RU2818763C1 - Method and apparatus for producing paracetamol from para-nitrosophenol and/or para-nitrophenol in acetic acid medium - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to chemical engineering, particularly to a method of producing paracetamol from para-nitrosophenol and/or para-nitrophenol, as well as to an apparatus for realizing said method. Proposed method includes the following stages: a) preparing a solution of para-nitrosophenol and/or para-nitrophenol in acetic acid; b) feeding the solution from step a) into a reactor with an inert atmosphere while stirring and maintaining temperature in range from 40 to 55 °C; c) dosing zinc metal in the form of powder into the reactor at a controlled feed rate; d) stirring the reaction mixture until the reaction is complete while maintaining the temperature in range of 40 to 55 °C; e) cooling the reaction mixture to 3–7 °C for extraction of fine crystalline zinc acetate from reaction solution; f) removing the reaction mixture from the reactor into a separation device; g) separating solid zinc acetate as a retentate and a solution of para-aminophenol in acetic acid as a permeate; h) removing the solution of para-aminophenol in acetic acid from the separation device; i) feeding a solution of para-aminophenol in acetic acid from step h) into a reactor with a stirrer, forced maintenance of temperature in range from 10 to 140 °C and possibility of creating inert and/or rarefied atmosphere; j) boiling a solution of para-aminophenol in acetic acid at reduced pressure with distillation of part of watered acetic acid at temperature from 60 to 120 °C; k) boiling a solution of para-aminophenol in acetic acid at pressure of 2 to 3 atm. and temperature of 120 to 140 °C until complete reaction; l) cooling the reaction mixture to separate crystalline paracetamol from the reaction solution; m) removing the reaction mixture from the reactor into a separation device; n) separating the solid paracetamol from the liquid reaction mixture; o) washing paracetamol with acetic acid; p) drying of solid paracetamol and its unloading with obtaining of finished product.

EFFECT: providing a novel method of producing paracetamol, characterized by simplicity of implementation from hardware and technological points of view, availability and low cost of starting reagents and low power consumption, as well as providing high purity of the obtained end products without using additional labour-intensive purification steps.

19 cl, 3 dwg, 4 ex

Description

The present invention relates to the field of chemical technology, in particular to a new method for producing paracetamol from para- nitrosophenol and/or para- nitrophenol in acetic acid, as well as to a plant for implementing this method.

para- Acetylaminophenol (acetaminophen, paracetamol) is a drug, analgesic and antipyretic from the anilide group, which has an antipyretic effect. According to the mechanism of action, paracetamol blocks cyclooxygenase 1 and cyclooxygenase 2 mainly in the central nervous system, affecting the centers of pain and thermoregulation. In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on cyclooxygenase, which explains the almost complete absence of anti-inflammatory effect. The absence of a blocking effect on the synthesis of prostaglandins in peripheral tissues determines the absence of a negative effect on water-salt metabolism and the mucous membrane of the gastrointestinal tract.

Paracetamol is included in the list of essential medicines of the World Health Organization, as well as in the list of vital and essential medicines in the Russian Federation. Therefore, there is still significant interest in the development and implementation of new effective methods of synthesis in the research and production fields paracetamol, meeting the modern realities of constantly rising raw materials and increasingly stringent requirements for ensuring environmentally friendly production.

The traditional method for the synthesis of paracetamol (APAP) is the acylation reactionpair-aminophenol (PAP). Acetic anhydride (US20040138509A1, US4565890A) is widely used as an acylating agent. The reaction proceeds smoothly in a wide variety of solvents (ethyl acetate, acetic acid, water), with high yields. However, as disadvantages should note the relatively high cost of acetic anhydride and the strict regulation of the circulation of this reagent.

It is possible to introduce acetic anhydride into two-stage processes for the synthesis of paracetamol, where the reaction to obtain para- aminophenol is combined with its simultaneous acylation without isolating an intermediate compound. The state of the art describes two-stage methods for the synthesis of paracetamol from para- nitrosophenol (RU2574733, RU2495865, RU2461543). However, such a transformation can only be carried out in a single reaction vessel if the catalytic hydrogenation method is used for the reduction step. This approach, in turn, involves the use of expensive hydrogenation catalysts and special equipment for working with hydrogen gas under pressure.

The use of cheaper acetic acid is known in the prior art as an acylating agent.

A method for the synthesis of paracetamol by acylation of para- aminophenol with acetic acid using the reactive distillation method is described (US9102589). The proposed technology combines a reaction apparatus with a distillation column. The column is used to simultaneously distill off excess water, separate the water-acetic mixture, and return glacial acetic acid to the reaction volume. Disadvantages include the extremely cumbersome hardware design of this process, the long-term process, and the use of high temperatures that negatively affect the reaction mixture.

The preparation of paracetamol by acylation of para- aminophenol by boiling in dilute acetic acid is described (CN111170880A). There is no provision for removing water from the reaction medium during the reaction; the chemical transformation takes place within 3 hours. This Chinese patent uses an acid with a moisture content of ~70%, but our laboratory studies have shown that the presence of excess water critically affects conversion. Similar data are described in the literature (US9102589). At this concentration it is impossible to achieve high degrees of conversion and obtain the declared yield of 91%. The addition of 0.5 wt.% to the reaction mixture described in the patent. sodium metabisulfite cannot affect the acylation process, and only prevents side oxidation processes.

The use of esters such as methyl or ethyl acetate as an acylating agent is described (JP2002105037A). However, for such a reaction to occur, extremely high temperatures (up to 350°C) and pressure (50 atm) are required; the transformation is carried out in an autoclave. Also, in addition to the formation of the target N-acetyl derivative, paracetamol, the formation of a by-product of N-alkylation has been noted in the literature.

Methods using acetyl chloride as an acylating agent are not discussed in detail, since O-acylation occurs as a side process with the formation of a harmful impurity 4'-acetoxyacetanilide.

para- Aminophenol serves as the main raw material for the synthesis of paracetamol and is an extremely valuable product of organic synthesis. This compound is used to produce medicines, dyes, and is used as an antioxidant in the production of rubber. Several approaches to the industrial production of para- aminophenol have been described (Scheme 1), but the main method of synthesis is the reduction of para- nitro or para- nitrosophenol. This is the fastest and least expensive method.

Several approaches to carrying out this chemical transformation have been described.

Scheme 1. Main synthetic approaches for the production of para- aminophenol

Catalytic hydrogenation with hydrogen has become quite widespread (RU2461543, CN104356007A, CN104447362A, WO2021219647A, CN112279781A, SU536167A1, Green Chem., 2019, 21, 6381-6389). The reduction of para- nitro or para- nitrosophenol with hydrogen leads to a high-quality product and is relatively easy, but requires expensive hydrogenation catalysts. It is proposed to use deposited palladium on carbon, platinum or activated nickel metal. Such catalysts can withstand a limited number of synthetic cycles, after which they require replacement. Regeneration of such catalysts is extremely difficult. Raney nickel is pyrophoric, and given that the reduction is proposed to be carried out in an environment of organic solvents (alcohols, ethyl acetate), increased safety requirements are imposed on the work. For the described processes, hydrogen gas is used under pressure up to 20-30 atm, which also requires special precautions and special hardware design.

The reduction of para- nitrosophenol by electrolytic method in a weak solution of sulfuric acid is described (DE2256003A1). The result can be a high quality product at relatively low cost. However, this method requires complex hardware design, and the selection of optimal technological parameters (current density, reagent concentrations) during the reaction process is difficult. The result is greatly influenced by the choice of material for the electrodes.

