RU2243219C1 - Method for preparing n-acyl-derivatives of 4-aminoantipyrine - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of biologically active compounds, namely, to methods for preparing N-acyl-derivatives of 4-aminoantipyrine eliciting analgetic and anti-inflammatory effect. The condensation process of free acid with 4-aminoantipyrine is carried out in inert organic solvent not mixing with water and forming azeotrope with water in the absence of any condensing or moisture absorbing reagents, in the presence of catalytic amounts of strong acid catalysts, such as benzenesulfonic acids and toluenesulfonic acids. Water formed in the reaction process is distilled off by azeotrope with solvent wherein reaction is carried out and with recovery of solvent to reaction mass after separating water. Method provides stable high yields of products, simplifying isolation and purifying products, reducing number of technological procedures and reduced toxicity of technological process and waste formed.

EFFECT: improved preparing method.

2 cl, 2 tbl, 1 ex

Description

The invention relates to the field of synthesis of biologically active compounds, and in particular to methods for producing N-acyl derivatives of 4-aminoantipyrine with analgesic and anti-inflammatory effects.

A known method of producing antipyrylamides of carboxylic acids C ₁ -C ₇ by reacting 4-aminoantipyrine with the corresponding acid in sulfuric acid at 70-98 ° C, and sulfuric anhydride is used as a water-stripping agent (USSR AS No. 1011641, BI No. 14, 100, 1983 )

The disadvantages of the described method include the impossibility of synthesizing antipyrylamides of carboxylic acids with a carbon number in the alkyl residue of more than 7, as well as unsaturated and aromatic acids.

The closest in technical essence to the claimed invention is a method for producing 4-acylaminoantipyrine by acylation of 4-aminoantipyrine (3 mol) with free acid (3 mol) in an indifferent solvent (for example, dry benzene), by dropping a solution of phosphorus trichloride (1.25 mol) into the warming reaction mass for 15-20 minutes at a temperature of not more than 70 ° C. Then the mass is stirred at the boil for 2-4 hours until the evolution of gaseous hydrogen chloride, which is absorbed by water, ceases. After that, the solvent is distilled off, isopropyl alcohol is added and the solvent is again distilled off (alcohol azeotrope with benzene). After distillation, the reaction mixture is dissolved in isopropyl alcohol and 60% aqueous isopropyl alcohol is added with stirring, then it is cooled to 10 ° C and neutralized with sodium hydroxide or potassium solution to pH 9. The precipitate of the corresponding acylaminoantipyrine is filtered off and washed with 20% isopropyl alcohol. Yield 82-89% (Schmidt E.V. et al. // Chem. Pharm. Journal. - 1982, No. 1, P.61).

The disadvantages of the described production method include the use of an aggressive and highly toxic phosphorus trichloride reagent, high sensitivity of the reaction mass to moisture, which reduces the yield and quality of the target products, the release of aggressive gas, hydrogen chloride, during the reaction, the absorption and utilization of which presents certain technological difficulties and the formation of toxic waste containing salts of phosphorous acid.

An object of the present invention is to eliminate highly toxic reagents and wastes from the process.

The problem is achieved in that the process of condensation of the acid with 4-aminoantipyrine is carried out in an indifferent organic solvent, immiscible with water and forming an azeotrope with it, in the absence of any condensing or moisture-absorbing reagents, in the presence of strong acid catalysts, such as benzene and toluenesulfonic acids and the water formed during the reaction is distilled off with an azeotrope with a solvent, in which the reaction is carried out with the return of the solvent to the reaction mass after separation of water.

When choosing a solvent for the process, it is useful that the solvent does not mix with water, because after azeotropic distillation and separation, the solvent can be returned to the reaction mass.

Another important difference of the present invention is the presence of catalytic amounts of arylsulfonic acid (for example, benzene and toluenesulfonic acids), which can reduce the process time.

