KR20010064949A - Method for preparing 3-(1-cyanoalkyl) benzoic acid - Google Patents

Abstract

PURPOSE: A method of preparing 3-(1-cyanoalkyl)benzoic acid, an important pharmaceutical intermediate to prepare anti-inflammatory drug Ketoprofen, using alkali metal salts 2-chlorobenzoate as a starting material is provided to prevent splash phenomenon of liquid ammonia caused by neutralization heat when 2-chlorobenzoic acid is directly added to liquid ammonia containing other raw materials. CONSTITUTION: The preparation method of 3-(1-cyanoalkyl)benzoic acid represented by the chemical formula 1 comprises the steps of (i) preparing alkali metal salts 2-chlorobenzoate represented by the chemical formula 2 (wherein R1 is hydrogen or C 1-C4 branched or straight chain alkyl group and M is Li, Na, K) by neutralizing 2-chlorobenzoic acid with alkali such as sodium hydroxide, potassium hydroxide in the equivalent ratio of 1:1 in a solvent such as water, methyl alcohol, ethyl alcohol, benzene, toluene, xylene in the temperature range of 25 to 100deg.C for 0.5-6hrs; (ii) reacting sodium amide/sodium and alkyl nitrile (R1CH2CN) in the temperature range of -35 to 30deg.C for 0.5hr at normal pressure to 7atm. in the liquid ammonia; (iii) adding alkali metal salts 2-chlorobenzoate prepared in the first step to resultant compound of the second step for 1.5hr as stirring, wherein other reacting conditions are the same as the second step; and then (iv) adding sequentially water and chloric acid to eliminate remaining sodium amide and filter out the solid products, 3-(1-cyanoalkyl)benzoic acid.

Description

Method for preparing 3- (1-cyanoalkyl) benzoic acid {Method for preparing 3- (1-cyanoalkyl) benzoic acid}

The present invention relates to a method for preparing 3- (1-cyanoalkyl) benzoic acid, and more particularly, to a method for preparing 3- (1-cyanoalkyl) benzoic acid using a 2-chlorobenzoic acid metal salt as a starting material. It is about.

In general, 3- (1-cyanoalkyl) benzoic acid is an important pharmaceutical intermediate used as a raw material of ketoprofen widely used as an anti-inflammatory analgesic.

Looking at the example of the conventional manufacturing method of 3- (1-cyanoalkyl) benzoic acid, German Patent Nos. 2708142 and 2708143, 3- (chloromethyl) benzoic acid methyl ester and sodium cyanide are reacted to give 3- (1-cyanoalkyl) benzoic acid. A process for preparing 3- (1-cyanoethyl) benzoic acid is described by preparing cyanomethyl) benzoic acid methylester and then going through several steps again. This method has a problem of using sodium cyanide, which is very toxic and is not economical because 3- (1-cyanoethyl) benzoic acid has to be prepared in several steps.

Another method is to react 2-chlorobenzoic acid with sodium and alkylnitrile in a liquid ammonia solvent to produce 3- (1-cyanoalkyl) benzoic acid (ER Biehl; H.-M. Li, J Org. Chem. 1966, 31 , 602 .; ER Biehl; H.-M. Li, J. Org . Chem. 1969, 34 , 500.). However, the above production method uses a liquid ammonia of more than 20 times the amount of 2-chlorobenzoic acid as a raw material, and contains 6 times and 3 times sodium of 2-chlorobenzoic acid and a relatively expensive alkylnitrile. There is a disadvantage to be used. In addition, a lot of neutralization heat is generated when 2-chlorobenzoic acid as a raw material is added to a mixture of liquid ammonia as a solvent and other raw materials, and there are many risks, such as splashing of low temperature liquid ammonia. there is a problem.

Accordingly, the inventors of the present invention have found a method of preparing 3- (1-cyanoalkyl) benzoic acid using a 2-chlorobenzoic acid metal salt as a starting material. It is finished.

Accordingly, it is an object of the present invention to provide a method for preparing 3- (1-cyanoethyl) benzoic acid that is industrially easy to produce, safe and economical.