Sodium sulfides and polysulfides, hydrogen sulfide, sulfur dioxide, dithionite, bisulfite or sodium metabisulfite (CN103772217A, CN104356007A, US377256, US3223727) can be used as reagents for the “sulfide” method. The use of sulfides has a number of advantages: low cost of reagents and technically simple isolation of the product. However, due to the low chemical activity of the reducing agent, a significant excess of it is required to carry out this transformation. As a result, a large amount of liquid waste is generated that needs to be disposed of. The reaction is also accompanied by the release of a noticeable amount of toxic hydrogen sulfide, which requires additional equipment to capture and neutralize it, and strict environmental control.

Reduction with metals in an acidic environment is a well-established laboratory method for the reduction of aromatic nitro- and nitroso compounds. The industrial application of this technique is also described (CN1562959A, CN105218406A, CS203892B1). The metals commonly used are carbonyl iron and zinc powder.

When performing the reduction reaction of para- nitrophenol with iron (CN1562959A) or zinc (CN105218406A) in hydrochloric acid, the target para- aminophenol is formed in the form of a hydrochloride. If it is necessary to isolate the product in free base form, an additional neutralization step is required. This requires the use of additional reagents and creates excess waste.

When using iron in acetic acid to reduce nitroaromatic compounds, the reaction proceeds with great heating, becomes very thick, and an amorphous mass of iron salts is formed as waste, which makes complete isolation of the product extremely difficult (WO2004014382A1). These factors make scaling such a process problematic.

para- Nitrosophenol is used much less frequently as a starting compound for the production of para- aminophenol, since it is not a sufficiently stable substance. The patent CS203892B1 proposes the reduction of para- nitrosophenol with iron in hydrochloric acid, however, in this case, iron compounds that are difficult to separate at this stage are also formed, and therefore para- aminophenol is not isolated in its individual form, and the reaction mixture is subjected to further transformations.

Thus, the prior art does not describe the use of zinc metal in acetic acid for the reduction of nitroso compounds. Although using this technique would produce a useful by-product - zinc acetate.

Zinc acetate dihydrate is a valuable substance, used as a food additive as a flavor and aroma enhancer (E650), as a source of zinc, an essential trace element for the body, and is also a component in the production of cosmetics. In addition, zinc acetate is used as a starting compound for the preparation of nano-structured zinc oxide and the preparation of other zinc salts.

The main method for obtaining zinc acetate dihydrate is to dissolve zinc oxide or hydroxide in acetic acid in the presence of water (RU2483056C2, CN1059196C, CN1696099A, TWI243814B). For the technical implementation of this process, specialized equipment is described (CN212041433U, CN209714555U).

Thus, at present, there is still a significant need to develop new methods for producing paracetamol, a valuable product in chemical technology, combined with the production of other valuable products, characterized by a reduced amount of recycled waste, energy-efficient process implementation, and also eliminating or at least minimizing the above disadvantages of the prior art and providing the person skilled in the art with a wider choice of means and technologies to achieve the necessary characteristics of paracetamol, in particular for use in further synthetic chains.

Therefore, the objective of the present invention was to provide a new method for the combined production of paracetamol and zinc acetate, characterized by ease of implementation from a hardware and technological point of view, availability and low cost of starting reagents and reduced energy consumption costs, as well as ensuring high purity of the resulting final products without the use of additional labor-intensive purification stages.

This problem was solved through a new method for obtaining paracetamol frompair-nitrosophenol and/orpair-nitrophenol, including the following stages:

a) preparing a solution of para- nitrosophenol and/or para- nitrophenol in acetic acid;

b) feeding the solution from stage a) into a reactor with an inert atmosphere with stirring and forced maintenance of the temperature in the range from 40 to 55 ° C;

c) dosing zinc metal in powder form into the reactor at a controlled feed rate;

d) stirring the reaction mixture until the reaction is complete while maintaining the temperature in the range from 40 to 55 °C;

e) cooling the reaction mixture to 3 - 7 °C to separate fine-crystalline zinc acetate from the reaction solution;

f) withdrawing the reaction mixture from the reactor to a separation device;

g) separating solid zinc acetate as a retentate and a solution of para- aminophenol in acetic acid as a permeate;

h) removing the solution of para- aminophenol in acetic acid from the separating device;

i) feeding a solution of para- aminophenol in acetic acid from stage h) into a reactor with a stirrer, forced maintenance of temperature in the range from 10 to 140 ° C and the possibility of creating an inert and/or rarefied atmosphere;

j) boiling a solution of para- aminophenol in acetic acid under reduced pressure with distillation of part of the watered acetic acid at a temperature of 60 to 120 ° C;

k) boiling a solution of para- aminophenol in acetic acid at a pressure of 2 to 3 atm and a temperature of 120 to 140 °C until the reaction is complete;

l) cooling the reaction mixture to separate crystalline paracetamol from the reaction solution;

m) removing the reaction mixture from the reactor to a separation device;

n) separating solid paracetamol from the liquid reaction mixture;

o) washing paracetamol with acetic acid;

p) drying the solid paracetamol and discharging it to obtain the finished product.

As previously shown in the review of the state of the art, several approaches to the industrial production of para- aminophenol are known, and the main precursor for its production is para- nitrophenol. The use of paranitrosophenol is very limited.

This is due to the fact that para- nitrophenol as a starting material for the reduction reaction to para- aminophenol looks more attractive due to its greater chemical stability. However, para- nitrophenol is a less accessible and more expensive raw material for production, since it cannot be obtained with high yield directly from phenol by nitration reaction due to the low regioselectivity of this reaction.

para- Nitrosophenol, in turn, can be obtained with high yield and selectivity directly from phenol, however, it has less chemical stability, which imposes special requirements for the process of its recovery: sufficiently mild process conditions must be ensured to exclude the formation of by-products and, as a consequence, guarantee the required purity of the final product. Therefore, when such a reduction method is discovered, the general synthetic approach based on the nitrosation of phenol and the reduction of para- nitrosophenol to para- aminophenol becomes significantly more profitable due to the almost doubling of the total yield of the final product.

The authors of the invention managed to develop a new method for producing paracetamol, based on the reduction of para- nitrosophenol, which meets the necessary requirements. In addition, the authors found that the proposed method is also suitable for producing paracetamol based on a mixture of para- nitrosophenol and para- nitrophenol, as well as pure para- nitrophenol, which gives the method versatility and high flexibility in the context of the choice and quality of the starting product.

The proposed method according to the invention is based on the reduction reaction of para- nitrosophenol and/or para- nitrophenol with hydrogen released during the interaction of metallic zinc with acetic acid, accompanied by the formation of zinc acetate, and further acylation of the resulting para- aminophenol with acetic acid in a single medium.

Unlike two-stage methods implemented in one vessel, the method according to the invention is also implemented in a single medium of acetic acid, but at the same time, due to the removal of by-products, it allows one to influence the amount of impurities that arise when exposed to high temperatures, and, therefore, provides increased purity of the final products. At the same time, the developed conditions provide effective separation without the need to use expensive equipment and increased energy costs.