In addition, in order to reduce the process time, it is desirable to choose a solvent with a higher boiling point, which is shown by the example of the reaction of 4-aminoantipyrine with stearic acid in the presence of toluenesulfonic acid (Table 1, paragraphs 1-3).

It is significant that the end of the reaction can be judged by the cessation of the release of water from the condensate of the vapor of the reaction mixture.

The observance of molar ratios of reagents is also important. The influence of the ratios of the reagents on the yield of the target product and the process time is shown by the example of the interaction of 4-aminoantipyrine (AAP) with phenylacetic acid (FUA) in the presence of toluenesulfonic acid (TSC) under the conditions of the claimed invention (Table 2). Thus, a decrease in the amount of FAA below 0.005 mol per 0.01 mol of AAP leads to an unjustified consumption of valuable AAP reagent, a significant decrease in the yield of the target product and an increase in the cost of cleaning the target product from unreacted AAP (Table 2, paragraph 1). On the other hand, an increase in the amount of FAA over 0.02 mol per 0.01 mol of AAP leads only to unproductive consumption of FAA and an increase in the cost of cleaning the final product from an excess of FAA (Table 2, Clause 3).

An important condition for the process is the presence of a catalyst in the reaction mass. So, in the absence of a catalyst, the reaction proceeds at an insignificant rate (Table 2, Clause 4) due to the low concentration of catalytic protons formed upon dissociation of the initial carboxylic acid. The use of a catalyst amount below 0.00001 mol per 0.01 mol of AAP leads to an increase in the duration of the process, and an increase in excess of 0.001 mol does not lead to an improvement in any process parameters, but rather to an increase in catalyst consumption and difficulties in cleaning the target product (table .2, paragraphs 5-6).

The found conditions for the synthesis of acyl derivatives of 4-aminoantipyrine and certain molar ratios of reagents are also valid for scaling of reagent loads. Thus, a proportional increase in the number of reagents by a factor of 10 leads only to a slight increase in the process time (Table 2, item 7), which indicates the importance of the molar ratios of the reagents, and not their absolute values.

The developed method allows to significantly expand the range of carboxylic acids that enter into the acylation reaction of 4-aminoantipyrine due to long chain alkyl-, arylalkylcarboxylic acids, as well as acids containing unsaturated double bonds, thereby increasing the availability and quantity of potentially possible biologically active acylaminoantipyrins.

Thus, the combination of newly introduced features allows one to obtain acyl derivatives (including those containing reactive unsaturated bonds) of 4-aminoantipyrine, with high yields with a significant reduction in the toxicity of the reagents and waste generated.

Example

2.03 g (0.01 mol) of AAA, 2.70 g (0.01 mol) of stearic acid, 0.02 g (0.0001 mol) of TSC are charged into a one-necked flask equipped with a Dean-Stark reflux condenser. and 30 ml of p-xylene. The reaction mass is boiled for 1.5 hours until the evolution of water with an azeotrope ceases. At the end, the solvent is removed (preferably under vacuum), then 5 ml of isopropyl alcohol is added and the solvent is removed again (for more complete removal of xylene with an azeotrope with isopropyl alcohol). The hot residue is dissolved in 10 ml of isopropyl alcohol and 12 ml of 5% sodium carbonate solution are added. After cooling, the precipitate formed is filtered off and recrystallized from 60% aqueous isopropyl alcohol. Yield 78-80%.

Claims (1)

A method for producing N-acyl derivatives of 4-aminoantipyrine by acylation of 4-aminoantipyrine in an organic solvent medium with a free carboxylic acid, which is an alkyl-, arylalkyl-carboxylic acid, characterized in that the process is carried out in the presence of catalytic amounts of arylsulfonic acid at a boiling point of azeotropic water at a molar ratio of reagents 4-aminoantipyrine 1 Alkyl, arylalkyl-carboxylic acid 0.5: 2.0 Arylsulfonic acid 0.001: 0.01