RU2427568C2 - Method of producing 2-methyl-4-halogen-phenoxyacetates of tris-(2-hydroxyethyl)ammonium (2-methyl-4-halogen-phenoxyacetoxyprotatranes) - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically active pluripotential compounds - 2-methyl-4-halogen-phenoxyacetates of tris-(2-hydroxyethyl)-ammonium of general formula given below referred to as chlorocresacin and bromocresacin respectively, by reacting 4-halogen-substituted 2-methyl-phenoxyacetic acid, where the halogen is chlorine or bromine, with triethanolamine. 4-halogen-substituted 2-methyl-phenoxyacetic acid is obtained via chlorination with sulphuryl chloride, where catalyst used is aluminium powder in an ester solution and bromation is carried out using elementary bromine in a glacial acetic acid medium. The obtained compounds have proven to be highly efficient biologically active substances with unique physiological action, for example as biostimulators or adaptogen. The method is characterised by replacement of chlorine gas with sulphuryl chloride which is more suitable for use in preparations.

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EFFECT: method enables to obtain desired products with high degree of purity.

2 cl, 5 ex

Description

The invention relates to a method for producing 2-methyl-4-halogen-phenoxyacetates of tris- (2-hydroxyethyl) ammonium (2-methyl-4-halogen-phenoxyacetoxy protatranes) of the general formula

used under the name chlorocresacin or previously unknown bromocresacin, respectively.

These compounds have established themselves as highly effective biologically active substances with a unique physiological effect on living organisms. Their predecessor, Tris (2-hydroxyethyl) ammonium 2-methyl-phenoxyacetate (2-methyl-phenoxyacetoxyprotatran), is a trekrezan drug that is also used in agriculture as an effective biostimulant and adaptogen called crezacin. It is produced by the pharmaceutical industry and is used to increase the immunological activity of the body, prevent and treat heart attack and other cardiovascular diseases, prevent colds, in case of asthenic conditions, to increase physical, mental performance and prevent overwork, prevent pathological changes in the body that accompany various stressful exposure (hypoxia, overheating, hypothermia), as an antidote for poisoning with heavy salts allov and organic solvents, reducing withdrawal phenomena [Burov UV, MG Voronkov, V. Diakov et al. Pat. RF 2063749, 1977 // Bull. Invent., 1996. No. 20. Register of medicines of Russia. M .: Informkhim, 1995. P.487].

Chlorocresacin and its analogue tris- (2-hydroxyethyl) ammonium 2-bromo-phenoxyacetate - bromphenacin possess pronounced antitumor activity [Sof'ina Z. P., Voronkov MG, Dyakov MG and others // Chem.-farm. Zh., 1978. T. 12, No. 4. S.74-77]. So, chlorcresacin reliably suppresses the proliferation of tumor cells of P815 mastocytoma, B16 melanoma, L210 lymphoma and G27 hepatoma, inhibits the metastasis of G27 hepatoma cells in the lungs and B16 melanoma. It can function not only as an immunosuppressant, but also as an immunostimulant. [Kolesnikova O. P., Mirskova A. N., Adamovich S. N., Mirskov R. G., Kudaeva O. T., Voronkov M. G. // DAN. 2009, Vol. 425, No. 4, p. 566-560].

Chlorcresacin 2-3 times accelerates the growth of embryonic cells [Kassin V.Yu., Nikolaev M.P., Mironova L.L., Rolik I.S., Konyushko O.I., Mirskova A.N., Voronkov M. G. // Russian Otolorology, 2004, T. 12, No. 5, S.85-87].

Bromfenacin also proved to be a highly effective phytohormone [Voronkov MG, Semenova NV, Tseytlina VR, Yakovleva ZM, DAN. 1994. V.335, No. 3. S.390-392]. It stimulates the germination of cereal seeds in the dark, and in the light inhibits this process, i.e. exhibits a photodynamic effect [Svarinsky R.A., Platonova R.N., Semenova N.V., Lyubimtsev I.V., Voronkov M.G. // DAN, 1980, Vol. 250, No. 2, S. 508-512].