This method, according to the invention, also makes it possible to realize the following advantages:

• the use of metallic zinc allows for a controlled exothermic reaction without the risk of dangerous overheating; when carrying out the reaction, heating of the chemical apparatus is necessary only at the initial stage, thus increasing the overall energy efficiency of the process. In contrast to the use of metallic iron as a reducing agent, during the reaction using metallic zinc powder, no critical density jumps occur in the reaction medium, which allows mass and heat transfer processes to occur effectively; the resulting crystalline precipitate of zinc acetate coagulates into sufficiently large aggregates; cooling of the reaction mass, as in the case of using iron, which greatly facilitates filtration and ensures complete separation of the liquid phase without loss of dissolved para- aminophenol;

• the reduction process of para- nitrosophenol and/or para- nitrophenol accelerates the reaction of zinc metal with acetic acid, so that zinc acetate as a valuable by-product in the para- aminophenol synthesis can be obtained much faster than in the case of a separate synthesis in which the metal zinc reacts with acetic acid without the presence of any other substances, and in addition, the saturation of the reaction solution with para- aminophenol significantly affects the solubility of zinc acetate, increasing the degree of its extraction in the form of a crystalline precipitate;

• cheap acetic acid is used as an acylating agent, which is also a solvent;

• simultaneous distillation of acetic acid and water released during the reaction under reduced pressure at the acylation stage shifts the chemical equilibrium and significantly reduces the total reaction time, which allows the method to be carried out in a semi-continuous mode;

• the implementation of continuous distillation of the solvent simplifies the separation of solid paracetamol from the reaction mass by increasing the concentration of the reaction solution, which significantly reduces the total time of the technological cycle required to obtain one batch of paracetamol and also simplifies the possibility of recycling acetic acid;

• Removal of excess water from the reaction solution allows the use of wet feedstock.

• after isolating solid paracetamol from the reaction mass, the mother liquor can be completely used for subsequent technological cycles, which significantly reduces the amount of waste.

Thus, the presented new method, according to the invention, is characterized by cheap and readily available reagents, as well as a reduction in the amount of waste sent for disposal, allows, without the use of special equipment, to obtain and isolate several economically significant products, which is simple from a hardware and technological point of view, providing a modern yield and high purity, up to 98% in the case of paracetamol.

Another object of the present invention is a plant for implementing the specified method for producing paracetamol, including

• container for preparing a solution of para- nitrosophenol and/or para- nitrophenol in acetic acid;

• a hopper with a dosing screw for supplying zinc;

• a reactor for the reduction of para- nitrosophenol and/or para- nitrophenol with zinc in acetic acid, equipped with a stirrer, a gas supply to create an inert atmosphere, a system for maintaining a given temperature of the reaction mixture, an inlet for supplying a solution of para- nitrosophenol and/or para- nitrophenol in acetic acid , an inlet for supplying zinc and an outlet for the reaction mixture;

• a first suction filter for separating solid zinc acetate as a retentate and a solution of para- aminophenol in acetic acid as a permeate, configured to receive the reaction mixture from the para- nitrosophenol and/or para- nitrophenol recovery reactor, withdraw solid zinc acetate and remove para- aminophenol solution, also equipped with a stirrer, inlet and outlet for liquid streams, connection for gaseous streams and connection for a vacuum device;

• distribution comb system for redirecting liquid flows of the first nutsch filter;

• line for supplying liquid flows to the distribution comb system;

• a container for acetic acid connected through a shut-off valve to the liquid flow supply line to the distribution comb system;

• a solvent container connected through a shut-off valve to the liquid flow supply line to the distribution comb system;

• a container for drainage fractions connected to a comb distribution system;

• a reactor for the production of paracetamol, equipped with an anchor stirrer, a gas supply to create an inert atmosphere, a system for maintaining a given temperature of the reaction mixture, a refrigerator for condensing acetic acid vapors with the ability to remove condensed acetic acid, a vapor temperature sensor, an input for supplying a solution of para- aminophenol in acetic acid , an inlet for supplying acetic acid, an outlet for the reaction mixture, and configured to create a reduced or increased pressure inside the reactor;

• a second suction filter for separating solid paracetamol, configured to receive the reaction mixture from the paracetamol production reactor, output solid paracetamol and output the separated liquid reaction mixture, and also equipped with a stirrer, an inlet for acetic acid, a connection for gaseous flows and a connection for a vacuum device;

• container for receiving condensed acetic acid from the paracetamol production reactor;

• line for supplying acetic acid to the second suction filter and/or paracetamol production reactor;

• line for removing waste fractions from the second suction filter;

wherein the outlet for liquid streams of the first nutsche filter is connected through a distribution comb system to the inlet for supplying a solution of para- aminophenol to the paracetamol production reactor;

and wherein the container for receiving condensed acetic acid from the paracetamol production reactor is connected to the acetic acid supply line to the second nutsche filter and/or the paracetamol production reactor.

The presented installation allows for a new method of producing paracetamol both in batch mode and in semi-continuous mode: carrying out both reactions - reduction and acylation, simultaneously in a mutually harmonized mode, and all devices operate without downtime. In addition, the installation according to the invention makes it possible to separate by-products and redirect circulation flows for their reuse. The installation provides the ability to flexibly regulate the nature of the acylation process, having the ability to influence the speed and completeness of the reaction by changing the pressure and temperature in the paracetamol production reactor.

Detailed description of the essence of the technical solution

Figure 1 shows one of the installation options for implementing the method according to the invention.

The following detailed description of the method is given with reference to the one shown in FIG. 1 installation option, however, does not impose any restrictions on the hardware implementation of the method proposed in the invention.

In step a) of the method according to the invention, a solution of para- nitrosophenol or para- nitrophenol in acetic acid is prepared in a container (E2.1). It is preferable to prepare a saturated solution of para- nitrosophenol or para- nitrophenol in acetic acid to maximize productivity and reduce liquid waste, however, according to the invention, the use of a more dilute solution is also possible. Also, a mixture of para- nitrosophenol and para- nitrophenol can be used in the method. It is described that during the synthesis of para- nitrosophenol, due to a violation of the nitrosation reaction, the product can contain up to ~25% para- nitrophenol. Such a mixture can also be used in the described method.

In addition, para- nitrosophenol and/or para- nitrophenol, both in dry and wet states, can be used to obtain a solution. However, too much water in the feed reduces the overall solubility of para- nitrosophenol and/or para- nitrophenol in acetic acid, which reduces the overall efficiency of the process; Therefore, an acceptable moisture range for the use of para- nitrosophenol and/or para- nitrophenol from the point of view of the present invention is the range of water content from 0 to 50% by weight, based on the weight of para- nitrosophenol and/or para- nitrophenol. Moreover, the use of para- nitrosophenol in a wet state is preferable, since it has greater chemical stability, since in this case oligomerization processes are inhibited.

At the next technological stage b), using a peristaltic pump (H2.1), the solution prepared at stage a) is loaded from the container (E2.1) into the reactor (P2.1). Moreover, both the entire solution prepared at stage a) and part of the solution prepared at stage a) in the amount necessary for carrying out stage b) can be supplied to the reactor.

Then a weak gas current is connected to create an inert atmosphere for purging the system in order to prevent the accumulation of hydrogen released during the interaction and the possible formation of a dangerous hydrogen-air mixture in the free space above the liquid.

The gas used to create the inert atmosphere can be nitrogen, argon or helium, preferably nitrogen.

With active mixing with a mixer M2.1, preferably with a top drive, stage c) is started, at which, using a dosing screw from the hopper (B2.1), metallic zinc powder is dosed at a controlled speed, focusing on the intensity of the interaction that has begun, the rate of heat release and the amount of solid phase in the reaction mixture. In a preferred embodiment, the zinc feed rate is in the range of 15 to 75 g/min, particularly preferably in the range of 30 to 60 g/min.

According to the present invention, the molar ratio of the total added metallic zinc to the reduced para- nitrosophenol is in the range from 2:1 to 10:1, preferably in the range from 2:1 to 6:1, and to para- nitrophenol in the range from 3: 1 to 10:1, preferably in the range from 3:1 to 6:1.