The method for preparing 3- (1-cyanoalkyl) benzoic acid represented by Chemical Formula 1 for achieving the above object is a 2-chlorobenzoic acid metal salt represented by the following Chemical Formula 2 under 5 to 20 times liquid ammonia. The alkylnitro compound and sodium amide or sodium are mixed at an equivalent ratio of 1: 1: 1 to 1: 3: 6 and reacted for 10 minutes to 5 hours at -80 to 100 캜 and atmospheric pressure to 10 atmospheres.

R ₁ CH ₂ CN

Wherein R ₁ is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and M is an alkali metal selected from the group of lithium, sodium and potassium.

Hereinafter, the present invention will be described in more detail.

As described above, unlike the conventional method for directly reacting 2-chlorobenzoic acid with sodium and alkylnitro compounds when preparing 3- (1-cyanoalkyl) benzoic acid, the 2-chlorobenzoic acid metal salt is used in the present invention. By using it as a starting material, it has the same effect as having previously neutralized 2-chlorobenzoic acid, and can prevent the phenomenon of liquid ammonia due to heat of neutralization when reacted with sodium amide and alkylnitro compound in a solvent of liquid ammonia.

The 2-chlorobenzoic acid metal salt represented by Chemical Formula 2 according to the present invention may be obtained by neutralizing 2-chlorobenzoic acid with a basic substance in an equivalent ratio of 1: 1 in the presence of a solvent. At this time, when the equivalent weight of 2-chlorobenzoic acid is large, the reaction is not completed, and when the amount of the basic substance is large, there is a problem in that the inorganic impurity that is difficult to remove is increased in the prepared 2-chlorobenzoic acid metal salt.

Here, as the solvent used, one selected from the group consisting of water, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, diethyl ether, methyl thibutyl ether, dibutyl ether, benzene, toluene, and xylene can be used. And preferably, water, methyl alcohol, ethyl alcohol, benzene, toluene and xylene. At this time, 2 to 20 times the solvent of 2-chlorobenzoic acid is used.

The basic substance which can be used for the neutralization reaction is one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, methoxy lithium, methoxy sodium, methoxy potassium, ethoxy lithium, ethoxy sodium and ethoxy potassium. And sodium hydroxide and potassium hydroxide.

In the neutralization reaction, the mixture is reacted at a temperature of 25 ° C. to 100 ° C. for 30 minutes to 6 hours, wherein M is lithium, sodium in the 2-chlorobenzoic acid metal salt of Chemical Formula 2 prepared through the neutralization reaction. It is selected from the group consisting of potassium, and preferably sodium and potassium. If the temperature of the neutralization reaction exceeds 100 ℃ there is a problem that the yield of the 2-chlorobenzoic acid metal salt is lowered, if less than 25 ℃ the reaction time takes a long time it is difficult to use industrially.

3- (1-cyanoalkyl) benzoic acid according to the present invention, as described above, the 2-chlorobenzoic acid metal salt, the alkylnitro compound of the formula (3), and sodium amide or sodium 1: 1: 1 to 1: 3 It is prepared by mixing under a liquid ammonia of 5 to 20 times in an equivalent ratio of: 6 and reacting for 10 minutes to 5 hours at -80 to 100 캜 and atmospheric pressure (1 atmosphere) to 10 atmospheres.

Formula 3

R ₁ CH ₂ CN

Here, R ₁ is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and when looking at the alkylnitro compound in more detail, acetonitrile, propionitrile, butylonitrile, isobutylonitrile, valeronitrile , Isovaleronitrile, hexanenitrile, and one selected from the group consisting of, acetonitrile and propionitrile are preferable.

The 3- (1-cyanoalkyl) benzoic acid of the present invention may be prepared by using sodium amide or by reacting metal sodium with ammonia to make sodium amide and using it continuously.

Herein, the mixed amount of the 2-chlorobenzoic acid metal salt of Chemical Formula 2, the alkylnitro compound of Chemical Formula 3, and sodium amide or sodium is in an equivalent ratio of 1: 1: 1 to 1: 3: 6, preferably 1: 1: 2 to 1: 2: 5, most preferably 1: 1: 3 to 1: 1.5: 4.5. When the alkylnitro compound is less than 1 equivalent ratio to the 2-chlorobenzoic acid metal salt, there is a problem that the reaction is not completed. When the ratio is more than 3 equivalent ratio, it is difficult to use industrially. Sodium amide or sodium is equivalent to 1 equivalent ratio of the 2-chlorobenzoic acid metal salt. If it is less than the amount of reaction intermediate produced is reduced, if the equivalent ratio exceeds 6 there is a problem that is difficult to use industrially.

