JPH10330313A - Production of benzoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject high-purity derivative on an industrial scale at a low cost needing no extraction operation by reacting a specific phenylalkyl halide derivative with a specific hydroxybenzoic acid ester derivative under specific conditions. SOLUTION: The objective derivative of formula III is obtained by the following process: a phenylalkyl halide derivative of formula I (A is a 2-5C alkylene; X is a halogen) (e.g. 1-bromo-4-phenylbutane) with a hydroxybenzoic acid ester derivative of formula II (R is a 1-6C alkyl) (e.g. methyl p-hydroxybenzoate) in the presence of an alkali (hydrogen)carbonate (e.g. potassium carbonate) in a solvent of isopropyl alcohol at a temperature from 10 deg.C to the refluxing temperature for about 1 hr to 30 min; the isopropyl alcohol is removed; the resultant product is separated into the aqueous phase and the organic phase, and the aqueous phase is removed; to the organic phase are added water and an alkali (e.g. sodium hydroxide), and the mixture is treated by hydrolysis at 10-80 deg.C for about 1 hr to 30 min; and finally, the solution is made weak acidic by adding an acid (e.g. hydrochloric acid).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an improved method for producing a phenylalkoxybenzoic acid derivative which is useful as an intermediate for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art The phenylalkoxybenzoic acid derivative of the present invention is a known compound described in, for example, JP-A-3-95144 and JP-A-7-25819.

[0003]

The former method has a problem that an expensive solvent or a highly reactive reagent such as sodium methoxide is used, and the purification method is complicated. The latter method is a method in which a phenylalkyl halide derivative and a hydroxybenzoic acid ester derivative are reacted in the presence of a basic substance, and an alkaline aqueous solution is added to the reaction mixture to hydrolyze the reaction mixture. Use a solvent that is inert to the reaction such as a polar solvent, and after completion of the reaction with the aqueous alkaline solution, add water to perform extraction, wash the resulting aqueous layer with an organic solvent, and then neutralize with an acid. However, since foaming occurs violently during the acid precipitation, there is a disadvantage that the volume of the reactor cannot be sufficiently utilized. An object of the present invention is an industrially advantageous and economical method that does not require an extraction operation, does not cause foaming during acid precipitation, and can obtain a target product with high purity and high yield without washing with an organic solvent. Another object of the present invention is to provide a method for producing a phenylalkoxybenzoic acid derivative which is also advantageous.

[0004]

The present invention provides a phenylalkyl halide derivative represented by the general formula (1) and a hydroxybenzoic acid ester derivative represented by the general formula (2) in the presence of an alkali carbonate or an alkali hydrogen carbonate. Under an isopropyl alcohol solvent, the reaction is carried out. After completion of the reaction, the aqueous phase and the organic layer obtained by removing the isopropyl alcohol are separated to remove the aqueous phase, and water and alkali are added to the organic layer for hydrolysis. To obtain a benzoic acid derivative represented by the general formula (3).

[0005]

Embedded image (In the formula, A represents an alkylene group having 2 to 5 carbon atoms, and X represents a halogen.)

[0006]

Embedded image (In the formula, R represents an alkyl group having 1 to 6 carbon atoms.)

[0007]

Embedded image (Wherein, A is the same as above.)

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The starting material of the present invention has the general formula (1)
In the phenylalkyl halide derivative of 2, the alkylene group having 2 to 5 carbon atoms represented by A includes, for example, ethylene, propylene, butylene, and pentylene groups. Examples of the halogen represented by X include chlorine, bromine and iodine. Examples of the compound of the general formula (1) include, for example, 1-bromo-4-phenylethane, 1-bromo-4-phenylpropane,
Examples include -bromo-4-phenylbutane, 1-bromo-4-phenylpentane, and those obtained by substituting a bromo group with a chlorine group or an iodine group. The phenylalkyl halide derivative of the general formula (1) is disclosed in JP-A-3-9514.
4, known compounds described in JP-A-7-25819, which are easily available compounds.

