RU2574733C1 - Method for producing paracetamol - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: producing paracetamol involves the catalytic hydrogenation of p-nitrosophenol with Pd/C or Ni-Re catalysts at 20-70°C in a combination with acetylation in aqueous ethanol or aqueous isopropanol in the presence of acetic anhydride.

EFFECT: advanced method for producing p-acetylaminophenol using inexpensive solvents and ensuring a high product yield.

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Description

The invention relates to the field of organic chemistry, and in particular to a method for producing p-acetylaminophenol I (paracetamol), which has an analgesic effect and is an integral part of a number of drugs.

Known, protected by patents, methods for producing p-acetylaminophenol from various derivatives of phenol or aniline. Thus, when p-aminophenyl acetate is heated for 5 hours at a temperature of 120 ° C, paracetamol is formed with a yield of 43% [1].

Upon heating of 4-acetoxyacetophenone in a mixture with sulfur and aqueous ammonia, p-acetylaminophenol was obtained in 61% yield [2].

Single-stage reduction-acetylation of p-nitrophenol was carried out by its interaction with potassium thioacetate in the presence of X-405 Triton [3]. The yield of p-acetylaminophenol is 80%.

Closest to the claimed method according to the feedstock and its chemical transformations are the syntheses of paracetamol from p-nitrosophenol II (Scheme 1) described in the patents [4, 5].

Scheme 1

The method described in [4] is realized by catalytic hydrogenation of p-nitrosophenol with hydrogen in a solution of ethyl acetate in the presence of a Pd-containing catalyst at temperatures of 20-45 ° C and subsequent acylation with acetic anhydride without isolation of intermediate p-aminophenol.

To implement the method described in the patent [5], a cheaper, commercially available Ni-Raney catalyst is used. However, in this case, a higher temperature of 65-70 ° C is required to carry out the hydrogenation process.

In both methods, the resulting p-aminophenol without isolation from the reaction mixture is acylated with acetic anhydride to form the desired paracetamol in 80-85% yield, based on the starting p-nitrosophenol.

A significant drawback of these methods is the use of a flammable, toxic and expensive solvent - ethyl acetate (ethyl acetate).

Actually used in the methods [4, 5], ethyl acetate has a maximum allowable concentration in air (MPC) of 0.04%, and a flash point of 2.2 ° C [6]. At the same time, a much more affordable solvent - ethyl alcohol is less toxic (MPC 0.1%) and significantly less fire hazard (ethanol flash point 12.2 ° C). In addition, the elimination of ethanol fires is simpler because unlike ethyl acetate, it mixes with water in any proportions. Since ethyl acetate is obtained from acetic acid and ethanol, it is obvious that the latter is a more affordable and cheaper solvent.

At the same time, it was found in laboratory conditions that upon the preparation of paracetamol using commonly used available solvents: ethyl (or isopropyl) alcohols, analogously to methods [4, 5], the formation of difficult to separate product mixtures takes place. This is apparently due to the fact that the highly reactive p-aminophenol formed during the reduction of nitrosophenol is able to enter various side transformations in alcohols under the conditions of the hydrogenation reaction.

The objective of the present invention is to develop a catalytic system for the hydrogenation reaction simultaneously with acetylation and to obtain a high-quality target product in high yield using cheap available solvents.

However, the prospects for solving this problem are far from obvious, since it is known that changing even one of the parameters (solvent) requires the selection of other parameters of the catalytic system (catalyst, reaction temperature).

Thus, it was found that during the hydrogenation of p-nitrosophenol in dioxane at 40-45 ° C in the presence of acetic anhydride over the Ni-Re catalyst, the hydrogenation reaction ceases after 2-2.5 hours (complete conversion of the initial nitroso derivative occurs). However, a diazobenzene derivative was isolated from the reaction mass as the main product (Scheme 2, Example 1).

Scheme 2

In the laboratory, it was also found that when paracetamol is heated in isopropyl alcohol in the presence of acetic anhydride, it quickly (0.5-1 hour) converts into the diacetyl derivative IV (Scheme 3, Example 2).

Scheme 3

At the same time, it was experimentally established that when heating paracetamol in isopropyl alcohol in the presence of acetic anhydride with the addition of water, the formation of a diacetyl derivative does not occur (example 3).

The problem is solved by the described method for producing paracetamol I, which consists in the fact that the catalytic hydrogenation process is carried out simultaneously with the acetylation process in the presence of acetic anhydride in aqueous ethanol or aqueous isopropanol.

The amount of acetic anhydride used for acetylation was determined experimentally. For complete effective binding of the resulting aminophenol, it is sufficient to add a 2.0-fold excess of acetic anhydride with respect to the starting p-nitrosophenol.