In addition, sodium amide or sodium and alkylnitrile are mixed under liquid ammonia, and the temperature range is -80 to 100 ° C, preferably -50 to 50 ° C, and most preferably -35 to 30 ° C. The reaction is carried out at atmospheric pressure, preferably at atmospheric pressure to 8 atmospheres, most preferably at atmospheric pressure to 7 atmospheres, for 10 minutes to 5 hours, preferably 10 minutes to 1 hour, and most preferably 30 minutes. At this time, if the temperature is less than -80 ℃ there is a problem that the reaction rate is slow, and if it exceeds 100 ℃ high pressure is formed there is a problem that industrial use is difficult. In addition, if the pressure exceeds 10 atm, there is a problem that the side reaction product increases, if the reaction time is less than 10 minutes, the reaction is not completed, if more than 5 hours the side reaction product is increased.

The 2-chlorobenzoic acid metal salt was added to the mixture thus prepared and stirred. The conditions at this time are the same as the mixing temperature of sodium amide or sodium nitrile, and the reaction time is 30 minutes to 5 hours, preferably 1 hour to 3 hours, and most preferably 1.5 hours. If the reaction time is less than 30 minutes, a large amount of unreacted material remains, and if it exceeds 5 hours, there is a problem in that the side reaction product increases.

After the reaction, the temperature is raised to room temperature, and 3- (1-cyanoalkyl) benzoic acid is prepared by adding water and hydrochloric acid.

As described above, in the method for preparing 3- (1-cyanoalkyl) benzoic acid according to the present invention, by using the 2-chlorobenzoic acid metal salt represented by the formula (2), the amount of alkylnitrile and sodium amide is compared with the prior art. It is economical because it can reduce 1 to 2 equivalents, and can reduce the risk due to heat generation at the time of raw material input, so it can be used industrially.

Hereinafter, the present invention will be described in more detail, but the scope of the present invention is not limited thereto.

Example 1

After putting 2.55 g of sodium hydroxide and 10 mL of water in a 250 mL reactor, 10 g of 2-chlorobenzoic acid was added at 0 ° C. for 5 minutes. After the addition, the temperature of the reactor was raised to room temperature and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure to give a white solid. It was heated to 40 ° C. under reduced pressure and dried to obtain 11.4 g of sodium 2-chlorobenzoate.

In addition, a 500 mL reactor was prepared and the temperature thereof was lowered to -78 ° C, and 200 mL of liquid ammonia was added thereto. 10.9 g of sodium amide and 8 mL of propionitrile were added dropwise thereto to the reactor, and the temperature of the reactor was adjusted to -33 ° C and stirred for 0.5 hour. 10 g of sodium 2-chlorobenzoate prepared above was added at the same temperature, followed by stirring for 1 hour. The temperature of the reactor was raised to room temperature to remove all liquid ammonia, and water was added dropwise to remove all remaining sodium amide. After adding dropwise addition of concentrated hydrochloric acid, 5.2 g of 3- (1-cyanoethyl) benzoic acid was produced by filtering the produced solid. It was confirmed by nuclear magnetic resonance analysis that the prepared solid was 3- (1-cyanoethyl) benzoic acid.

1 H NMR (300 MHz, CDCl ₃ ) 1.70 (d, 3H), 4.05 (q, 1H), 7.65 (m, 2H),

8.15 (s, 2 H) 9.55 (br s, 1 H).

Example 2

0.36 g of potassium hydroxide and 2 mL of water were added to a 50 mL reactor, and 1.0 g of 2-chlorobenzoic acid was added at 0 ° C for 1 minute. After the addition, the temperature of the reactor was raised to room temperature and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure to give a white solid. It dried by heating at 40 degreeC under reduced pressure, and obtained 1.2 g of potassium 2-chlorobenzoate.