In the hydroxybenzoic acid ester derivative represented by the general formula (2) as another starting material of the present invention,
As alkyl having 1 to 6 carbon atoms represented by R, methyl,
Ethyl, propyl, butyl, pentyl and hexyl groups can be mentioned. As an example of the compound of the general formula (2),
For example, o, m or methyl p-hydroxybenzoate,
ethyl o, m or p-hydroxybenzoate, propyl o, m or p-hydroxybenzoate, o, m or p
Butyl-hydroxybenzoate, pentyl o, m or p-hydroxybenzoate, hexyl o, m or p-hydroxybenzoate. The hydroxybenzoic acid ester derivative of the general formula (2) is also disclosed in JP-A-3-951.
No. 44, and known compounds described in JP-A-7-25819, which are easily available compounds.

Next, the phenylalkyl halide derivative of the formula (1) and the hydroxybenzoic acid ester derivative of the formula (2) are reacted in an isopropyl alcohol solvent in the presence of alkali carbonate or alkali hydrogen carbonate. The aqueous phase and the organic layer obtained by removing the organic layer are separated to remove the aqueous phase, and water and an alkali are added to the organic layer to carry out hydrolysis, whereby the phenylalkoxybenzoic acid represented by the general formula (3) is obtained. Derivatives can be obtained. Examples of the alkali carbonate include sodium carbonate and potassium carbonate, and examples of the alkali hydrogen carbonate include sodium hydrogen carbonate and potassium hydrogen carbonate.
Of these, potassium carbonate is particularly preferred. The amount of alkali carbonate or alkali hydrogencarbonate used is usually about 1 to 5 mol, preferably about 2 to 3 mol, per 1 mol of compound (1).

As a solvent, isopropanol is used. The purity of the phenylalkoxybenzoic acid derivative obtained by using methanol other than isopropanol, for example, methanol is low. Cannot be obtained and cannot be used practically. The reaction is carried out under normal pressure, increased pressure or reduced pressure, usually at 10 ° C. to reflux temperature, preferably 6 ° C.
It is preferably carried out in the range of 0 ° C. to the reflux temperature for about 1 to 30 hours, preferably for 6 to 23 hours. After completion of the reaction, the aqueous phase and the organic layer obtained by removing isopropyl alcohol are separated to remove the aqueous phase, and water and alkali are added to the organic layer for hydrolysis. By removing isopropanol as the solvent after the completion of the alkylation reaction, the amount of the alkali compound used in the next step can be reduced. In addition, the method of the present invention does not require an extraction operation, does not cause foaming at the time of acid precipitation, and can provide the target product with high purity and high yield without washing with an organic solvent.

Examples of the alkali compound include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as sodium methoxide and sodium ethoxide. The amount of the alkali compound to be used is generally about 1-5 mol, preferably 2 mol, per 1 mol of compound (1).
The amount is preferably about 3 mol. The hydrolysis reaction is usually 10
At a temperature of ~ 80 ° C, preferably 20-60 ° C, about 1-3
It is preferably performed for 0 hour, preferably for 6 to 23 hours. After the completion of the hydrolysis, the liquid is weakly acidified by adding an acid to obtain a desired crystal of the phenylalkoxybenzoic acid derivative represented by the general formula (3). Examples of the acid include hydrochloric acid and sulfuric acid.

In the present invention, the phenylalkoxybenzoic acid derivative of the general formula (3) obtained above can be separated by ordinary isolation and purification methods, for example, filtration, extraction, concentration, cooling crystallization, poor solubility. Crystallization by addition of a solvent, chromatography and the like can be mentioned.

[0014]

EXAMPLES Hereinafter, reference examples, examples and comparative examples will be described. Example 1 Into a 1 L flask were placed 450 ml of isopropanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.g of anhydrous potassium carbonate.
After adding 0 g, the mixture is reacted under reflux for 20 hours. After confirming the reaction end point by high performance liquid chromatography,
Add ml and heat the reaction mixture to recover isopropanol. After recovery, the reaction mixture is separated into two layers, an aqueous layer and an organic layer, so that the lower aqueous layer is removed. Water 50
0 ml and sodium hydroxide 40.8 g.
Let react for hours. After completion of the reaction, the mixture was cooled to room temperature, 116 ml of concentrated hydrochloric acid was added to make the solution pH slightly weak, and the precipitated crystals were collected by filtration to obtain 128.2 g of 4- (4-phenylbutoxy) benzoic acid, melting point: 129.2. ~ 130.6 ° C (yield 96.
4%).