A multistage method for the preparation of tris- (2-hydroxyethyl) ammonium 2-methylphenoxyacetate (trekrezan or crezacin) is patented [Pat. RF 2074171], based on the interaction of sodium 2-methylphenolate with the sodium salt of monochloracetic acid, synthesized separately. Sodium 2-methylphenolate is obtained by the reaction of 2-methylphenol with sodium hydroxide, and the sodium salt of monochloracetic acid by the interaction of this acid with sodium carbonate. 2-Methylphenoxyacetic acid is isolated by acting on the resulting sodium salt of HCl. The final stage of the process is the interaction of the acid with triethanolamine in acetone or isopropyl alcohol.

Chlorcresacin was synthesized in a similar way, while the chlorination of 2-methylphenol with gaseous chlorine was added to the above stages of the process. The disadvantage of this process is its high complexity, due to its multi-stage.

A known method of producing crezacin based on the interaction of mono-chloroacetic acid with 2-methylphenol in an aqueous solution of sodium hydroxide at pH 9-10, with the allocation of 2-methyl-phenoxyacetic acid from its salt with hydrochloric acid and its subsequent interaction with triethanolamine in a solvent miscible with water (alcohol, acetone, dioxane) or without solvent [Voronkov MG, Dyakov VM, Semenova NV et al. // Auth. certificate №515742 Yu.I. 1976, No. 20]. The disadvantage of this method is its low processability, due to the complexity of the purification of the original commodity monochloracetic acid. There are no data on the prospects of obtaining by this method the corresponding tris- (hydroxyethyl) ammonium salts of halogen-substituted 2-methyl-phenoxyacetic acid.

Closest to the claimed method are methods for the synthesis of krezacin by the interaction of 2-methylphenoxyacetic acid with triethanolamine [Sofyina ZP, Voronkov MG, Dyakov MG and others // Chem.-farm. Zh., 1978. T. 12, No. 4. P.74-77] and the synthesis of chlorcresacin by the interaction of 2-methyl-4-chloro-phenoxyacetic acid with triethanolamine [Kolesnikova OP, Mirskova AN, Adamovich SN, Mirskov RG, Kudaeva O. T., Voronkov M.G. // DAN. 2009, T.425, No. 4, S.556-560] in ethanol, while the known [Pat. RF 2069655] method of chlorination of 2-methyl-phenoxyacetic acid with gaseous chlorine. However, in a number of pharmaceutical industries, the use of gaseous chlorine is unsafe, and therefore undesirable. Also known is the method of chlorination of 2-methyl-phenoxyacetic acid with sulfuryl chloride in the presence of finely divided elemental sulfur in a solution of glacial acetic acid [Pat. USA 4,345,097]. The disadvantage of this method is that it is difficult to get rid of finely dispersed sulfur, as a result, the purity of the resulting 2-methyl-4-chloro-phenoxyacetic acid (chlorination product - intermediate in the claimed process) is 93.5%. In addition, the use of glacial acetic acid as a solvent for industrial production is less preferred than an inert ether. In industry, inert solvents, such as ether, are usually preferred over aggressive ones such as acetic acid.

Bromcresacin has not been known to date.

The aim of the present invention is to develop a new method for the synthesis of practically valuable and biologically active compounds with a wide spectrum of activity: tris- (2-hydroxyethyl) ammonium salts of 2-methyl-4-chloro (bromo) -phenoxyacetic acids - chlorcresacin and previously unknown bromocresacin, respectively. The goal is achieved in that the synthesis of the initial 4-chloro (bromo) -substituted 2-methyl-phenoxyacetic acid, then involved in the reaction with triethanolamine, is carried out:

a) in the case of 2-methyl-4-chloro-phenoxy-acetic acid by chlorination of 2-methyl-phenoxy-acetic acid with sulfuryl chloride, aluminum powder is used as a catalyst and the process proceeds in a solution of sulfuric ether;

b) in the case of 2-methyl-4-bromo-phenoxy-acetic acid - bromination of 2-methyl-phenoxy-acetic acid with bromine in ice cold CH ₃ COOH, powdered aluminum or mercury acetate is also a catalyst for the process.

A distinctive feature of the present invention from the prototype is the replacement of chlorine gas with liquid sulfuryl chloride more convenient for preparative use and the use of catalysts - powdered aluminum and mercury acetate in the studied processes, which allow optimizing the halogenation of 2-methyl-phenoxyacetic acid. It should be noted that the catalysts, both aluminum and mercury acetate, are completely separated from the reaction mixture by filtration, and they do not contaminate intermediate products - 2-methyl-4-halogen-phenoxyacetic acids, which ultimately allows to obtain the target products: chlorine and bromocresacins with a high degree of purity (see examples).

