactors in series, and • a step C of acylation of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously. 14. Method according to one of claims 10 to 13, comprising: • a step A of nitrosation of the phenol, to obtain p-nitrosophenol, said step A of nitrosation being carried out continuously, at a temperature below 10 ° C, • a step B of hydrogenation of the p-nitrosophenol compound, to obtain p-aminophenol: said hydrogenation step B being carried out continuously in three reactors in series, and • a step C of acylation of 4-aminophenol, to obtain paracetamol, said acylation step C being carried out continuously. 15. Method according to one of claims 10 to 14, further comprising a step D of purifying the paracetamol, in particular by continuous distillation, continuous liquid-liquid extraction and/or by crystallization, in particular by continuous crystallization.