When dosing zinc metal powder, it is necessary to ensure its uniform distribution throughout the reaction volume and prevent clumping of the reagent, i.e. avoid a large concentration gradient and the occurrence of local overheating. In addition, since the interaction occurs with heating of the reaction mixture in the reactor, the temperature is forced to be maintained in the range from 40 to 55 °C. Temperature control is carried out using a sensor (TT2.1); when the temperature rises above 50°C, cooling is carried out using a system for maintaining a given reactor temperature (P2.1), preferably using a cooling coil. During the reaction, abundant precipitation of fine-crystalline precipitate of zinc acetate is observed.

After complete addition of the calculated amount of zinc in step d), the reaction mixture in the reactor (P2.1) is further stirred until the reaction is complete, without allowing the temperature to rise above 55°C.

In the context of the present invention, the term “ until the reaction is complete ” means achieving a conversion of the starting reagent of at least 95%.

According to the method of the present invention, it is very important to maintain the temperature at this stage in the range from 40 to 55 °C (preferably from 45 to 50 °C), since heating above this temperature range will lead to an excessive acceleration of the reaction of zinc with acetic acid and too much rapid release of hydrogen. Hydrogen gas will be removed from the reaction medium and will not have time to be spent on the reduction reaction, which will reduce the conversion of para- nitrosophenol and reduce the yield of the product.

At the next stage e) the reaction mixture is cooled to 3-7 °C for more complete extraction of zinc acetate from the solution, and the mixture is kept at this temperature for 20 - 90 minutes with constant stirring, and the intensity of stirring and the design of the stirrer blades should be as follows to prevent the formation of a layer of sediment at the bottom of the reactor during the entire process. The authors have found that in order to best counteract the settling of the solid fraction during the implementation of the method according to the invention, the upward flow created by the stirrer should be directed vertically along the axis of the reactor. In particular, the authors were able to achieve this operating mode using a paddle mixer with flat blades inclined at an angle from 30° to 60° to the vertical. In the preferred embodiment, a blade angle of 45° creates sufficient flow intensity with less energy consumption. The diameter of the stirrer is preferably from 25 to 60% of the diameter of the reaction vessel, particularly preferably 40%. The number of stirrer blades is defined as the ratio of the height of the reaction liquid level in the reactor to the diameter of the stirrer, rounded up, and varies from 3 to 6, preferably 3. The height of the stirrer blade is 0.2 of the stirrer diameter.

Then, in step f), the cold reaction mixture is transferred by gravity from the reactor (P2.1) to the separating device by opening valve 1.2.

According to the method of the present invention, the separating device is any device that can effectively separate the solid fine crystalline precipitate and the liquid reaction solution. In a preferred embodiment, the separation device may be selected from a centrifuge or a suction filter.

In a specific embodiment, the method according to the invention uses a suction filter as the separating device.

At stage g), by opening tap 3.2, the lower part of the nutsch filter (F2.1) is connected to the vacuum system and filtering is carried out. In this case, a solution of para- aminophenol in acetic acid passes as a permeate to the lower part of the filter, while a solid residue of fine-crystalline zinc acetate remains in the upper part as a retentate.

The distribution “comb” system used in the developed installation is a system of pipelines and shut-off devices (taps) and allows you to easily and with great flexibility redirect the flow of working fluids, using only one pump (H2.2).

Next, with a system of taps, a container with glacial acetic acid (E2.2) is connected to the upper part of the nutsche filter (position of taps: 9.2 open; 10.2 closed; 2.2 open from left to right; 5.2 open; 6.2 closed; 7.2 open; 8.2 closed) and with using a pump (H2.2) to wash zinc acetate from residual para- aminophenol, glacial acetic acid is supplied from the container (E2.2) in separate portions (from 2 to 4). During the supply of acetic acid for washing, the vacuum from the filter (F2.1) is turned off with valve 3.2, the sediment is mixed with a manually driven stirrer (MP2.1) and the vacuum is reconnected with valve 3.2, performing filtration.

The resulting para- aminophenol solution at method stage h) is removed from the bottom of the suction filter (F2.1) using a pump (H2.2) along the line leading to the reactor P3.1 (tap 2.2 - open to the left-up; taps 5.2 , 8.2 - open; valves 6.2, - closed).

After step h), the remaining wet zinc acetate may, if necessary, be further washed with an organic solvent to remove residual acetic acid, further purify, and speed up subsequent drying. To do this, a distribution comb system is used to connect the upper part of the nutsch filter to a container with a washing solvent (E2.3) (position of taps: 9.2 closed; 10.2 open; 2.2 open from left to right; 5.2 open; 6.2 closed; 7.2 open; 8.2 closed) and pump the flushing solvent with the pump (H2.2). To remove solvent from the lower part of the nutsch filter (F2.1), it is connected to a container for storing liquid waste (E2.4) (position of taps: 2.2 open from left to top; 5.2 open; 6.2 open; 7.2 closed; 8.2 closed).

As a solvent for washing, organic solvents miscible with water, in which zinc acetate is slightly soluble, can be used, such as, in particular, methyl alcohol, acetone, dioxane and mixtures thereof.

The washed zinc acetate on the filter is dried either in a stream of air (taps position: 2.2 closed; 3.2 open; 4.2 open) or using a vacuum (taps position: 2.2 closed; 3.2 open; 4.2 closed; 7.2 closed), and unloaded from the suction filter to obtain solid zinc acetate as a finished product.

As used herein, the term " zinc acetate " includes both anhydrous zinc acetate and any hydrate and/or solvate forms thereof. Preferably, in the method according to the invention, zinc acetate is obtained in hydrated form, in particular in the form of zinc acetate dihydrate.

At the next technological stage, the amino group is acylated para-aminophenol when boiled in acetic acid. Acetic acid, present as a solvent, acts directly as an acylating agent, and one molecule of water is released. This reaction is reversible; laboratory studies have shown that as the amount of water in the reaction medium increases, the reaction rate slows down significantly and the conversion decreases. At water content >15% chemical conversionpair-aminophenol does not exceed 75%. The optimal amount of water in the final reaction solution should not exceed 5%, in this case conversion can be ensuredpair-aminophenol in paracetamol up to 98%. Thus, the determining parameter for this transformation is the removal of water from the reaction medium to shift the chemical equilibrium towards the formation of paracetamol. This can be achieved by distilling off the watered solvent from the reaction mass. Water does not form azeotropic mixtures with acetic acid, however, simple distillation distills off acetic acid with a concentration of 75 to 90%, which allows the required amount of water to be removed.

To carry out acylation at stage i), a solution of para- aminophenol in acetic acid, separated at stage h), is fed into a paracetamol reactor P3.1, equipped with a system for maintaining a given temperature of the reaction mixture, designed to provide operating temperatures in the range from 10 to 140 °C. In a preferred embodiment, the system for maintaining a given temperature of the reaction mixture of the P3.1 reactor is a heating/cooling jacket with a coolant and a reaction mixture temperature sensor.

Mixing in the P3.1 reactor is carried out using an M3.1 anchor-type mechanical stirrer with a minimum gap with the reactor walls to effectively remove a layer of solid sediment from them. In the plane of the stirrer there are recesses for the thermocouple TT3.1 and the bottom valve 7.3 so that these devices do not touch the stirrer during its operation. The bottom drain break valve makes it possible to completely drain the reaction mass from the P3.1 reactor even in the event of heavy sedimentation.

