RU2615760C1 - Method for n-(4-methyl-3-chlorophenyl)-2-acetoxy-3,5-dichlorobenzamide preparation - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a process for preparation of N-(4-methyl-3-chlorophenyl)-2-acetoxy-3,5-dichlorobenzamide with anthelmintic activity. The method for N-(4-methyl-3-chlorophenyl)-2-acetoxy-3,5-dichlorobenzamide preparation is implemented in toluene by acetylation of 3,5-dichlorsalicylic acid to form 2-acetoxy-3,5-dichlorobenzoic acid. Its acid chloride is then prepared and reacts with 4-methyl-3-chloroaniline with subsequent isolation of the target product. At that, 3,5-dichlorsalicylic acid acetylation is carried out with acetyl chloride at a molar ratio of 1:2 at a temperature of 65 to 90°C, acid chloride of 2-acetoxy-3,5-dichlorobenzoic acid, is obtained by exposure to thionyl chloride at a molar ratio of 1:1.5 with addition of a catalytic amount of dimethylformamide at 76-80°C for 1 h. Acid chloride reaction with 4-methyl-3-chloroaniline is carried out in the presence of aqueous sodium bicarbonate at a molar ratio of 1.05:1:1.2, respectively at a temperature of 18-22°C, and the desired product is isolated by filtration as a precipitate.

EFFECT: provision of a compound with a high yield as the result of development of a safe, low waste, economical and efficient method.

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Description

The invention relates to the field of organic chemistry, and in particular to a method for producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I, which has an anthelmintic effect, does not exhibit embryotoxicity in animal experiments and is therefore promising to create drugs for the treatment of human and animal helminthiases [Mikhaylitsyn, F.S. Antihymenolepoid activity of the compound MCT-02 / F.S. Mikhailitsyn, D.P. Sevbo, S.N. Trusov, G.A. Gitsu, A.Yu. Malakhova // Medical parasitology and parasitic diseases. - 2010. - No. 1. - S. 47-48; Kozlov, S.A. Embryotoxic properties of the domestic anthelmintic Nadinata / S.A. Kozlov, M.B. Musaev // Medical parasitology and parasitic diseases. - 2015. - No. 3. - S. 55-58].

A known method of producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide from commodity 3,5-dichlorosalicylic acid II (Scheme 1).

In accordance with scheme 1, upon boiling of 3,5-dichlorosalicylic acid II with 4-methyl-3-chloroaniline in toluene in the presence of phosphorus trichloride, N- (4-methyl-3-chlorophenyl) -2-hydroxy-3,5- is obtained dichlorobenzamide III. It is purified by crystallization from a mixture of 1,4-dioxane and aqueous 2-propanol. The output at the stage is 85.5% [Trusov, S.N. Obtaining compounds MCT-01 and its anti-hymenolepoid activity / S.N. Trusov, D.P. Sevbo, G.A. Gitsu, F.S. Mikhailitsyn // Medical parasitology and parasitic diseases. - 2011. - No. 3. - S. 43].

Next, the obtained N- (4-methyl-3-chlorophenyl) -2-hydroxy-3,5-dichlorobenzamide III is acetylated with an 8-fold excess of acetic anhydride in the presence of pyridine in acetone at room temperature. The reaction mass is poured into water, the precipitate is filtered off and dried. The yield of crude N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I in terms of III is 83%, and in terms of II - 71.0% [Mikhaylitsyn, F.S. Antihymenolepoid activity of the compound MCT-02 / F.S. Mikhailitsyn, D.P. Sevbo, S.N. Trusov, G.A. Gitsu, A.Yu. Malakhova // Medical parasitology and parasitic diseases. - 2010. - No. 1, - S. 47-48].

The disadvantages of Scheme 1 include the use of toxic, carcinogenic and inaccessible chemicals (phosphorus trichloride, pyridine), the presence of a large amount of liquid waste at the acetylation stage, the inability to regenerate a large excess of acetic anhydride, pyridine and an acetone solvent.

Alternative methods for the preparation of N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide are not described in the literature.

The objective of the invention was to obtain a product with a higher yield, the development of a safe, low-waste, economical and effective method for its synthesis.

The problem is solved by creating a method for producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide, characterized in that acetylation of 3,5-dichlorosalicylic acid is carried out in toluene with the formation of 2-acetoxy-3, 5-dichlorobenzoic acid, then its acid chloride is obtained and the acid chloride is reacted with 4-methyl-3-chloroalanine to further isolate the target product, the acetylation of 3,5-dichlorosalicylic acid being carried out with acetyl chloride in a molar ratio of 1: 2 at a temperature from 65 to 90 ° C, 2-acetoxy-3,5-dichloride lorbenzoic acid is obtained by exposure to thionyl chloride in a molar ratio of 1: 1.5 with the addition of a catalytic amount of dimethylformamide at 76-80 ° С for 1.0 h, the reaction of the acid chloride with 4-methyl-3-chloroaniline is carried out in the presence of an aqueous solution of sodium bicarbonate in the molar ratio, respectively, of 1.05: 1: 1.2 at a temperature of 18-22 ° C, and the target product is isolated by filtration in the form of a precipitate (scheme 2).

