JPH064562B2 - Method for purifying 2- (substituted aryl) propionic acid or a salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to 2- (substituted aryl) propionic acid or a salt thereof (hereinafter simply referred to as “substituted”) used as an intermediate for pharmaceuticals and pharmaceuticals and other organic chemicals. (Referred to as "propionic acid"). More specifically, it relates to a purification method for producing a highly pure substituted propionic acid, which is purified by subjecting a halogenated byproduct such as a halogenated derivative of substituted propionic acid that is by-produced together with the substituted propionic acid in the process of synthesis to hydrogen treatment. It is a thing.

[Prior Art and Problems to be Solved by the Invention] Many methods have conventionally been proposed as a method for producing propionic acid. For example, regarding 2- (p-isobutylphenyl) propionic acid, as a method of using isobutylacetophenone acetylated with acetyl chloride in the presence of an aluminum chloride catalyst as a starting material, (1) alkali metal hydroxide Darzen reacts with α-chloroacetic acid in the presence of salt to form an epoxy compound
As a combination of reactions, JP-A-47-39051, JP-A-49-95398, JP-A-49-108040, and JP-A-51-23235.
JP-A-51-65730, JP-A-52-71437, JP-A-52-8
5140, JP-A-53-63345, JP-A-57-31639 and (2) A combination of methylation reaction with chloroform in the presence of a phase transfer catalyst such as quaternary ammonium salt. As British Patent 971700
JP-A-51-105028, JP-A-52-14742, JP-A-52-
Methods such as 139037, JP-A-52-111534, JP-A-53-90237, JP-A-53-34744, and JP-A-56-16437 have been proposed.

Further, as a method of directly starting from isobutylbenzene, (1) a method in which a method of reacting with an acyl halide compound with an aluminum chloride catalyst is combined, the method is described in British Patent No. 971700, JP-A-51-41338, and JP-A-51338. -100041,
JP-A-52-105146, JP-A-52-108949, JP-A-53-501
No. 35, JP-A-53-18532, JP-A-54-39042, (2) chloromethylation by reacting with formalin in the presence of hydrochloric acid, or a direct halogenation in combination with Grignard reaction as halogenated isobutylbenzene For example, JP-A-47-39050, JP-A-50-40541, JP-A-51-16637, JP-A-51-100042 and JP-A-52-65243
No. 51-101949, No. 52-131553, No. 54
-39042, JP-A-56-97246, JP-A-58-35145 and (3) a method in which an alkylation reaction in which a halogen compound is reacted with a metal chloride catalyst such as aluminum chloride is combined is disclosed in -133351, JP-A-51-36432, JP-A-51-
54525, JP 51-54531, JP 51-56498, JP 52-131551, JP 53-12837, JP 54-19932.
And Japanese Patent Laid-Open No. 58-8045 are disclosed.

Regarding 2- (m-benzoylphenyl) propionic acid, JP-A-55-4311, JP-A-55-7225, and JP-A-
Methods such as 55-36450 and JP-A-56-113736 have been proposed. Furthermore, JP-A-59-98037 and JP-A-53-18533.
No. 6,088,058 discloses another method for producing 2- (substituted aryl) propionic acid.

However, in the conventional method in which these various reactions are combined, a halogen compound that easily causes a side reaction in the synthesis process is used as a raw material, or a halogen compound such as aluminum chloride is used as a catalyst.
As described above, in a production method using a reaction reagent that easily dehalogenates during the reaction and tends to release a free halogen molecule or a halogen ion, various side reactions occur due to the free halogen molecule, and the starting material However, the halogenated by-product, which is an intermediate in the synthetic process or the desired reaction product, is inevitable for the intended use of the desired product. For substituted propionic acid used in fields where high purity and high safety are required, it is not preferable that halogenated by-products are mixed even in a small amount. Recrystallization is usually performed as a purification operation to remove impurities. However, in the purification by recrystallization, in the case of a component such as a halogenated by-product that is not particularly preferable to be mixed in the target product, a relatively large amount of the substituted propionic acid must be left in the liquid, and the crystal substitution A decrease in the recovery rate of propionic acid is unavoidable. Further, in order to remove the halogenated by-product, a complicated post-treatment process such as repeated recrystallization is required.