In addition, a 100 mL reactor was prepared, and after the temperature thereof was lowered to -78 ° C, 20 mL of liquid ammonia was added thereto. 1.9 g of sodium amide and .08 mL of propionitrile were added dropwise thereto to the reactor, and then the temperature of the reactor was adjusted to -33 ° C and stirred for 0.5 hour. 1 g of potassium 2-chlorobenzoate prepared above was added at the same temperature, followed by stirring for 1 hour and 30 minutes. The temperature of the reactor was raised to room temperature to remove all liquid ammonia, and water was added dropwise to remove all remaining sodium amide. Concentrated hydrochloric acid was added dropwise thereto, and the resulting solid was filtered to prepare 0.5 g of 3- (1-cyanoethyl) benzoic acid.

Example 3

After putting 2.55 g of sodium hydroxide and 10 mL of water in a 250 mL reactor, 10 g of 2-chlorobenzoic acid was added at 0 ° C. for 5 minutes. After the addition, the temperature of the reactor was raised to room temperature and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure to give a white solid. It was heated to 40 ° C. under reduced pressure and dried to obtain 11.4 g of sodium 2-chlorobenzoate.

Furthermore, after lowering the temperature of the 500 mL reactor to -78 ° C, 300 mL of liquid ammonia was added thereto. 0.2 g of iron nitrate and 7.7 g of sodium were added to the reactor and stirred for 30 minutes. Then, 8 mL of propionitrile was added dropwise thereto, and the temperature of the reactor was adjusted to −33 ° C. and stirred for 0.5 hour. 10 g of sodium 2-chlorobenzoate prepared above was added at the same temperature, followed by stirring for 1 hour. The temperature of the reactor was raised to room temperature to remove all liquid ammonia, and water was added dropwise to remove all remaining sodium amide. After adding dropwise addition of concentrated hydrochloric acid, the resulting solid was filtered to prepare 4.99 g of 3- (1-cyanoethyl) benzoic acid. It was confirmed by nuclear magnetic resonance analysis that the prepared solid was 3- (1-cyanoethyl) benzoic acid.

1 H NMR (300 MHz, CDCl ₃ ) 1.70 (d, 3H), 4.05 (q, 1H), 7.65 (m, 2H),

8.15 (s, 2 H) 9.55 (br s, 1 H).

Example 4

After putting 2.55 g of sodium hydroxide and 10 mL of water in a 250 mL reactor, 10 g of 2-chlorobenzoic acid was added at 0 ° C. for 5 minutes. After the addition, the temperature of the reactor was raised to room temperature and stirred for 30 minutes. The reaction solution is concentrated under reduced pressure to give a white solid. It was heated to 40 ° C. under reduced pressure and dried to obtain 11.4 g of sodium 2-chlorobenzoate.

In addition, after the temperature of the 100 mL reactor was lowered to -78 ° C, 50 mL of liquid ammonia was added thereto. 4.5 g of sodium amide and 2.7 mL of propionitrile were added dropwise to the reactor, followed by stirring for 30 minutes. 3.4 g of sodium 2-chlorobenzoate prepared above was added thereto, and the conditions of the reactor were changed to 7 atm and 0 ° C, followed by stirring for 1 hour and 30 minutes. The pressure in the reactor was reduced to normal pressure to remove all liquid ammonia, and water was added dropwise to remove all remaining sodium amide. After adding dropwise addition of concentrated hydrochloric acid, the produced solid was filtered to prepare 1.6 g of 3- (1-cyanoethyl) benzoic acid. It was confirmed by nuclear magnetic resonance analysis that the prepared solid was 3- (1-cyanoethyl) benzoic acid.

1 H NMR (300 MHz, CDCl ₃ ) 1.70 (d, 3H), 4.05 (q, 1H), 7.65 (m, 2H),

8.15 (s, 2 H) 9.55 (br s, 1 H).

Example 5

After lowering the temperature of the 1000 mL reactor to −78 ° C., 430 g of liquid ammonia was added thereto. 0.3 g of iron nitrate and 21 g of sodium were added to the reactor and stirred for 30 minutes. Then, 24 mL of propionitrile was added dropwise thereto, and the temperature of the reactor was adjusted to −33 ° C. and stirred for 0.5 hour. 40 g of sodium 2-chlorobenzoate prepared in the same manner as in Examples 1 to 4 was added at the same temperature, followed by stirring for 1 hour and 30 minutes. The amount of gas ammonia generated at this time was measured using a cumulative gas generation meter. The volume of gas ammonia generated at this time was 84.9 L, and the heat of reaction was about 21 kcal. The temperature of the reactor was raised to room temperature to remove liquid ammonia, and water was added dropwise to remove all remaining sodium amide. After adding dropwise addition of concentrated hydrochloric acid, the produced solid was filtered to prepare 18 g of 3- (1-cyanoethyl) benzoic acid. It was confirmed by nuclear magnetic resonance analysis that the prepared solid was 3- (1-cyanoethyl) benzoic acid.