The described method for producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I consists in the fact that acetylation of 3,5-dichlorosalicylic acid II is carried out first with the formation of 2-acetoxy-3,5- dichlorobenzoic acid IV, then 2-acetoxy-3,5-dichlorobenzoic acid chloride V is obtained and the acid chloride V is reacted with 4-methyl-3-chloroalanine to form N- (4-methyl-3-chlorophenyl) -2-acetoxy-3 5-dichlorobenzamide I.

It has been proposed to carry out acetylation of 3,5-dichlorosalicylic acid II with acetyl chloride. The experiments were carried out in toluene at the boiling point of the reaction mixture, which increased with the consumption of acetyl chloride from 65 to 100 ° C. It is proposed to absorb released hydrogen chloride with water to form technical hydrochloric acid. The progress of the reaction was monitored by thin layer chromatography and IR spectroscopy. 2-Acetoxy-3,5-dichlorobenzoic acid IV was isolated as a precipitate, which was filtered and dried.

The excess acetyl chloride, the optimum temperature and reaction time were determined experimentally. It turned out that for the complete effective passage of the reaction, it is enough to add 2.0 times the amount of acetyl chloride with respect to the initial 3,5-dichlorosalicylic acid II and the temperature, which during the reaction changes from 65 to 90 ° C for about 10 hours. thin-layer chromatography it was found that at temperatures above 90 ° C, a side reaction begins, self-acylation of 3,5-dichlorosalicylic acid II is possible with the formation of a dimer.

The most convenient method for producing carboxylic acid chlorides was the treatment of the acid with an excess of thionyl chloride in the presence of a dimethylformamide catalyst, since this method leads to the formation of only gaseous waste - sulfur dioxide and hydrogen chloride. Experimentally, using IR spectroscopy, it was found that the reaction of 2-acetoxy-3,5-dichlorobenzoic acid IV with 1.5 times the amount of thionyl chloride in the presence of dimethylformamide proceeds at a temperature of 76-80 ° C for 1 h. Suggested as diluent use toluene to better mix the reaction mass.

It has been proposed to use 2-acetoxy-3,5-dichlorobenzoic acid chloride V for acylation of 4-methyl-3-chloroaniline in toluene in the presence of an aqueous solution of sodium bicarbonate as an acceptor of protons. The molar ratio of 2-acetoxy-3,5-dichlorobenzoic acid chloride V: 4-methyl-3-chloroaniline: sodium bicarbonate is 1.05: 1.00: 1.20. Using thin-layer chromatography, it was shown that after complete mixing of the reagents, it is sufficient to hold the reaction mass for 1 h at 20 ° C. The precipitated precipitate of N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I was separated by filtration, washed with a 5% aqueous solution of sodium bicarbonate to remove inorganic substances and unreacted 2-acetoxy-3,5-dichlorobenzoic acid IV, then washed with toluene to purify the unreacted amine and dried. Purification was carried out by recrystallization from 2-propanol. It was found that with repeated use of the toluene mother liquor from the isolation of technical N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I, the yield of the latter can be increased from 83 to 93%. The quality of the product does not deteriorate, as proved by the melting point.

The described method for producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I compared with the known has the following advantages:

1. The use of inaccessible highly toxic carcinogen phosphorus trichloride is excluded.

2. At the stage of acetylation of 3,5-dichlorosalicylic acid II there is no use of toxic pyridine, and the released hydrogen chloride can be disposed of with water to obtain suitable hydrochloric acid suitable for use.

3. The acetyl chloride and solvent toluene used in the production can be regenerated, which makes production more economical.

4. It is possible to reuse (up to four times) the mother toluene solution at the stage of obtaining technical N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I according to the proposed scheme without loss of quality of the target product. Moreover, its total yield without a purification step according to the proposed scheme is slightly higher (76.5%) than according to the known scheme (71.0%).

Example 1

Preparation of 2-acetoxy-3,5-dichlorobenzoic acid.