The present inventors have completed the present invention by discovering that the halogenated by-product contained in the substituted propionic acid is easily dehalogenated by performing hydrogen treatment in the presence of a transition metal catalyst. is there. Therefore, an object of the present invention is to provide a method capable of efficiently recovering highly pure substituted propionic acid.

[Means for Solving Problems] An object of the present invention is to provide a purification method for efficiently producing highly pure 2- (substituted aryl) propionic acid or a salt thereof.

That is, 2- (substituted aryl) propionic acid or a salt thereof containing a halogenated by-product is used in a liquid phase in the periodic table.
A purification method for producing high-purity 2- (substituted aryl) propionic acid or a salt thereof by dehalogenating the halogenated by-product by contacting with hydrogen in the presence of a Group VIII transition metal catalyst. Is provided.

The purification method of the present invention will be specifically described below.

The 2- (substituted aryl) propionic acid obtained by the method of the present invention is a carboxylic acid having a substituted aryl group at the 2-position of a carboxylic acid and a total carbon number of 8 to 18.

That is, in the case of (substituted aryl) propionic acid having a total carbon number of 19 or more, the water solubility is insufficient even under basic conditions and the efficiency of dehalogenation is deteriorated, which is not preferable. The substituted aryl group includes a lower alkyl-substituted phenyl group such as a phenyl group, a methylphenyl group, an ethylphenyl group, a dimethylphenyl group, a propylphenyl group and a butylphenyl group, and a methoxyphenyl group containing an oxygen atom, an ethoxyphenyl group, a propoxy group. Alkoxy group-substituted phenyl group such as phenyl group and butoxyphenyl group, substituted phenyl group such as alkylphenoxyphenyl group and alkylbenzyl group, and substituted naphthyl group such as methylnaphthyl group and methoxynaphthyl group. . Further, in the 2- (substituted aryl) propionic acid which is the object of the present invention, these substituted aryl groups are introduced at the 2-position of the carboxylic acid, and the hydrogen atom bonded to the 2-position carbon is active. It is easily halogenated, and the superiority of the method of the present invention is particularly apparent, which is preferable.

Specific examples of 2- (substituted aryl) propionic acid include:
2- (alkylphenyl) such as 2-phenylpropionic acid and 2- (p-isobutylphenyl) propionic acid
2- (aryloxyphenyl) propionic acid such as propionic acid and 2- (m-phenoxyphenyl) propionic acid, 2- (arylcarboxyphenyl) propionic acid such as 2- (m-benzoylphenyl) propionic acid and 2- ( 2- (methoxynaphthyl) propionic acid such as 6-methoxynaphthyl) propionic acid and the like can be mentioned.

The method of the present invention can be used for any substituted propionic acid containing a halogenated by-product or a salt thereof, which has been synthesized by a conventionally known publicly known method.

The substituted propionic acid containing a halogenated by-product, which is the starting material of the method of the present invention, is either a product isolated after the synthetic reaction or a liquid containing a concentrated halogenated by-product obtained by purification by recrystallization. Can be used.

In the method of the present invention, dehalogenation, that is, hydrogen treatment, is performed in the liquid phase. 2- (Substituted aryl) propionic acid or a salt thereof is used as a liquid phase in a state of being dissolved in a suitable organic solvent or water.

As an organic solvent, it does not interfere with the hydrogen treatment reaction and
As long as it can dissolve (substituted aryl) propionic acid or a salt thereof, the solvent used in the above recrystallization operation and other appropriate solvents can be used. A low boiling point is desirable in order to easily remove the solvent from the reaction system after the hydrogen treatment. Examples of organic solvents include n-hexane and n.
Typical examples are paraffins such as heptane, cycloparaffins such as cyclohexane, alcohols such as methanol, ethanol and ethylene glycol, and ethers such as acetone, dioxane and tetrahydrofuran. These organic solvents and water can be used as a mixture of two or more kinds.

When using a salt of 2- (substituted aryl) propionic acid, water for dissolution is required. In this case, other organic solvent may be present together with water.

The catalyst used in the hydrogen treatment of the method of the present invention is
Although it is a Group II transition metal, Pt, Ph, and Pd are preferable catalysts because of their high efficiency. These catalysts may be in a metallic state as long as they have so-called hydrogenation activity, or may be in a state of being supported on a carrier such as activated carbon, alumina, silica, or silica-alumina. In addition, compounds of transition metals such as chlorides and acetates that can be reduced to an active metal under the condition of hydrogen treatment may be used.

