RU2302405C1 - P-aminobenzoic acid ethyl ester (anestesine) production process - Google Patents

Abstract

FIELD: industrial organic synthesis.

SUBSTANCE: invention relates to technology of producing biologically active compounds employed in medicine as anesthetics and showing local anesthetic activity. Proposed synthesis process offers a series of technical and economic advantages such as high process output due to diminished number of stages, eliminated use of strong oxidants, high purity of products, reduced purification procedures by replacing chemical methods with electrochemical ones, higher selectivity of process controlled by maintenance of current and voltage, interaction of promoters, and enabled carrying out the process continuously while controlling purity and quality of product.

EFFECT: enhanced process efficiency and improved quality of product.

2 tbl, 2 ex

Description

The invention relates to the pharmaceutical industry, and in particular to a technology for producing organic and biologically active compounds, and can be used in medicine as an anesthetic with a local anesthetic effect.

A known method of producing ethyl ester of p-aminobenzoic acid by hydrogen reduction of ethyl ester of p-nitrobenzoic acid in a solvent in the presence of a palladium-triphenylphosphine carbon-based catalyst (RF Patent No. 2203885, publ. 05.10.2003, Method for producing ethyl ester of p-aminobenzoic acid // Obraztsova I.I., Efimov O.A., Eremenko N.K. and others).

The main disadvantages of this method are the use of an expensive palladium-containing catalyst, the preparation of which requires scarce reagents, gases; a significant number of operations and time.

There is also a method of producing ethyl ester of p-aminobenzoic acid from paratoluidine in three stages (Berkenheim A.M. Workshop on synthetic, medicinal and odoriferous substances and photo reagents. M-L., Goskhimizdat, 1942, p. 54-60):

Stage I: Paratoluidine Acetylation

Stage II: oxidation of paraacetotoluidine to paraacetoaminobenzoic acid

Stage III: production of p-aminobenzoic acid ethyl ester (anestezin) from paraacetoaminobenzoic acid.

The disadvantages of this method are the complexity and complexity of the process, the need for costs of a large number of expensive and scarce reagents, strong oxidizing agents and reducing agents, low purity of the final products. The disadvantages include the problem associated with waste - iron sludge contaminated with amines.

The closest in essence the proposed method is a method for producing anesthesin from paranitrotoluene in three stages (Berkenheim A.M. Workshop on synthetic, medicinal and odoriferous substances and photo reagents. M-L., Goskhimizdat, 1942, p. 54-60)

Its essence lies in the fact that in the first stage, p-nitrotoluene is oxidized with a chromium mixture (a mixture of sodium dichromate and concentrated sulfuric acid) to p-nitrobenzoic acid

I stage

In a second step, p-nitrobenzoic acid ethyl ester is obtained.

II stage

In a third step, p-nitrobenzoic acid ethyl ester is reduced to p-aminobenzoic acid ethyl ester (anestezin)

III stage

The disadvantages of this method of synthesis of anestezin are multi-stage, the use of oxidizing agents, concentrated sulfuric acid, potassium permanganate, sophisticated equipment and other materials. Synthesis is costly and time consuming.

The task of the invention is to increase the productivity of the process with the possibility of continuous monitoring of the purity and quality of products.

EFFECT: high selectivity of the process, regulated by maintaining current, potential, and introducing promoters.

The essence of this method of obtaining ethyl ester of p-aminobenzoic acid (anestezin) from p-nitrotoluene is that the processes of oxidation of p-nitrotoluene and reduction of ethyl ester of p-nitrobenzoic acid are combined and carried out electrochemically in a diaphragm electrolyzer at an anode and cathode current density of 0 , 1 A / cm ² and a concentration of 0.4 mol / L.

The essence of the proposed method is that the processes of oxidation of p-nitrotoluene (stage I) and reduction of ethyl ester of p-nitrobenzoic acid (stage II) are carried out simultaneously in an electrolyzer with separated anode and cathode spaces. P-nitrotoluene at the anode in the anode compartment is oxidized to p-nitrobenzoic acid according to the reaction equation

and p-nitrobenzoic acid ethyl ester is reduced at the cathode to anestezin in accordance with the reaction equation

It should be noted that the amount of electricity for the complete oxidation of p-nitrotoluene and for the complete reduction of the ethyl ester of p-nitrobenzoic acid, i.e. in both total reaction equations, it is identical and equal to six Faraday (6F), which, of course, contributes to the unhindered electrochemical combination of these two processes. Both starting materials are dissolved in acetonitrile, which has electrochemical stability in a wide range of anodic (+2.4 V) and cathodic (-3.5 V) potentials. Acetonitrile mixes well with aqueous solutions of sulfuric acid, giving the system sufficient electrical conductivity.

Electrolysis of the anodic process of oxidation of p-nitrotoluene and the cathodic process of reduction of ethyl ester of p-nitrobenzoic acid is carried out in the same electrolyzer using the same solvent - acetonitrile and the same background electrolyte - an aqueous solution of sulfuric acid for both starting materials. A smooth Pt-th anode and a tin cathode are used as electrodes, and a perfluorinated cation exchange membrane is used as a diaphragm.

In addition to reaction (4), the conjugated oxygen evolution proceeds at the anode

which usually affects the yield of the main substance - p-nitrobenzoic acid. Therefore, an anolyte is supplemented with ammonium thiocyanate (NH ₄ CNS) at a rate of 1 g / l, which inhibits the release of oxygen.

