KR101393009B1 - A process for preparing 2-(4-formylphenyl)propionic acid by using carbon-based catalyst - Google Patents

Abstract

The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid using a carbon catalyst, and more particularly, to a process for producing 2- (4- (hydroxymethyl) (4-formylphenyl) propionic acid in a high yield in an environmentally friendly environment without using a toxic crystallization solvent by carrying out an oxidation reaction with an aqueous solution of sodium hypochlorite (NaOCl) will be.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid by using a carbon catalyst,

The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid using a carbon catalyst, and more particularly, to a process for producing 2- (4- (hydroxymethyl) (4-formylphenyl) propionic acid in a high yield in an environmentally friendly environment without using a toxic crystallization solvent by carrying out an oxidation reaction with an aqueous solution of sodium hypochlorite (NaOCl) will be.

The 2- (4-formylphenyl) propionic acid 2- (4-formylphenyl) propionic acid is a very useful compound used as a preparation intermediate of pelubiprofen as shown in the following reaction scheme (1).

[Reaction Scheme 1]

As is well known, pelubiprofen is a nonsteroidal analgesic and antiinflammatory agent (NSAID) developed by Sankyo Corporation of Japan. The substance has pharmacological activity in treating various kinds of diseases such as osteoarthritis, rheumatoid arthritis, musculoskeletal pain, post-operative aftereffects, back pain, toothache and the like. It has also been reported that ibuprofen has a very high pharmacological activity compared to similar non-steroidal anti-inflammatory analgesics (Theories and Applications of Chem. Eng., 2002, Vol. 8, No. 1).

JP-A-04-368353 discloses a method for synthesizing 2- (4-formylphenyl) propionic acid, which is known in the art, by reacting 2- [4- (hydroxymethyl) phenyl] There has been reported a method of oxidizing 2- [4- (hydroxymethyl) phenyl] propionic acid} with an aqueous solution of sodium hypochlorite (NaOCl) in an ethyl acetate solvent and an acidic condition.

[Reaction Scheme 2]

The method disclosed in Japanese Laid-Open Patent Publication No. 2000-34832 has an advantage that the problem of the waste treatment can be solved simply by decomposing the oxidizing agent after the reaction as an oxidation reaction not including a metal compound. However, due to the flexible substances generated during the reaction, it is required to undergo a purification process through recrystallization, and this purification process causes a reduction in the yield of the overall reaction.

Also, since the purity of the final product, pelubiprofen, is lowered by the supernatant which is not completely removed during the purification process, and the carbon tetrachloride used in the crystallization process is classified as a substance having high hepatotoxicity, Can not be guaranteed.

1. Japanese Laid-Open Patent Application No. 04-368353

Therefore, a problem to be solved by the present invention is to provide a process for producing 2- (4-formylphenyl) propionic acid, which is an intermediate for preparing felubipropene, using a carbon catalyst, And to provide a novel manufacturing method which can be manufactured with high efficiency.

The process for producing 2- (4-formylphenyl) propionic acid according to the present invention comprises: (a) dissolving 2- [4- (hydroxymethyl) phenyl] propionic acid in an ester solvent, adding 1N acid ) Aqueous solution and a carbon catalyst selected from activated carbon, graphite or graphene; (b) dropwise adding 1 to 1.5 equivalents of a 10% aqueous solution of sodium hypochlorite (NaOCl) to the 2- [4- (hydroxymethyl) phenyl] propionic acid at a temperature of 30 to 40 ° C and stirring Wow; (c) filtering the carbon catalyst and washing the residue with an aqueous solution of sodium thiosulfate (Na ₂ S ₂ O ₃ ) to decompose and remove unreacted sodium hypochlorite (NaOCl); (d) separating and concentrating the organic layer, and crystallizing with a mixed solvent of ethyl acetate and a saturated hydrocarbon solvent; And a control unit.

The present invention relates to a process for the production of 2- (4-formylphenyl) propionic acid by reacting 2- [4- (hydroxymethyl) phenyl] propionic acid as a starting material with sodium hypochlorite (NaOCl) The yield of the target material is improved by about 15% or more and the purity of the target material is improved by about 10% or more as compared with the conventional method.

In addition, instead of using toxic carbon tetrachloride as a crystallization solvent, a mixed solvent of ethyl acetate and a saturated hydrocarbon solvent is used as a crystallization solvent, so that a desired material can be produced economically and economically.

1 is a nuclear magnetic resonance spectrum of 2- (4-formylphenyl) propionic acid prepared according to the present invention.

The process for preparing 2- (4-formylphenyl) propionic acid using the carbon catalyst according to the present invention is represented by the following reaction formula (3).

[Reaction Scheme 3]

In the present invention, first, 2- [4- (hydroxymethyl) phenyl] propionic acid as a starting material is dissolved in an ester solvent. As the ester solvent, at least one selected from methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate may be used, and ethyl acetate is most preferably used.

Next, 1 equivalent of an aqueous 1N acid solution is added, and a carbon catalyst is added. As the acid aqueous solution, any one or more selected from hydrochloric acid, sulfuric acid, acetic acid, nitric acid, and phosphoric acid may be used, and an aqueous hydrochloric acid solution is preferably used. When the amount of the acid aqueous solution is less than 1 equivalent, the reaction is not completed and the extraction is not completed completely after the completion of the reaction. Conversely, when the amount is more than 1 equivalent, the amount of the byproducts generated increases, .