The reaction temperature of the method of the present invention is preferably 20 ° C to 170 ° C. Dehalogenation efficiency is poor at temperatures lower than 20 ° C,
Processing time is long and not practical. Further, at a temperature higher than 170 ° C., nuclear hydrogenation of the aromatic ring of the substituted propionic acid becomes remarkable, which is not preferable. Hydrotreating pressure is not an essential element of the present invention. That is, the pressure may be any pressure higher than normal pressure, and may be higher than the pressure at which the reaction system maintains a liquid phase. Therefore, the reaction pressure can be appropriately selected depending on the reaction temperature. From a practical point of view, a pressure range up to 80 kg / cm ² is preferable.

In the method of the present invention, it is preferable to carry out hydrotreating under basic conditions. That is, the halogen produced by dehalogenation is rapidly neutralized with a basic substance to form an inactive halogen salt, whereby the produced halogen is converted into a dehalogenated product and 2- (substituted aryl) propionic acid. This is because it is possible to prevent recombination. In this case, in order to allow the neutralization to proceed rapidly, the presence of water in the liquid phase is desirable in order to allow the basic substance to exist in the form of an aqueous solution.

For this reason, it is necessary to add a basic substance to make it basic. These basic substances include organic amine compounds such as amines such as trimethylamine, triethylamine and tributylamine, alkali metal lower alcoholates such as sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide, In addition to alkali metal salts of lower carboxylic acids such as sodium acetate and potassium acetate, alkali metal hydroxides such as ammonia, sodium hydroxide and potassium hydroxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate Examples include inorganic alkali metal substances such as carbonates. Practically, a lower carboxylic acid metal salt and an inorganic alkaline substance are preferable in terms of handling. The amount of the basic substance added is such that, when the substituted propionic acid is obtained as a free acid according to the method for producing the substituted propionic acid, the acid and the halogen produced by dehalogenation are neutralized to become basic. An excess amount, or, when the substituted propionic acid is obtained as a salt, may be an amount that simply neutralizes the dehalogenated halogen to make it basic.

Water may be present in a liquid phase, and for example, alcohols such as methanol, ethanol and ethylene glycol, and water-soluble organic solvents such as acetone, dioxane and tetrahydrofuran may be dissolved and coexistent.

The amount of water is the same as that of the basic substance and 2- (substituted aryl).
An amount that can dissolve propionic acid is sufficient.

[Operation of the Invention] As described above, according to the method of the present invention, a highly purified substituted propionic acid containing substantially no halogenated by-product can be produced. For this reason, even when it is used in a field such as a medicine requiring special purification, for example, recrystallization treatment is facilitated, and crystals can be efficiently recovered. Further, in the method of the present invention, the halogenated by-product is converted to the desired substituted propionic acid by hydrogen treatment. Therefore, a component that should originally be an impurity brings about a secondary benefit that it can be recovered as a target product.

[Example] 2- (Substituted aryl) propionic acid described in Table 1 was synthesized by a known method. The results are also shown in Table 1.

10 g of the above 2- (substituted aryl) substituted propionic acid
After adding 20 g of sodium hydroxide aqueous solution gradually to 00 g of water with stirring to make the mixture alkaline to pH 8 to 8.5 and completely dissolved, 0.5 g of Pd catalyst supported on activated carbon (supported amount 2.5 wt%) Along with it, it was put in a pressure resistant container equipped with an agitator. And pressurized to 10 kg / cm ² with hydrogen, the temperature 60
The mixture was stirred at 7 ° C for 7 hours for reaction. After the reaction was completed, the Pd catalyst was removed by passing over, and 35% hydrochloric acid was gradually added to the solution to adjust the pH to 2
Acidified to ~ 3. At this time, the liquid became cloudy and the substituted propionic acid as a product was precipitated. Against this once 2
Extraction of the precipitate was repeated 4 times by adding 5 ml of n-hexane. N-Hexane was removed under reduced pressure to obtain powdery crystals or liquid. Table 2 shows the recovery rate and chlorine content of these hydrotreated products.