According to the method of the invention, it is possible to use a wet initial solution of para- aminophenol in acetic acid (water content up to 15%). This represents an additional advantage when building a process chain where para- aminophenol comes from the previous stage undried.

At stage k) of the method according to the invention, hot coolant is supplied to the reactor jacket, a stirrer is connected, and a rarefied atmosphere is created by connecting the reaction volume to the vacuum system by opening valve 6.3 and bringing the reaction mass to a boil. If necessary, the vacuum depth can be adjusted by valve 5.3, by sucking air from the atmosphere or by supplying gas to create an inert atmosphere by valve 1.3, control is carried out according to the readings of the MA3.1 pressure gauge/vacuum gauge. Depending on the depth of vacuum, boiling is carried out at a temperature in the range from 60 to 120 °C, preferably in the range from 60 to 100 °C.

Distillation of watered acetic acid from the reaction mixture by lowering the pressure in the system significantly reduces the time required for the reaction, provides the necessary concentration of the solvent and improves the subsequent isolation of the product, and also reduces the temperature required for distillation, thereby providing milder conditions and, as a consequence, less the resulting impurities. So, for example, at 300-450 mmHg. watered acetic acid is removed from the system at a rate of 68-110 ml/min at a vapor temperature of ~75°C (according to TT3.2 data).

When boiling the reaction solution, vapors of watered acetic acid are constantly removed from reactor P3.1 and condensed using a refrigerator, in the preferred embodiment, using a downdraft refrigerator HX3.1 with a cooling jacket (see Fig. 1), while connecting a vacuum system to create the reduced pressure in the paracetamol production reactor is located on the container for receiving condensed acetic acid. The temperature of the vapor is controlled by a TT3.2 thermocouple; according to its readings, one can judge the humidity of the distilled acetic acid. The distillation of acetic acid is collected in container E3.1. The design of the E3.1 tank is designed to withstand an operating pressure range of 0.3-2 atm.

In another embodiment, a reactor assembly with a reflux condenser OX3.1 with a cooling coil can be used (see Fig. 2), while the connection of the vacuum system to create a reduced pressure in the paracetamol production reactor is located on the refrigerator for condensation of acetic acid vapor. The use of a reflux condenser includes the possibility of selecting distillate through tap 4.3 into container E3.1, since such a system operates on the principle of a complete condensation head.

Distillation of watered acetic acid makes it possible to reduce the reaction time to 2.5-4 hours (the usual time until 95% conversion of the initial reagent is at least 5 hours).

Since a fairly dilute solution is introduced into the paracetamol synthesis reaction at a time para-aminophenol, it is rational to accumulate the mass of the product in the reactor at the acylation stage. That is, portions of fresh solution continue to be fed into reactor P3.1pair-aminophenol from the recovery stage, without unloading the previous portion of the reaction mass from reactor P3.1. Since the reaction is accompanied by distillation of the solvent, by the time the next portion of the solution is readypair-aminophenol in reactor P3.1 a sufficient amount of free working volume is already formed. This mode can be ensured only in the case of distillation at reduced pressure, so that its speed allows ensuring the required free volume of the reactor during the passage of the reduction stages. In this case, for example, three portions of the solution can be sequentially loaded into the reactor P3.1pair-aminophenol. This technological technique provides the required total reaction time and greatly simplifies the process of isolating paracetamol from the reaction mixture.

Thus, in one embodiment, the method is carried out in a semi-continuous mode, in which steps a) to f) are carried out first, and then steps b) and g) and then all subsequent steps are carried out simultaneously.

In a preferred embodiment, steps b) to j) are repeated three times before performing step k).

To ensure complete reaction in the next step k), the concentrated reaction mixture is boiled at elevated pressure in the range of 2 to 3 atm and a temperature of 120 to 140 °C. To do this, reactor P3.1 is disconnected from the vacuum system by closing valve 6.3, and the flow of air or gas is shut off to create an inert atmosphere. Preferably, the duration of boiling the reaction mixture under these conditions is from 15 to 40 minutes and allows to achieve a conversion of para- aminophenol of at least 95%.

The combination of distilling off watered acetic acid, first at reduced and then at elevated pressure, developed in the method according to the invention also makes it possible to obtain purer paracetamol, since at the initial stage of acylation, when a large amount of para- aminophenol is present in the reaction solution, long-term overheating is eliminated by creating a reduced pressure , which reduces the risk of decomposition and the formation of impurities, and when the content of para- aminophenol in the reactor is significantly reduced, increasing the temperature allows the reaction to be brought to the required high conversion values.

To carry out stage l) of the method according to the invention, the heating of reactor P3.1 is stopped, the coolant is switched to cooling mode and the reaction mixture is cooled to a temperature in the range of 5 - 10 °C. Paracetamol crystallizes from the reaction mixture, and during the process of precipitation of the product, unreacted para- aminophenol remains in solution. The reaction mixture is kept under these conditions for 30-60 minutes for the most complete release of crystalline paracetamol.

Next, at stage m), the reaction mixture is removed from reactor P3.1; for this, the bottom drain rupture valve 7.3 is opened and the paracetamol suspension is transferred by gravity into the separating device. The remaining crystalline mass on the walls and working plane of the mixer is washed off by feeding a small portion of glacial acetic acid from container E3.2.

The separation of solid paracetamol from the liquid reaction mixture at stage n) of the method is carried out by passing the reaction mixture through a separating device, preferably a suction filter F3.1. The liquid that has passed through the filter is collected at the bottom of the Nutsch filter, and the solid paracetamol separated on the Nutsch filter is squeezed out by connecting the filter to a vacuum system.

Then, at step o), the solid paracetamol precipitate is washed with a minimum amount of acetic acid. For washing, you can use either glacial acetic acid from container E3.2, or water-distilled acetic acid, feeding it into the Nutsch filter F3.1 from container E3.1 with pump H3.1 (taps 11.3, 14.3 - open, taps 2.3, 13.3 - closed).

If necessary, the sediment can be additionally washed with a small amount of clean cold water.

The combined filtrates are transferred from the bottom of the suction filter into container E3.3. These drains can be reused in the next technological cycle or for preparing the initial solution for the reaction, or the combined drains can be concentrated as part of a separate run in the P3.1 reactor, for the most complete extraction of paracetamol.

The washed solid paracetamol residue is dried under vacuum for a period of 60 to 360 minutes and discharged as the final product.

The figures show:

In FIG. 1 shows a technological diagram of one of the embodiments of the installation according to the invention.

In FIG. 2 shows a flow diagram of an embodiment of a reactor for the production of paracetamol with a reflux condenser of the installation according to the invention.

In FIG. Figure 3 shows a diagram of the loading of batches of initial reagents and illustrative time intervals of the main stages of the method in a semi-continuous mode.

Legend:

P2.1 Para- nitrosophenol and/or para- nitrophenol reduction reactor

F2.1 The first suction filter for separating solid zinc acetate dihydrate and para- aminophenol solution.