The invention is illustrated by the following examples.

Example 1

To a solution of 1.66 g of 2-methyl-phenoxyacetic acid in 10 ml of diethyl (sulfur) ether containing 0.01 g of Al powder, 1.35 g of sulfuryl chloride was added with stirring. The reaction mixture is heated to boiling for 4 hours and filtered hot. The filtrate is cooled to 0-5 ° C. The white crystalline precipitate formed is filtered off with suction, washed with ether and dried in vacuo. The yield of 2-methyl-4-chloro-phenoxyacetic acid with so pl. 111-112 ° C 2.9 g (98%).

Found,%: C 53.23; H 4.31; S117.72.

C ₉ H ₉ O ₃ Cl Calculated,%: C 53.86; H 4.49; Cl 17.71.

Example 2

To a solution of 1.66 g of 2-methyl-phenoxyacetic acid in 7 ml of ice-cold CH ₃ COOH with the addition of 0.01 g of powdered A1, 0.8 g of bromine is added with stirring. The reaction mixture is heated for 5 hours at 45-50 ° C. The reaction mixture is filtered, the solvent is distilled off from the filtrate at 100 mm Hg. The remaining crystalline precipitate is washed with small portions of cold water and dried in a vacuum desiccator. The yield of 2 methyl-4-bromo-phenoxyacetic acid with so pl. 124-125 ° C 2.1 g (86%).

Found,%: C 43.44; H 4.04; Br 32.37.

C ₉ H ₉ O ₃ Br Calculated,%: C 44.08; H 3.67; Br 32.65.

Example 3

To a solution of 1.66 g of 2-methyl-phenoxyacetic acid in 7 ml of ice-cold CH ₃ COOH with the addition of 0.01 g of Hg (OCOCH ₃ ), 0.8 g of bromine was added with stirring. The reaction mixture is heated for 4 hours at 45-50 ° C. Processing the reaction mixture is carried out analogously to example 2.

The yield of 2-methyl-4-bromo-phenoxyacetic acid was 2.2 g (91% of theory).

Example 4

To a solution of 4.0 g of 2-methyl-4-chloro-phenoxyacetic acid in 10 ml of acetone, 3.0 g of triethanolamine was added with stirring. The reaction mixture was kept for 0.5 h, the precipitate formed was filtered off, washed with ether and dried in vacuo. Received 6.8 g (98%) of chlorocresacin with a so pl. 87-88 ° C [lit. data 91-92 ° С Sofyina Z.P., Voronkov M.G., Dyakov M.G. and others // Chem.-farm. Zh., 1978. T. 12, No. 4. S.74-77].

Found,%: C 51.43; H 6.87; N, 4.20; Cl 10.10.

C ₁₅ H ₂₄ O ₆ NCl Calculated,%: C 51.50; H 6.90; N, 4.01; Cl 10.16.

Example 5

To a solution of 0.73 g of 2 methyl-4-bromo-phenoxyacetic acid in 10 ml of ethanol, 0.45 g of triethanolamine is added with stirring. The reaction mixture was kept for 0.5 h. At the end of the reaction, the reaction mixture was cooled to 0-5 ° C, 10 ml of ether was added. The resulting crystalline precipitate was filtered off, washed with ether and dried in vacuo. Obtained 1.0 g (94.3%) of bromocresacin with so pl. 86-87 ° C.

Found,%: C 45.62; H 6.01; N, 3.51; Br 20.59.

C ₁₅ H ₂₄ O ₆ NBr Calculated,%: C 45.69; H 6.09; N, 3.55; Br 20.30.

Claims (2)

1. The method of obtaining 2-methyl-4-halogen-phenoxyacetate tris- (2-hydroxyethyl) -ammonium of the General formula

respectively called chlorocresacin and bromocresacin, by the interaction of 4-halogen-substituted 2-methyl-phenoxyacetic acid, where halogen is chlorine or bromine, with triethanolamine, characterized in that the 4-halogen-substituted 2-methyl-phenoxyacetic acid is obtained by chlorination with sulfuryl chloride, where it is used as a catalyst powdered aluminum in an ether solution, and the bromination is carried out by elemental bromine in glacial acetic acid. 2. The method according to claim 2, characterized in that the bromination process of 2-methyl-phenoxyacetic acid is catalyzed by powdered aluminum or mercury acetate.