Comparative Example 1 450 ml of methanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.0 g of anhydrous potassium carbonate were added to a 1 L flask, and the mixture was refluxed for 20 minutes. Let react for hours. After confirming the end point of the reaction by high performance liquid chromatography, 300 ml of water is added, and the reaction mixture is heated to recover methanol. After recovery, the reaction mixture is separated into two layers, an aqueous layer and an organic layer.
Exclude the lower aqueous layer. 450 ml of water and 40.8 g of sodium hydroxide are added to this organic layer, and the mixture is reacted at 100 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated hydrochloric acid (120 ml) was added to make the solution weakly acidic pH4, and the precipitated crystals were collected by filtration to give 4- (4-phenylbutoxy) benzoic acid (121.2).
g, melting point 123.4-127.7 ° C. (yield 91.0%). Since the melting point is lower than that of Example 1, the purity is low.

Comparative Example 2 A 1 L flask was charged with 450 ml of isopropanol, 79.5 g of methyl p-hydroxybenzoate, 105.0 g of 1-bromo-4-phenylbutane and 100.g of anhydrous potassium carbonate.
After adding 0 g, the mixture is reacted under reflux for 20 hours. After confirming the end point of the reaction by high performance liquid chromatography,
ml and 58.5 g of sodium hydroxide were added, and the mixture was reacted under reflux for 1 hour. After completion of the reaction, the mixture is cooled to room temperature and concentrated hydrochloric acid 18
0 ml was added to adjust the solution to a slightly acidic pH4. During this acid precipitation,
Due to vigorous foaming, the reaction solution was transferred to a 3 L flask. The precipitated crystals were collected by filtration to give 125.1 g of 4- (4-phenylbutoxy) benzoic acid, melting point 128.5 to 130.0.
° C (95.2% yield).

Reference Example 1 Starting from the 4- (4-phenylbutoxy) benzoic acid obtained in Example 1 as a starting material, for example, the following JP-A-3-951
8- [4- (4)
-Phenylbutoxy) benzoyl] amino-2- (5-
(Tetrazolyl) -4-oxo-4H-1-benzopyran (pranlukast, an anti-asthmatic drug) can be synthesized.

[0018]

According to the method of the present invention, no extraction operation is required, no foaming occurs during acid precipitation, and the desired product can be obtained in high purity and high yield without washing with an organic solvent. An industrially and economically advantageous method for producing a phenylalkoxybenzoic acid derivative can be provided.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Shuichi Kishimoto 18-23, Yoshino-cho, Suita-shi, Osaka Showa Kako Co., Ltd. Inside the Suita Plant (72) Inventor Masanori Shimizu 18-23, Yoshino-cho, Suita-shi, Osaka Showa (72) Inventor: Shizuo Akasaki 18-23, Yoshino-cho, Suita-shi, Osaka Prefecture Showa Chemical Co., Ltd. 18--23, Yoshino-cho, Suita-shi, Osaka Showa (72) Inventor Kaoru Kodera 18-23, Yoshino-cho, Suita-shi, Osaka Showa Chemical Co., Ltd.

Claims (1)

[Claims] 1. A phenylalkyl halide derivative represented by the general formula (1) and a hydroxybenzoic acid ester derivative represented by the general formula (2) in an isopropyl alcohol solvent in the presence of alkali carbonate or alkali hydrogen carbonate. After completion of the reaction, the aqueous phase and the organic layer obtained by removing isopropyl alcohol after the completion of the reaction are separated to remove the aqueous phase, and water and an alkali are added to the organic layer to carry out hydrolysis to obtain a compound of the general formula (3)
A method for producing a benzoic acid derivative, characterized by obtaining a benzoic acid derivative represented by the formula: Embedded image (In the formula, A represents an alkylene group having 2 to 5 carbon atoms, and X represents a halogen.) (In the formula, R represents an alkyl group having 1 to 6 carbon atoms.) (Wherein, A is the same as above.)