RU2030387C1 - Method of synthesis of 2-methoxy-5-chlorobenzoic acid - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 2-methoxy-5-chlorocarboxylic acid, empirical formula is C₈H₇O₂₂Cl, content of basic substance is 97.42% , m. p. is 96-97 C. Reagent 1: 2-methoxybenzoic acid. Reagent 2: chlorine. Reaction conditions: in the medium of carbon tetrachloride, at boiling, in the presence of iodine and ester of lower alcohol and aliphatic or aromatic acid taken at concentration 1.5-5% of initial acid mass following by distillation of solvent and isolation of the end product by known methods. EFFECT: improved method of synthesis. 1 tbl

Description

 The invention relates to the pharmaceutical industry, specifically to methods for producing 2-methoxy-5-chlorobenzoic acid, used as an intermediate for the synthesis of the drug glibenclamide.

 A known method of producing 2-methoxy-5-chlorobenzoic acid with a yield of 45% methylation of methyl ester of 5-chlorosalicylic acid with dimethyl sulfate in the presence of 2 N, sodium hydroxide solution in acetone followed by hydrolysis of the ester / 1 /. The method involves the preliminary esterification of 5-chlorosalicylic acid with methanol in order to obtain its methyl ester. The disadvantages of this method are the low yield of the target product and the use of 5-chlorosalicylic acid, which is not produced on an industrial scale in the USSR.

Also known is a process for preparing 2-methoxy-5-chlorobenzoic acid by chlorinating 2-methoxybenzoic acid in ethanol or isopropanol fold excess mixture of 35% hydrochloric acid and 30% hydrogen peroxide at a ratio of 1: 1 and a temperature of 17-22 ^{° C} for 20 22 hours, followed by processing the reaction mixture with a 40% sodium hydroxide solution and isolating the desired hydrochloric acid product in a yield of 70-77%, so pl. 96-97 ^about C / 2 /.

 The disadvantages of this method are the relatively low yield of the target product, the duration of the process and the danger of the formation of peroxide compounds.

 As a prototype, the method / 3 / was chosen, namely, that 2-methoxybenzoic acid was chlorinated with gaseous chlorine (molar ratio 1: 1) in glacial acetic acid medium while cooling with ice, the reaction mixture was allowed to stand overnight at room temperature and the precipitate was filtered off. The technical product yield is 90%, excluding the content of the main substance. It can be assumed that the resulting 5-chloro-2-methoxybenzoic acid is of poor quality, because it is subjected to further purification from diluted ethyl alcohol.

The yield of purified 5-chloro-2-methoxybenzoic acid is not shown, only mp. 80-81 ^about With, although the melting point of 5-chloro-2-methoxybenzoic acid obtained by the method / 2 /, (96-97) ^about C.

 This method provides insufficiently high yield and quality of the target product.

 The purpose of the invention is to increase the yield and quality of the target product.

 This goal is achieved by the claimed method, including the chlorination of 2-methoxybenzoic acid with gaseous chlorine in a medium of carbon tetrachloride when boiling in the presence of iodine, taken in an amount of 0.5-1.0% by weight of the original acid, and an ester taken in an amount of 1.5 -5.0% by weight of the starting acid, followed by distillation of the solvent and isolation of the target product by known methods.

 As the ester, esters of lower alcohols and fatty or aromatic acids are used, for example ethyl acetate, 2-methoxybenzoic acid methyl ester.

 The difference between the proposed solution and the prototype is a new set of features: the process in carbon tetrachloride when boiling in the presence of iodine, taken in an amount of 0.5-1.0% by weight of the starting acid, and an ester taken in an amount of 1.5-5, 0% by weight of the starting acid.

 The process is carried out at boiling in an inert solvent known as chlorination - carbon tetrachloride. The chlorination progress was monitored by TLC in an ethyl acetate: methanol: 25% ammonia = 6: 2: 1 system on Silufol UV-254 plates. The parameters of the proposed method are selected experimentally and justified in examples 1-5 (see table).

 The use of iodine additives to initiate chlorination reactions is a well-known technique in organic chemistry. However, in the claimed conditions, the process in the presence of iodine only without additives of ether leads to a decrease in yield (from 95-97% to 82%) and the quality of the target product (example 6).

 To reduce the yield and quality also leads to chlorination in the presence of additives only ester (example 7).

In accordance with the claimed method receive 5-chloro-2-methoxybenzoic acid of high purity (mp. 96-97) ^about With the content of by-products no more than 2%, with a yield of 95.02-97.35% (in the prototype 90%, mp (80-81) ^о С), reaction time 2-44 hours. Carbon tetrachloride is a cheaper solvent than glacial acetic acid, and is easily regenerated from a mixture with water, unlike acetic acid, which is important for the industrial implementation of the method of chlorination of 2-methoxybenzoic acid.