20.7 g of 3,5-dichlorosalicylic acid (0.1 mol), 14.2 ml of acetyl chloride (0.2 mol) and 20 ml of toluene are stirred in a three-necked flask, the temperature is raised during this time from 65 to 90 ° C, which takes about 10 hours. After cooling, 2-acetoxy-3,5-dichlorobenzoic acid is filtered off, washed with toluene and the precipitate is dried. Yield 21.2 g (85% of theory). Using thin-layer chromatography, it was found that the product is homogeneous. In the IR spectrum, characteristic bands of the ester group ν _{C = O} 1762 cm ^-1 and a carboxyl group not hydrogen-bonded ν _{C = O} 1691 cm ^-1 are observed, and there is no band of the carboxyl group of the starting acid. The melting point of the obtained 2-acetoxy-3,5-dichlorobenzoic acid is 152-153 ° C.

Preparation of 2-acetoxy-3,5-dichlorobenzoic acid chloride.

21.2 g of the obtained 2-acetoxy-3,5-dichlorobenzoic acid, 9.5 ml of thionyl chloride, 0.1 ml of dimethylformamide and 10 ml of toluene were stirred in a three-necked flask at 76-80 ° C for 1.0 h. Excess thionyl chloride and toluene were distilled off in vacuo to give 24.0 g of a bottom residue. In the IR spectrum, the presence of bands of the acid chloride and ester groups ν _{C = O} 1775 cm ^-1 and the absence of the band of the carboxyl group of 2-acetoxy-3,5-dichlorobenzoic acid was observed, which indicates the complete progress of the reaction.

Preparation of N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I.

8.57 g (0.102 mol) of sodium bicarbonate, 80 ml of water, 12.0 g of 4-methyl-3-chloroaniline (0.085 mol) and 30 ml of toluene are mixed in a three-necked flask. A solution of 24.0 g of the obtained 2-acetoxy-3,5-dichlorobenzoic acid acid chloride V in 80 ml of toluene dried over sodium hydroxide is added dropwise to the flask with stirring. The temperature in the flask was maintained between 18-22 ° C using a bath of cold water. One hour after the completion of the instillation of the toluene solution of 2-acetoxy-3,5-dichlorobenzoic acid chloride V, the precipitated precipitate of N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I was filtered off, washed with 5% aqueous sodium hydrogen carbonate solution, water and toluene and dried. Yield 24.8 g (83% of theory, calculated on 4-methyl-3-chloroaniline).

For purification, 24.8 g of the obtained technical N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I was dissolved in 375 ml of 2-propanol at a temperature of 80-82 ° С, the hot solution was clarified 0, 5 g of activated carbon, filtered hot, cooled to 18-22 ° C, the precipitate was filtered off, washed with 70 ml of 2-propanol and dried. Received 18.6 g of purified N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I. Melting point 162-163 ° C. The IR spectrum contains bands of the amide group ν _NHamide = 3307 cm ^-1 and ν _{C = Oamide} = 1660 cm ^-1 , as well as the band of the ester group ν _{C = O} 1774 cm ^-1 . In the PMR spectrum, δ, ppm: 2.28 (s, 3H, CH ₃ -Ar), 2.32 (s, 3H, CH ₃ -CO), 7.22 (d, 1H), 7, 47 (d, 1H), 7.76 (d, 1H), 7.81 (s, 2H), 10.46 (s, 1H, NH). According to HPLC, the content of the basic substance is 99%.

Example 2

Obtaining N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I with repeated use of toluene mother liquor.

It differs from Example 1 in that a three-necked flask was charged not with 30 ml of toluene but with 140 ml of the toluene layer obtained after filtration of technical N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide I (example one). Received 27.8 g of product (93% of theory), which was purified as described in example 1. Melting point 162-163 ° C. IR and PMR spectra are similar to the spectra of example 1. According to HPLC, the content of the basic substance is not less than 99%.

The proposed method is proposed to be used in the synthesis of a drug substance to obtain drugs.

Claims (1)

A method of producing N- (4-methyl-3-chlorophenyl) -2-acetoxy-3,5-dichlorobenzamide, characterized in that acetylation of 3,5-dichlorosalicylic acid is carried out in toluene with the formation of 2-acetoxy-3,5-dichlorobenzoic acid, then get its acid chloride and carry out the reaction of the acid chloride with 4-methyl-3-chloroaniline with further isolation of the target product, moreover, the acetylation of 3,5-dichlorosalicylic acid is carried out with acetyl chloride in a molar ratio of 1: 2 at a temperature from 65 to 90 ° C, the acid chloride 2-acetoxy-3,5-dichlorobenzoic acid by exposure to thionyl chloride in a molar ratio of 1: 1.5 with the addition of a catalytic amount of dimethylformamide at 76-80 ° С for 1 h, the reaction of the acid chloride with 4-methyl-3-chloroaniline is carried out in the presence of an aqueous solution of sodium hydrogen carbonate in a molar ratio, respectively 1 , 05: 1: 1.2 at a temperature of 18-22 ° C, and the target product is isolated by filtration in the form of a precipitate.