In order to avoid losses of the target product during its isolation, the amount of added water should not exceed the amount of water required for recrystallization of the resulting paracetamol (5-7 ml of water per 1 g of paracetamol).

The presence of water in the reaction mass not only prevents acetylation at the oxy group of the resulting aminophenol, but also allows you to simply control the end of distillation of alcohols at the end of the hydrogenation-acetylation process (by a sharp change in temperature after the end of distillation of alcohols) and thereby avoid overheating of the reaction mass during isolation of the target product.

To implement the proposed method of hydrogenation-acetylation in aqueous alcohols, various types of catalysts can be used:

- Pd / C (palladium on charcoal, 5-10%).

- Ni-Re.

Since palladium catalysts are more active, in the case of their use, the hydrogenation-acetylation reaction can be carried out at temperatures of 20–40 ° C, while a temperature of 60–70 ° C is required to implement the process on a less active Ni-Re catalyst.

Thus, the proposed method for the hydrogenation of p-nitrosophenol in aqueous alcohols in the presence of acetic anhydride, on the one hand, allows protecting the resulting p-aminophenol from side reactions, and, on the other hand, adding water prevents the formation of a side diacetyl derivative IV. Moreover, p-acetylaminophenol formed during the hydrogenation-acylation process is the final target product. It should be noted that the proposed method allows the use of cheap commodity hydrolysis 96% (with 4% water content) ethyl alcohol.

The end of the hydrogenation-acetylation reaction (the complete conversion of the initial nitrosophenol) is determined by the Lieberman reaction [7] for the absence of a nitroso group-containing compound in the reaction mixture (Example 6).

The target product - paracetamol is isolated by known methods, including filtration from a catalyst, distillation of the corresponding alcohol, cooling of an aqueous solution and filtering of the target product.

The identity of the samples of the target product obtained by the proposed method and the acylation of known p-aminophenol is confirmed by the coincidence of the melting point of the corresponding samples and the absence of temperature depression for the mixing sample. The NMR spectra of the compared samples are completely identical.

The described method for producing paracetamol in comparison with the known has the following advantages:

1. The solvents proposed for the preparation of paracetamol: ethanol or isopropanol are less flammable, less toxic, cheaper, are produced by the domestic industry and can be easily regenerated and reused.

2. The proposed method allows the use of various types of catalysts depending on the possibilities of production.

3. The proposed method for producing paracetamol allows the hydrogenation of nitrosophenol and acetylation of the resulting aminophenol to form the desired paracetamol in the same reactor.

4. The introduction of a one-reactor hydrogenation-acetylation process eliminates the stages of isolation and purification of intermediate p-aminophenol associated with the need for wastewater treatment, which reduces the consumption of reagents and significantly simplifies the process flow chart.

5. The end of the hydrogenation-acetylation reaction is controlled by a sensitive and simple analytical reaction to the nitroso group, which eliminates excessive energy consumption and positively affects the quality of the target product. The technical result is to block the side process of diacetylation while carrying out hydrogenation and acetylation reactions in aqueous alcohols in the presence of acetic anhydride.

Example 1. Hydrogenation of p-introsophenol on Ni-Re in dioxane

0.8 g of p-nitrosophenol, 0.8 g of Ni-Re paste washed with dioxane and squeezed on a Ni-Re filter, 50 ml of dioxane, 3.5 ml of acetic anhydride and 1 ml of triethylamine were stirred in a steel reactor at 45-45 ° C under a 2.5- hydrogen pressure 3.0 atm Using thin-layer chromatography, it was found that the complete conversion of the original occurs after 2 hours. The catalyst was filtered off. The solvent was distilled off in vacuo to a viscous precipitate. 3-5 ml of ice water was added to the residue and stirred for 1 hour. The resulting yellow precipitate was filtered off. The resulting precipitate was stirred in 5 ml of hot (65-70 ° C) ethanol and filtered. Received 0.42 g of a yellow precipitate with so pl. 185-187 ° C. Mass spectrum: m / z 298 (30%). ¹ H NMR spectrum, δ, ppm: 2.33 (s, 6H, 2 × COCH ₃ ), 7.33 (d, 4H, J = 8.6 Hz), 7.94 (d, 4H. J = 8.6 Hz).

Example 2. Acetylation of paracetamol with acetic anhydride

0.1 g of paracetamol is boiled in 5 ml of isopropyl alcohol in the presence of 0.1 ml of acetic anhydride for 0.5 hour. According to the analysis of the reaction mass by TLC using known samples of paracetamol I and diacetyl derivative IV as “witnesses”, it was found that the initial paracetamol completely turns into a diacetyl derivative.