Example 2 Alumina was immersed in an aqueous solution of chloroplatinic acid, dried under reduced pressure to remove water, and treated at 450 ° C. in a hydrogen stream for 3 hours to obtain a catalyst having a supported amount of 2.5%. The same 2-phenylpropionic acid as the starting material was added at a pressure of 15 kg / cm ² ,
Example 1 except that hydrogen treatment was carried out at a temperature of 90 ° C. for 8 hours.
Perform the same operation as above, with a recovery rate of 94% and a chlorine content of 13
White crystals of ppm were obtained.

Example 3 The same treatment as in Example 2 was carried out by using a catalyst having a supported amount of 2% obtained by impregnating asbestos with an aqueous solution of rhodium chloride, dipping it in a mixed aqueous solution of formalin and sodium hydroxide, and carrying out a reduction treatment. Then, white crystals having a chlorine content of 14 ppm and a recovery rate of 92% were obtained.

Comparative Example The same 2-phenylpropionic acid as the starting material of Example 1 was recrystallized using n-hexane according to the recrystallization operation of Example 1. The results are shown in Table 3.

As can be seen from the above results, 2 containing halogenated by-products
With respect to phenylpropionic acid, halogen cannot be removed efficiently by a simple recrystallization purification method.

Example 4 Starting material of Example 1, 2- (p-isobutylphenyl)
2.5 g of propionic acid was dissolved in 30 ml of n-hexane, and 0.13 g of Pd catalyst supported on activated carbon (supported amount 5 wt%) was added.
It was placed in a pressure-resistant container with a stirrer and a capacity of 200 ml. The reaction was carried out at a hydrogen pressure of 10 kg / cm ² and a temperature of 60 ° C. for 4 hours. After the completion of the reaction, the Pd catalyst was removed by passing over and the n-hexane was removed under reduced pressure to obtain a recovery rate of 96% and a chlorine content of 10 ppm.
(P-Isobutylphenyl) propionic acid was obtained.

[Effects of the Invention] As described in detail above, if the purification method proposed in the present invention is applied to the purification of 2- (substituted aryl) propionic acid or a salt thereof, 2- (substituted aryl) propion of high purity can be efficiently obtained. It can be an acid or a salt thereof. Therefore, even when further purification is required according to the purpose, for example, recovery in a post-treatment step such as recrystallization operation is easy and efficiency can be improved.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07B 61/00 300

Claims (7)

[Claims] 1. A 2- (substituted aryl) propionic acid or a salt thereof containing a halogenated byproduct in a liquid phase in the periodic table.
The halogenated by-product is dehalogenated by contacting with hydrogen in the presence of a Group VIII metal catalyst to obtain high-purity 2- (substituted aryl) propionic acid or a salt thereof. A method for purifying a substituted aryl) propionic acid or a salt thereof. 2. The transition metal catalyst of Group VIII of the Periodic Table,
2. The method according to claim 1, which is at least one selected from the group consisting of palladium, rhodium and platinum.
-(Substituted aryl) propionic acid or a salt thereof. 3. The 2- (substituted aryl) propionic acid is 2-phenylpropionic acid, 2- (alkylphenyl) propionic acid, 2- (aryloxyphenyl) propionic acid, 2- (arylcarboxyphenyl) propionic acid. The method for purifying high-purity 2- (substituted aryl) propionic acid or a salt thereof according to claim 1, which is at least one compound selected from the group consisting of and 2- (methoxynaphthyl) propionic acid. 4. The 2- (substituted aryl) propionic acid is 2- (p-isobutylphenyl) propionic acid, 2
-(M-phenoxyphenyl) propionic acid, 2- (m
-Benzoylphenyl) propionic acid and 2- (6-
The method for purifying 2- (substituted aryl) propionic acid or a salt thereof according to claim 1, which is at least one compound selected from the group consisting of (methoxynaphthyl) propionic acid. 5. The 2- (substituted aryl) according to claim 1, wherein the dehalogenation is carried out under basic conditions.
A method for purifying propionic acid or a salt thereof. 6. The method according to claim 1 or 5, wherein the dehalogenation is carried out in the presence of liquid phase water.
A method for purifying (substituted aryl) propionic acid or a salt thereof. 7. The dehalogenation is performed at a reaction temperature of 20 ° C. to 1 ° C.
The method for purifying 2- (substituted aryl) propionic acid or a salt thereof according to claim 1, which is carried out at 70 ° C.