B2.1 Hopper with dosing screw for supplying zinc

L2.1 Loading hatch for servicing the R2.1 reactor

M2.1 Mechanical stirrer

MP2.1 Manually driven agitator for agitating the sediment in the nutsch filter

GS2.1 Distribution comb system

LP2.1 Line for supplying liquid flows to the distribution comb system

H2.1 Peristaltic pump for supplying a solution of para- nitrosophenol and/or para- nitrophenol to the reactor P2.1

H2.2 Peristaltic pump for supplying liquids and working solutions to the distribution comb system of taps

E2.1 Container for preparing a solution of para- nitrosophenol and/or para- nitrophenol in acetic acid

E2.2 Container for storing glacial acetic acid

E2.3 Container for storing solvent for washing the sediment in the first nutsch filter F2.1

E2.4 Storage tank for process waste

TT2.1 Reactor temperature sensor P2.1

1.2 Valve for completely draining the contents of the reactor P2.1 into the Nutsch filter F2.1

2.2 Three-way valve for adjusting the output flows from the suction filter and transporting liquids from containers E2.2, E2.3, E2.4

3.2 Tap connecting the lower part of the nutsch filter F2.1 to the vacuum system

4.2 Tap for connecting to the atmosphere the upper part of the Nutsch filter F2.1

5.2 Shut-off valve for pump H2.2 from the distribution comb system

6.2 Valve of the distribution comb system, directing the flow into the drain tank E2.4

7.2 Valve of the distribution comb system, directing the flow to the upper part of the nutsch filter F2.1

8.2 Valve of the distribution comb system directing the solution of p-aminophenol into the reactor P3.1

9.2 Shut-off valve on the storage tank for glacial acetic acid E2.2

10.2 Shut-off valve on the solvent storage tank E2.3 for washing the sediment in the nut filter F2.1

P3.1 Paracetamol production reactor

F3.1 Second suction filter for separating solid paracetamol

L3.1 Loading hatch for servicing reactor R3.1

M3.1 Anchor type mechanical stirrer

MP3.1 Manually driven mixer for agitating the sludge in the nutsch filter F3.1

LP3.1 Line for supplying acetic acid to the second suction filter and/or paracetamol production reactor

LP3.2 Line for removing waste fractions from the second nutsch filter

HX3.1 Downdraft cooler with cooling jacket

OX3.1 Reflux condenser with cooling coil

H3.1 Peristaltic pump for supplying acetic acid

E3.1 Container for collecting distilled watered acetic acid

E3.2 Container for storing glacial acetic acid

E3.3 Storage container for combined drains

TT3.1 Temperature sensor

TT3.2 Temperature sensor, for measuring the temperature of vapors of distilled acetic acid

MA2.1 Pressure gauge/vacuum gauge

1.3 Gas supply valve to create an inert atmosphere in the R3.1 reactor

2.3 Valve for supplying glacial acetic acid to reactor P3.1 from container E3.2

3.3 Tap for supplying para- aminophenol solution to reactor R3.1 from the distribution comb system of taps GS2.1

4.3 Drain valve for removing acetic acid from refrigerator HX3.1

5.3 Valve for connecting to the external atmosphere of tank E3.1, also used to regulate pressure in the reactor system

6.3 Tap connecting container E3.1 to the vacuum system

7.3 Bottom breaking valve for draining the reaction mass from the reactor P3.1 into the Nutsch filter F3.1

8.3 Valve for connecting to the external atmosphere of the Nutsch filter F3.1

9.3 Tap for connecting the nutsch filter F3.1 to the vacuum system

10.3 Drain valve for removing filtrate from the bottom of the nutsch filter F3.1 into a container for storing combined drains E3.3

11.3 Shut-off valve on the acetic acid supply line

12.3 Shut-off valve on the clean water supply line

13.3 Shut-off valve on the supply line of glacial acetic acid from container E3.2

14.3 Stop valve on the supply line of watered acetic acid from container E3.1

The invention is further explained in more detail with the help of embodiment examples, which, however, do not impose limitations on the scope of the present invention.

EXAMPLES

Example 1 Combined synthesis of paracetamol and zinc acetate dihydrate from para- nitrosophenol

To carry out the synthesis, a laboratory installation was used, created in accordance with the scheme presented in Figure 1.

The following operating parameters and flows were used:

The total volume of the reactor R2.1 is 35 l

Working volume of reactor R2.1 27 l

Total volume of reactor R3.1 30 l

Working volume of reactor R3.1 20 l

Container volume E2.1 30 l

Container volume E2.2 20 l

Container volume E2.3 20 l

Container volume E2.4 50 l

Container volume E3.1 50 l

Container volume E3.2 50 l

Container volume E3.3 50 l

Pump capacity H2.1 ~1 l/min

Pump capacity H2.2 ~1 l/min

Screw productivity B2.1 42 g/min

Pump capacity H3.1 230 ml/min

The starting reagents were para- nitrosophenol, obtained in the laboratory by nitrosation of phenol (purity 97% (HPLC)), commercial zinc metal powder (PCR-1 brand), glacial acetic acid and deionized water.

Synthesis technique :

In container E2.1, 1183 g (9.61 mol) of wet para- nitrosophenol (water content 1.5 L) was dissolved in 14 L of glacial acetic acid. Using a peristaltic pump (H2.1), the prepared solution was fed into a reactor (R2.1), equipped with a top-drive mixer (M2.1), a cooling coil with temperature control using a sensor (TT2.1), a nitrogen supply and communication with an external atmosphere for the possibility of purging, loading hatch (L2.1). After complete introduction of the para- nitrosophenol solution, active stirring was turned on and 1288 g (19.7 mol) of PCR-1 metal zinc powder was dosed using a dosing screw from the hopper (B2.1) at a speed of 42 g/min. When the temperature increased above 50°C, cooling was connected using a cooling coil and the temperature was forcibly maintained in the range of 45 - 51°C. Abundant precipitation of fine-crystalline zinc acetate precipitate was observed. After the complete addition of the calculated amount of zinc (30 min), the reaction mixture in the reactor (R2.1) was stirred for an additional 1 hour to complete the reaction, without allowing the temperature to rise above 55°C. After this, the reaction mixture was cooled to 5°C for more complete extraction of zinc acetate from the solution, and the reaction mixture was kept at this temperature for 30 minutes.

The cooled reaction mixture was transferred by gravity from the reactor (R2.1) into a suction filter (F2.1). The lower part of the nutsch filter was connected to the vacuum system and filtration was carried out. In this case, the solution of para- aminophenol in acetic acid passed into the lower part of the filter, leaving a solid residue of fine-crystalline zinc acetate in the upper part. The suction filter was disconnected from the vacuum system and glacial acetic acid was supplied from the container (E2.2) in two separate portions (2 L and 2 L) using a pump (H2.2) to wash the zinc acetate from residual para- aminophenol. After each batch, the sediment was mixed with a manually driven stirrer (MP2.1), and by connecting the vacuum with tap 3.2, filtering was carried out. Then the Nutsch filter was disconnected from the vacuum system, the connection with the external atmosphere was restored, and the resulting solution of para -aminophenol from the lower part of the Nutsch filter (F2.1) was removed using a pump (H2.2) into the reactor P3.1.

The solution entering the reactor R3.1 after the recovery stage para-aminophenol, contained 12.8 liters of acetic acid. Such a volume was formed as a result of the following factors: on the one hand, part of the initial acetic acid (2.26 l) was consumed during interaction with zinc; and on the other hand, when washing zinc acetate, a total of 4 liters of solvent was added, which, taking into account the losses when the humidity of the washed sediment of zinc acetate dihydrate was 40%, amounted to an increase of 1.06 liters of glacial acetic acid.

After introducing the solution para-aminophenol into the reactor P3.1 with stirring turned on, a rarefied atmosphere was created in the reactor (350 mmHg) and the reaction mass was gradually brought to a boil by feeding hot coolant into the reactor jacket. When the reaction solution was boiled, vapors of watered acetic acid were removed from the reactor P3.1 for 2 hours through a downward cooler HX3.1 with a cooling jacket. The vapor temperature was controlled by a TT3.2 thermocouple and was ~75°C. The distillation of acetic acid was collected in container E3.1.