Example 1

100 ml (50 ml of acetonitrile and 50 ml of a 1.0 M aqueous solution of H ₂ SO ₄ ) of a solution containing 0.05 M p-nitrotoluene and 50 mg of ammonium thiocyanate are poured into the anode compartment of a diaphragm electrolyzer with a perfluorinated cation exchange membrane. The anode is a smooth platinum plate with a surface of 4 cm ² . In the cathode compartment pour 100 ml (50 ml of acetonitrile and 50 ml of a 1.0 M aqueous solution of H ₂ SO ₄ ) solution containing 0.05 M ethyl ester of p-nitrobenzoic acid. The tin electrode is a surface of 4 cm ² .

The electrolysis is carried out at a current density of 0.1 A / cm ² . The amount of transmitted electricity Q is 8.5 Ah. The temperature of the anolyte and catholyte during the electrolysis is maintained within the range of 25-30 ° C. In the process of electrolysis, weak continuous mixing of the solutions is carried out.

After electrolysis is complete, the product of anodic oxidation - p-nitrobenzoic acid and cathodic reduction - anesthesin is separated from the solvent by distillation.

The anolyte is washed with carbon tetrachloride to extract unreacted p-nitrotoluene, then p-nitrobenzoic acid is filtered off, washed with water and dried at 35-45 ° C. The yield is 92%.

The synthesized p-nitrobenzoic acid is used to obtain ethyl ester of p-nitrobenzoic acid in accordance with reaction equation (2) according to the known method described in the book: Agranomov A.Sh., Shabarov Yu.S. Laboratory work in an organic workshop. M., "Chemistry", 1974, p.77-78.

The catholyte after distillation of acetonitrile is washed with water and dried at 35-45 ° C. For thorough purification, anesthesin is recrystallized from ethanol using activated carbon. After such purification, anestezin is obtained in the form of a white crystalline powder. The purity of anestezin is determined by the melting point (91.5 ° C). Qualitative analysis of anestezin is carried out by specific reactions to the amino group and to the ether group (State Pharmacopoeia - X 1968).

Quantitative determination was carried out by the gravimetric method and the nitritometry method (Handbook of pharmacist-analyst. Kiev, "Health", 1989.) Anestezin yield was 97%.

Example 2

It is carried out analogously to example 1. Solutions of different molar concentrations of p-nitrotoluene and p-nitrobenzoic acid ethyl ester are subjected to oxidation and reduction. The data on the electrosynthesis of p-nitrobenzoic acid and anestezin at various molar concentrations of the starting materials are presented in Table 2. Below 0.1 mol / L, the yield of both products decreases, which is associated with the release of oxygen at the anode and hydrogen at the cathode. The decrease in current efficiency at C> 0.4 mol / L is due to a decrease in the solubility of the starting materials and electrosynthesis products under these conditions.

Table 1 presents the results of the electrosynthesis of p-nitrobenzoic acid and anestezin at various current densities, the same for both the anode and cathode. The maximum current efficiency of p-nitrobenzoic acid is observed at a current density of 0.1 A / cm. At higher current densities, the output decreases. This is due to the occurrence of side reactions of oxygen formation at the anode (6). The decrease in current efficiency of anestezin at a current density of 1> 0.1 A / cm ² is associated with the reaction of hydrogen reduction at the cathode

In addition, a decrease in the current efficiency of p-nitrobenzoic acid and anestezin at higher current densities than 0.1 A / cm ² can be caused by the consumption of a fraction of electricity for the oxidation and reduction of the solvent itself, acetonitrile.

The proposed method for the synthesis of anesthesin has a number of technical and economic advantages compared with known methods:

1. High productivity of the production process by reducing the number of stages of synthesis.

2. The exclusion of the use of strong oxidizing agents (conc. H ₂ SO ₄ , KMnO ₄ and others).

3. Obtaining high purity products, reducing cleaning procedures by replacing chemical synthesis methods with electrochemical ones.

4. Higher selectivity of the process, regulated by the maintenance of current, potential, the introduction of promoters.

5. The ability to carry out the process continuously with control of purity and product quality.

Thus, for the claimed method in the form in which it is described in the description, the possibility of its implementation is confirmed and it is intended for use in medicine, in the synthesis of organic and biologically active preparations and in fine chemical technology.

Table 1 The density of the anode and cathode current, A / cm ² The concentration of starting materials, mol / l Current output,% p-nitrobenzoic acid anestezin 0.01 0.05 80.0 88.5 0.02 0.05 82.5 94.0 0.04 0.05 84.0 94.5 0.06 0.05 87.7 96.0 0.08 0.05 90.5 97.0 0.1 0.05 92.0 97.0 0.2 0.05 89.0 95.0 0.3 0.05 79.0 90.5 table 2 The concentration of starting materials, mol / l The density of the anode and cathode current, A / cm ² Current output,% p-nitrobenzoic acid anestezin 0.01 0.1 78.0 88.5 0.02 0.1 79.5 88.0 0.05 0.1 92.0 97.0 0.1 0.1 92.0 97.0 0.2 0.1 93.5 96.0 0.4 0.1 93.0 96.0 0.5 0.1 85.0 89.0

Claims (1)

A method of obtaining ethyl ester of p-aminobenzoic acid (anestezin) from p-nitrotoluene, characterized in that the processes of oxidation of p-nitrotoluene and reduction of ethyl ester of p-nitrobenzoic acid are combined and carried out electrochemically in a diaphragm cell at an anode and cathodic current density of 0.1 A / cm ² and a concentration of 0.4 mol / L.