1 H NMR (300 MHz, CDCl ₃ ) 1.70 (d, 3H), 4.05 (q, 1H), 7.65 (m, 2H),

8.15 (s, 2 H) 9.55 (br s, 1 H).

Comparative Example 1

After lowering the temperature of the 1000 mL reactor to −78 ° C., 430 g of liquid ammonia was added thereto. 0.5 g of iron nitrate and 32 g of sodium were added to the reactor and stirred for 30 minutes. Then, 48 mL of propionitrile was added dropwise thereto, and the temperature of the reactor was adjusted to −33 ° C. and stirred for 0.5 hour. 40 g of ordinary sodium 2-chlorobenzoate was added at the same temperature, followed by stirring for 1 hour and 30 minutes. The amount of gas ammonia generated at this time was measured using a cumulative gas generation meter. The volume of gas ammonia generated at this time was 190.0 L, and the heat of reaction was about 47 kcal. The temperature of the reactor was raised to room temperature to remove liquid ammonia, and water was added dropwise to remove all remaining sodium amide. Concentrated hydrochloric acid was added dropwise thereto, and the produced solid was filtered to prepare 20 g of 3- (1-cyanoethyl) benzoic acid. It was confirmed by nuclear magnetic resonance analysis that the prepared solid was 3- (1-cyanoethyl) benzoic acid.

1 H NMR (300 MHz, CDCl ₃ ) 1.70 (d, 3H), 4.05 (q, 1H), 7.65 (m, 2H),

8.15 (s, 2 H) 9.55 (br s, 1 H).

Example 5 Comparative Example 1 Amount of raw materials used 40 g (0.22 mole) 40 g (0.26 mole) Sodium raw material 21 g 32 g Propionitrile Usage 24 mL 48 mL Reaction heat 21kcal 47 kcal

As can be seen in Table 1, the preparation method of 3- (1-cyanoalkyl) benzoic acid according to the present invention uses the amount of alkylnitrile and sodium amide by using the 2-chlorobenzoic acid metal salt represented by the formula (2). It is economical because it can be reduced by more than 1 equivalent compared with the prior art, and can reduce the risk of heat generation during the input of raw materials, which can be industrially used.

Claims (5)

2-chlorobenzoic acid metal salt represented by the following formula (2), alkylnitro compound represented by the following formula (3), and sodium amide or sodium under liquid ammonia were mixed at an equivalent ratio of 1: 1: 1 to 1: 3: 6 to -80 to A process for producing 3- (1-cyanoalkyl) benzoic acid represented by the following formula (1) to react for 10 minutes to 5 hours at 100 캜 and atmospheric pressure to 10 atmospheres. Formula 1 Formula 2 Formula 3 R ₁ CH ₂ CN Wherein R ₁ is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and M is an alkali metal selected from the group of lithium, sodium and potassium. [Claim 2] The 3- (1-cyanoalkyl) benzoic acid according to claim 1, wherein the 2-chlorobenzoic acid metal salt is prepared by neutralizing 2-chlorobenzoic acid with a basic substance in an equivalent ratio of 1: 1 in the presence of a solvent. Manufacturing method. The method of claim 2, wherein the basic material is one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, methoxy lithium, methoxy sodium, methoxy potassium, ethoxy lithium, ethoxy sodium and ethoxy potassium The manufacturing method of 3- (1-cyanoalkyl) benzoic acid which uses. The method of claim 2, wherein the solvent is one selected from the group consisting of water, alcohol, ether, benzene, toluene, and xylene. The method according to claim 1, wherein the alkylnitro compound is one selected from the group consisting of acetonitrile, propionitrile, butylonitrile, isobutylonitrile, valeronitrile, isovaleronitrile and hexanenitrile. Process for the preparation of-(1-cyanoalkyl) benzoic acid.