Then the vacuum system was turned off and the temperature of the reaction mixture was increased to 130°C, while the pressure in the reactor increased to 2.4 atm. Boiling was continued under these conditions for another 20 minutes.

Then the heating was stopped, the reaction mixture was cooled with stirring to a temperature of 6 °C and this temperature was maintained for 40 minutes.

The bottom valve 7.3 was opened and the paracetamol suspension was unloaded from the reactor P3.1 into the Nutsch filter F3.1. Using pump H3.1, 1 liter of glacial acetic acid was fed into the reactor from container E3.2 to wash the reactor walls and the working surface of the stirrer of any remaining crystalline mass. Connect the lower part of the nutsch filter to a vacuum system and squeeze out the sediment separated from the upper part of the nutsch filter. Then the solid paracetamol precipitate on the filter was washed with 0.5 liters of watered distilled acetic acid, feeding it into the nut filter F3.1 from container E3.1 with pump H3.1. The combined filtrates were removed from the bottom of the suction filter into container E3.3.

The washed solid residue of crystalline paracetamol was dried in a suction filter under vacuum for 5 hours.

As a result, 1336 g of crystalline paracetamol was obtained (purity 98% (HPLC), yield 92.1% of theory).

¹ H NMR (300 MHz, DMSO-d6) δ 1.99 (s, 3H), 6.68 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.8 Hz), 9 .12 (s, 1H), 9.64 (s, 1H).

¹³ C NMR (300 MHz, DMSO-d6) δ 24.2, 115.5, 121.3, 131.5, 153.6, 168.0

The remaining wet zinc acetate was further washed with 1.5 L of cold methyl alcohol to remove residual acetic acid and filtered again using vacuum.

The residue on the filter was dried in a stream of air for 30 minutes and discharged from the filter.

The result was 4114 g of solid zinc acetate dihydrate (purity >95% by NMR and elemental analysis, yield 95.3% of theory).

^1H NMR (300 MHz, _D2O ) δ 1.79 (s, 6H).

Example 2 Combined synthesis of paracetamol and zinc acetate dihydrate from para- nitrophenol

The example was carried out in accordance with the regimes and methods presented in example 1, with the only difference that 1200 g (8.63 mol) of para- nitrophenol was used to prepare the initial solution, and 1750 g (26.75 mol) of zinc was added to restore it at a speed of 58 g/min.

The result was 1290 g of crystalline paracetamol (purity 95% (HPLC), yield 99.0% of theory) and 5578 g of solid zinc acetate dihydrate (purity 96%, yield 94.2% of theory).

Example 3 Combined synthesis of paracetamol and zinc acetate dihydrate from para- nitrosophenol and para- nitrophenol

The example was carried out in accordance with the modes and methods presented in example 1, with the only difference that a mixture of 1005 g (8.17 mol) was used to prepare the initial solutionpair-nitrosophenol and 177 g (1.27 mol)pair-nitrophenol, and for its reduction 1353 g (20.7 mol) of zinc, which was added at a rate of 45 g/min.

The result was 1400 g of crystalline paracetamol (purity 96% (HPLC), yield 98.2% of theory) and 4266 g of solid zinc acetate dihydrate (purity 96%, yield 93.9% of theory).

Example 4 Combined synthesis of paracetamol and zinc acetate dihydrate from para- nitrosophenol in semi-continuous mode.

This synthesis was carried out in a laboratory setup created in accordance with the scheme presented in figure 1. Operating parameters and flows similar to example 1 were used. For clarity, in Fig. Figure 3 shows a diagram of the loading of batches of initial reagents and time intervals of the main stages of the method for example 4.

Synthesis technique :

In container E2.1, 1183 g of wet para- nitrosophenol (additional water content of 1.5 l) was dissolved in 14 l of glacial acetic acid. Using a peristaltic pump (H2.1), the prepared solution was fed into a reactor (R2.1), equipped with a top-drive mixer (M2.1), a cooling coil with temperature control using a sensor (TT2.1), and a gas supply to create an inert atmosphere and connection with the external atmosphere for the possibility of purging, loading hatch (L2.1). After complete introduction of the para- nitrosophenol solution, active mixing was turned on and 1260 g of PCR-1 metal zinc powder was dosed using a dosing screw from the hopper (B2.1) at a speed of 42 g/min. When the temperature increased above 50°C, cooling was connected using a cooling coil and the temperature was forcibly maintained in the range of 45 - 51°C. Abundant precipitation of fine-crystalline zinc acetate precipitate was observed. After the complete addition of the calculated amount of zinc (30 min), the reaction mixture in the reactor (R2.1) was stirred for an additional 1 hour to complete the reaction, without allowing the temperature to rise above 55°C. After this, the reaction mixture was cooled to 5°C for more complete extraction of zinc acetate from the solution, and the reaction mixture was kept at this temperature for 30 minutes.

The cooled reaction mixture was transferred by gravity from the reactor (R2.1) into a suction filter (F2.1).

After removing the reaction mixture into a suction filter (F2.1), a new batch of solution prepared from 1183 g of wet para- nitrosophenol and 14 L of glacial acetic acid was introduced into the reactor (R2.1), and the reduction procedure was completely repeated for 120 min.

In parallel, the lower part of the nutsch filter (F2.1) was connected to the vacuum system and filtration was carried out. In this case, the solution of para- aminophenol in acetic acid passed into the lower part of the filter, leaving a solid residue of fine-crystalline zinc acetate in the upper part. The suction filter was disconnected from the vacuum system and glacial acetic acid was supplied from the container (E2.2) in two separate portions (2 L and 2 L) using a pump (H2.2) to wash the zinc acetate from residual para- aminophenol. After each batch, the sediment was mixed with a manually driven stirrer (MP2.1), and by connecting the vacuum with tap 3.2, filtering was carried out. Then the Nutsch filter was disconnected from the vacuum system, the connection with the external atmosphere was restored, and the resulting solution of para -aminophenol from the lower part of the Nutsch filter (F2.1) was removed using a pump (H2.2) into the reactor P3.1.

The solution entering the reactor R3.1 after the recovery stage para-aminophenol, contained 12.8 liters of acetic acid.

After introducing the solution para-aminophenol into the reactor P3.1, with stirring turned on, a rarefied atmosphere was created in the reactor (350 mm Hg) and by supplying hot coolant into the reactor jacket, the reaction mass introduced from the suction filter was gradually brought to a boil. When the reaction solution was boiled, vapors of watered acetic acid were removed from reactor P3.1 for 2 hours through a downward cooler HX3.1 with a cooling jacket. The vapor temperature was controlled by a TT3.2 thermocouple and was ~75°C. The distillation of acetic acid was collected in container E3.1.

After 2 hours, a new batch of para- aminophenol solution obtained during this time was introduced into reactor P3.1 from the bottom of the suction filter (F2.1) and boiling of the reaction solution was continued under the same conditions for 2 hours with the removal of vapors of watered acetic acid.

In parallel, a third batch of solution prepared from 1183 g of wet para- nitrosophenol and 14 L of glacial acetic acid was launched into reactor R2.1, and the reduction procedure was repeated for 120 min.

After 2 hours, the third batch of para- aminophenol solution obtained during this time was introduced into reactor P3.1 from the bottom of the suction filter (F2.1) and boiling of the reaction solution was continued under the same conditions for 1 hour with the removal of vapors of watered acetic acid.

Then the vacuum system was turned off and the temperature of the reaction mixture was increased to 130°C, while the pressure in the reactor increased to 2.4 atm. Boiling was continued under these conditions for another 20 minutes.