Chlorination of 2-methoxybenzoic acid in a / 3 / (temperature ^0-5 ° C, glacial acetic acid, monitoring the termination of the process was carried out not by the number of missed chlorine, and, as in the present method, by TLC) process time was 24 hours the yield of non-recrystallized 5-chloro-2-methoxybenzoic acid 79.68%, so pl. 79-84 ^about C (example 8).

Example 1. A mixture of 30.70 g (30.42 g 100% 0.2 mol) of 2-methoxybenzoic acid, 0.15 g of crystalline iodine, 75 ml of carbon tetrachloride and 0.45 g of methyl ester 2- methoxybenzoic acid are heated to reflux 73-78 ^{° C} and chlorine gas was passed for 3 hours until the disappearance of the reaction mass of 2-methoxybenzoic acid (control by TLC).

Upon completion of the chlorination reaction mixture is distilled carbon tetrachloride at a temperature not higher than 100 mass ^C. The hot bottoms residue is poured into 600 ml of water, heated ^to 40 ° C, poured 14 ml of 42% sodium hydroxide solution and stirred to dissolve the sodium salt of chloromethoxybenzoic acid. The solution was cooled to 10 ^° C, acidified with dilute hydrochloric acid and incubated for one hour.

The precipitate was filtered off, washed with 150 ml of cold water and dried at 40-50 ^° C to give 36.56 g of 5-chloro-2-methoxybenzoic acid, m.p. 96-97 ^{° C} and the content of the main substance of 97.0%, 3-chloro-2-methoxybenzoic acid 1.5%, which is 95.02% based on the 2-methoxybenzoic acid.

 Examples 2-5 are carried out as described in example 1, in examples 4.5, ethyl acetate is used as an ester. The ratio of reagents, the duration of chlorination and the results are shown in the table.

PRI me R 6. The process without the addition of ester. A mixture of 30.70 g (30.42% 100 g, 0.2 mol) of 2-methoxybenzoic acid, 0.15 g of crystalline iodine and 75 ml of carbon tetrachloride was heated to reflux (73-78 ° ^C) and chlorine gas was passed for 3.5 hours until the disappearance of 2-methoxybenzoic acid in the reaction mass (control by TLC).

 Next, the mass is treated as described in example 1. Receive 5-chloro-2-methoxybenzoic acid with a yield of 82.15%, the content of the basic substance 93.15%, 3-chloro-2-methoxybenzoic acid 4.5%, 3.5 -dichloro-2-methoxybenzoic acid 1.5%.

PRI me R 7. The process without the addition of iodine. A mixture of 30.70 g (30.42% 100 g 0.2 mol) of 2-methoxybenzoic acid, 1.47 g of ethyl acetate and 75 ml of carbon tetrachloride was heated to reflux 73-78 ^{° C} and chloro passed for 10 hours until 2-methoxybenzoic acid disappears in the reaction mass.

 Next, the mass is treated as described in example 1. Receive 5-chloro-2-methoxybenzoic acid with a yield of 81.5%, the content of the basic substance 96.5%, 3-chloro-2-methoxybenzoic acid 2.5% and 3.5 -dichloro-2-methoxybenzoic acid 0.5%.

EXAMPLE EXAMPLE 8 A solution of 30.70 g (30.42% 100 g, 0.2 mol) of 2-methoxybenzoic acid in 75 ml of glacial acetic acid is cooled to 0-5 ^{° C} and at this temperature the solution was passed chlorine gas until the initial acid disappears in the reaction mass (24 h).

At the end of chlorination, the reaction mass is left overnight, the precipitate is filtered off, washed with cold water and dried. Get 5-chloro-2-methoxybenzoic acid with a yield of 79.68% and a basic substance content of 93.75%, so pl. 79-84 ^about S.

Claims (2)

 1. METHOD FOR PRODUCING 2-METHOXY-5-CHLORBENZOIC ACID by chlorinating 2-methoxybenzoic acid with gaseous chlorine in an organic solvent and isolating the target product, characterized in that the chlorination is carried out in carbon tetrachloride during boiling in the presence of iodine taken in an amount of 0.5 -1.0% by weight of the starting acid, and a lower alcohol ester of fatty or aromatic acids, taken in an amount of 1.5-5.0% by weight of the starting acid, followed by distillation of the solvent and isolation of the target product.  2. The method according to claim 1, characterized in that ethyl ester of acetic acid or methyl 2-methoxybenzoic acid is used as the ester.

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