Example 3. The reaction of paracetamol with acetic anhydride in aqueous alcohol

0.1 g of paracetamol is boiled in 5 ml of isopropyl alcohol in the presence of 0.1 ml of acetic anhydride and 1 ml of water for 0.5 hours. According to the analysis of the reaction mass by TLC using known samples of paracetamol 1 and diacetyl derivative IV, it was found that the original paracetamol remains unchanged in the reaction mass.

Example 4. Obtaining p-acetylaminophenol using a Pd / C catalyst

2.0 g (16.2 mmol) of p-nitrosophenol in 100 ml of ethanol (or isopropanol) are charged into a 1-liter metal reactor equipped with a stirrer, a thermometer sleeve, a manometer, gas supply tubes and a jacket connected to a water thermostat for heating and cooling the reaction mixture. ), 0.1 g of Pd / C (10%), 3.3 g (32.4 mmol) of acetic anhydride, 5-7 ml of water. The reaction mixture is stirred under a hydrogen pressure of 2.0-4.0 atm hydrogen at a temperature of 20-40 ° C for 0.5-2.0 hours. In the case of a negative reaction of the selected sample to the presence of nitrosophenol in the mixture (Lieberman reaction to the nitroso group), the reaction mass is filtered from the catalyst, the alcohol solvent is distilled off under vacuum. The aqueous residue is cooled to 10-15 ° C. And stirred at this temperature for 0.5-1.0 hours. The precipitated precipitate of paracetamol is filtered off, washed with 10-15 ml of ice water and dried. After drying, 2.00 g (82% of theory) are obtained. Mp 169-171 ° C (mp. Lit. 170-172 ° C). ¹ H NMR spectrum, δ, ppm: 1.98 (s, 3H, CH ₃ ), 6.62 (d, 2H, J = 4.5 Hz), 7.30 (d, 2H, J = 4.5 Hz), 8.86 (s, 1H, NH), 9.47 (s, 1H, OH).

To obtain pharmacopoeial paracetamol, the resulting product is recrystallized from distilled water with the addition of 0.1 g of activated carbon. Obtain 1.59 g (66%) of paracetamol that meets the requirements of the State Pharmacopoeia. In the case of a negative analysis of the crystals for color, additional crystallization is carried out with the addition of sodium hydrosulfite to clarify at the rate of 0.001 g per 1 g of paracetamol.

Example 5. Obtaining p-acetylaminophenol using a Ni-Re catalyst

2.0 g (16.2 mmol) of p-nitrosophenol in 100 ml of ethanol (or isopropanol) are charged into a 1-liter metal reactor equipped with a stirrer, a thermometer sleeve, a manometer, gas supply tubes and a jacket connected to a water thermostat for heating and cooling the reaction mixture. ), 0.2 g of Ni-Re, 3.3 g (32.4 mmol) of acetic anhydride, 10 ml of water. The reaction mixture is stirred under a hydrogen pressure of 2.0-4.0 atm hydrogen at a temperature of 60-70 ° C for 0.5-2.0 hours. In the case of a negative reaction of the selected sample to the presence of nitrosophenol in the mixture (Lieberman reaction to the nitroso group), the reaction mass is filtered from the catalyst, the alcohol solvent is distilled off under vacuum. The aqueous residue is cooled to 10-15 ° C. And stirred at this temperature for 0.5-1.0 hours. The precipitated precipitate of paracetamol is filtered off, washed with 10-15 ml of ice water and dried. After drying, 1.95 g (80% of theory) are obtained.

Example 6. Determination of nitrosophenol in the reaction mass (Lieberman reaction)

2 drops of a 20% solution of resorcinol in ethanol and 2 drops of concentrated sulfuric acid are pipetted onto the watch glass. After mixing the components, add 1 drop of the test solution. If a brown-violet color appears within 1 minute, turning into red-raspberry, this confirms the presence of a nitroso derivative in the test solution. The absence of staining indicates the absence of a nitroso derivative in the solution.

Information sources

1. Patent US 5221769 (1993); (A1).

2. Patent US 5932075 (1999); (A1).

3. Patent US 2004/138509 (2004); (A1).

4. Patent RU 2461543 (2011), (C1).

5. Patent RU 2495865 (2012), (C1).

6. Organic solvents. Publishing house "Foreign Literature". Moscow 1958 p. 92, 145.

7. Chemical encyclopedia. Scientific publishing house "Great Russian Encyclopedia". Moscow 1992 Volume 3, p. 275 (542).

Claims (1)

A method of producing paracetamol of formula I

by catalytic hydrogenation of p-nitrosophenol over Pd / C or Ni-Re catalysts at 20-70 ° C, acetylation of the resulting p-aminophenol and isolation of the target product, characterized in that the catalytic hydrogenation process is carried out simultaneously with the acetylation process in the presence of acetic anhydride in aqueous ethanol or aqueous isopropanol.