After this, the heating was stopped, the reaction mixture was cooled with stirring to a temperature of 6 °C and this temperature was maintained for 40 minutes.

The bottom valve 7.3 was opened and the paracetamol suspension was unloaded from the reactor P3.1 into the Nutsch filter F3.1. Using pump H3.1, 1 liter of glacial acetic acid was fed into the reactor from container E3.2 to wash the reactor walls and the working surface of the stirrer of any remaining crystalline mass. The lower part of the nutsch filter was connected to a vacuum system and the sediment separated from the upper part of the nutsch filter was squeezed out. Then the solid paracetamol precipitate on the filter was washed with 0.5 liters of watered distilled acetic acid, feeding it into the nut filter F3.1 from container E3.1 with pump H3.1. The combined filtrates were removed from the bottom of the suction filter into container E3.3.

The washed solid residue of crystalline paracetamol was dried in a suction filter under vacuum for 5 hours.

As a result, 3760 g of crystalline paracetamol was obtained (purity 98% (HPLC), yield 89.6% of theory) and a total of 12090 g zinc acetate dihydrate (purity 95% according to NMR and elemental analysis, yield 95.3% of theory).

Thus, as can be seen from the presented examples, the proposed method, according to the invention, leads to the simultaneous production of economically significant products: paracetamol and zinc acetate, with modern yields and excellent purity indicators using simple to perform stages carried out on standard chemical apparatus suitable for further industrial scaling, while the amount of waste removed is reduced to almost a minimum due to solvent recycling.

Claims (43)

1. A method for producing paracetamol from para -nitrosophenol and/or para -nitrophenol, including the following steps: a) preparing a solution of para -nitrosophenol and/or para -nitrophenol in acetic acid; b) feeding the solution from step a) into a reactor with an inert atmosphere with stirring and forced maintenance of the temperature in the range from 40 to 55°C; c) dosing zinc metal in powder form into the reactor at a controlled feed rate; d) stirring the reaction mixture until the reaction is complete while maintaining the temperature in the range from 40 to 55°C; e) cooling the reaction mixture to 3-7°C to separate fine-crystalline zinc acetate from the reaction solution; f) withdrawing the reaction mixture from the reactor to a separation device; g) separating solid zinc acetate as a retentate and a solution of para -aminophenol in acetic acid as a permeate; h) removing the solution of para -aminophenol in acetic acid from the separating device; i) feeding a solution of para -aminophenol in acetic acid from stage h) into a reactor with a stirrer, forced maintenance of temperature in the range from 10 to 140°C and the possibility of creating an inert and/or rarefied atmosphere; j) boiling a solution of para -aminophenol in acetic acid under reduced pressure and distilling off part of the watered acetic acid at a temperature of 60 to 120°C; k) boiling a solution of para -aminophenol in acetic acid at a pressure of 2 to 3 atm and a temperature of 120 to 140°C until the reaction is complete; l) cooling the reaction mixture to separate crystalline paracetamol from the reaction solution; m) removing the reaction mixture from the reactor to a separation device; n) separating solid paracetamol from the liquid reaction mixture; o) washing paracetamol with acetic acid; p) drying the solid paracetamol and discharging it to obtain the finished product. 2. The method according to claim 1, characterized in that the solution in step a) is prepared using glacial acetic acid. 3. Method according to claim 1, characterized in that the temperature in step c) is maintained in the range from 45 to 50°C. 4. The method according to claim 1, characterized in that zinc acetate is obtained in hydrate form, in particular in the form of zinc acetate dihydrate. 5. The method according to claim 1, characterized in that a suction filter is used as a separating device. 6. The method according to claim 1, characterized in that it is carried out in a semi-continuous mode, in which stages a)-f) are first carried out, and then stages b) and g) and then all subsequent stages are carried out simultaneously. 7. The method according to claim 6, characterized in that before performing step k), steps b)-j) are repeated three times. 8. The method according to claim 1, characterized in that at stage l) the reaction mixture is cooled to 5-10°C. 9. The method according to claim 1, characterized in that at stage j) distillation of part of the watered acetic acid is carried out at a pressure of 300 to 450 mm Hg. Art. 10. The method according to claim 1, characterized in that at stage o) washing of paracetamol is carried out with watered acetic acid, distilled off at stage j). 11. Installation for implementing the method for producing paracetamol according to claim 1, including: container for preparing a solution of steam -nitrosophenol and/or steam -nitrophenol in acetic acid; a hopper with a dosing screw for supplying zinc; a reactor for the reduction of para -nitrosophenol and/or para -nitrophenol with zinc in acetic acid, equipped with a stirrer, a gas supply to create an inert atmosphere, a system for maintaining a given temperature of the reaction mixture, an inlet for supplying a solution of para -nitrosophenol and/or para -nitrophenol in acetic acid, an inlet for supplying zinc and an outlet for the reaction mixture; a separation device for separating solid zinc acetate as a retentate and a solution of para -aminophenol in acetic acid as a permeate, configured to receive the reaction mixture from the reactor for the recovery of para -nitrosophenol and/or para -nitrophenol, outputting solid zinc acetate and outputting a steam solution - aminophenol, and also equipped with an inlet and outlet for liquid streams, a connection for gaseous streams and a connection for a vacuum device; a paracetamol production reactor equipped with an anchor stirrer, a gas supply to create an inert atmosphere, a system for maintaining a given temperature of the reaction mixture, a refrigerator for condensing acetic acid vapor with the ability to remove condensed acetic acid, a vapor temperature sensor, an input for supplying a solution of aminophenol vapor in acetic acid, an inlet for supplying acetic acid, an outlet for the reaction mixture and configured to create a reduced or increased pressure inside the reactor; a separating device for separating solid paracetamol, configured to receive the reaction mixture from the reactor for producing paracetamol, outputting solid paracetamol and outputting the separated liquid reaction mixture, and also equipped with an input for acetic acid, a connection for gaseous flows and a connection for a vacuum device; a container for receiving condensed acetic acid from the paracetamol production reactor; wherein the outlet for liquid streams of the separating device for separating solid zinc acetate and a solution of para -aminophenol in acetic acid is connected to the input for supplying a solution of para -aminophenol to the paracetamol production reactor. 12. Installation according to claim 11, characterized in that a downward cooler with a cooling jacket is used as a refrigerator for condensing acetic acid vapor in the paracetamol production reactor. 13. Installation according to claim 11, characterized in that a reflux refrigerator with a cooling coil is used as a refrigerator for condensing acetic acid vapor in the paracetamol production reactor. 14. Installation according to claim 12, characterized in that the connection of the vacuum system for creating reduced pressure in the paracetamol production reactor is located on the container for receiving condensed acetic acid. 15. Installation according to claim 13, characterized in that the connection of the vacuum system to create a reduced pressure in the paracetamol production reactor is located on the refrigerator for condensation of acetic acid vapors. 16. The installation according to claim 11, characterized in that it additionally includes a distribution comb system for redirecting liquid flows of the separation device for separating solid zinc acetate and a solution of para -aminophenol in acetic acid. 17. Installation according to claim 16, characterized in that the distribution comb system includes pipelines, shut-off devices and one pump for transporting liquid flows. 18. Installation according to claim 11, characterized in that the container for receiving condensed acetic acid from the paracetamol production reactor is connected to a separation device for separating solid paracetamol and/or a paracetamol production reactor. 19. Installation according to claim 11, characterized in that the separation device is selected from a centrifuge or a suction filter, preferably a suction filter.