As the carbon catalyst, at least one selected from activated carbon, graphite or graphene is used.

Next, 1 to 1.5 equivalents of a 10 wt% sodium hypochlorite (NaOCl) aqueous solution is slowly added dropwise while maintaining the temperature at 30 to 40 ° C. If the reaction temperature is lower than 30 ° C, the reaction hardly proceeds. On the other hand, if the reaction temperature exceeds 40 ° C, it is important to maintain the reaction temperature at 30 to 40 ° C.

When an aqueous solution of sodium hypochlorite (NaOCl) is added, an exothermic reaction occurs. Therefore, it is preferable to slowly drop to keep the reaction temperature. If the reaction time is longer than 1 hour, Be careful because it is easy to generate. When the reaction is completed, the carbon catalyst is filtered, and the residue is washed with an aqueous solution of sodium thiosulfate (Na ₂ S ₂ O ₃ ) to decompose and remove unreacted sodium hypochlorite (NaOCl).

Finally, the aqueous layer of the reaction solution and the organic layer were separated, dried over anhydrous sodium sulfate and concentrated, and then crystallized with a mixed solvent of ethyl acetate and a saturated hydrocarbon solvent to obtain 2- (4-formylphenyl) propionate Acid.

At this time, as the saturated hydrocarbon solvent used as a co-solvent, at least one selected from n-pentane, n-hexane, and n-heptane can be used. As the crystallization solvent, it is preferable to use a mixed solvent of ethyl acetate and n-heptane.

Hereinafter, an embodiment of the present invention will be described.

[Examples 1 to 13]

10 g of 2- [4- (hydroxymethyl) phenyl] propionic acid was placed in a reaction vessel of 250 ml, and 100 ml of the ester solvent shown in the following Table 1 was added thereto. 55.5 ml (1 eq.) Of a 1N aqueous acid solution was then added, followed by addition of a carbon catalyst (see Table 1) corresponding to 5-10% by weight of the starting material with stirring at 30 ° C.

Next, an aqueous solution of 10 wt% hypochlorous acid (NaOCl) was slowly added dropwise at a temperature of 30 to 40 ° C, stirred for 30 minutes, and then the carbon catalyst was filtered. The residue was washed with an aqueous solution of sodium thiosulfate (Na ₂ S ₂ O ₃ ) and the activity of hypochlorous acid was confirmed with KI starch paper.

After confirming that the activity of hypochlorous acid disappeared, the organic layer and the water layer were separated. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then crystallized with a mixed solvent of ethyl acetate and normal heptane to obtain a white solid The material was obtained. The yield and purity of the target material identified for each example are shown in Table 1 below.

Example

Carbon catalyst
reaction
menstruum
NaOCl
(equivalent weight) reaction
Temperature

Acid condition

yield

water
Kinds Addition amount One Activated carbon 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 93.0% 98.0% 2 Gra
Fight 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 92.9% 98.0% 3 Grapina 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 93.0% 98.0% 4 Activated carbon 10% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 93.0% 98.0% 5 Activated carbon 5% w / w Ethyl acetate 1.0 30 ~ 40 ℃ Hydrochloric acid 92.2% 97.5% 6 Activated carbon 5% w / w Ethyl acetate 1.5 30 ~ 40 ℃ Hydrochloric acid 92.1% 97.8% 7 Activated carbon 5% w / w Methyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 92.0% 97.9% 8 Activated carbon 5% w / w Propyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 91.8% 98.0% 9 Activated carbon 5% w / w Isopropyl acetate 1.2 30 ~ 40 ℃ Hydrochloric acid 91.8% 97.6% 10 Activated carbon 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Sulfuric acid 92.6% 97.9% 11 Activated carbon 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Acetic acid 91.8% 97.4% 12 Activated carbon 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ nitric acid 91.6% 97.5% 14 Activated carbon 5% w / w Ethyl acetate 1.2 30 ~ 40 ℃ Phosphoric acid 92.0% 96.9%

[Examples 14 to 15]

After the reaction was carried out under the same conditions as in Example 1, the target substance was obtained using the crystallization solvent shown in Table 2 below.

Crystallization solvent yield water Example 14 Ethyl acetate Normal pentane 92.6% 98.0% Example 15 Ethyl acetate Normal hexane 93.0% 97.9%

[Comparative Example]

In a reaction vessel of 250 ml, 10 g of 2- [4- (hydroxymethyl) phenyl] propionic acid was added, and 100 ml of ethyl acetate was added. Subsequently, 70 ml of 1N HCl was added and 46.7 ml (1.13 equivalents) of a 10 wt% aqueous hypochlorous acid solution (NaClO) were added at 30 ° C with stirring for 1 hour.

After standing at the same temperature for 10 minutes, the aqueous layer was separated, and the organic layer was washed with an aqueous solution of Na ₂ SO ₃ and the solvent was removed to separate the crystals. This crystal was recrystallized from 45 ml of carbon tetrachloride to obtain the target substance (yield 78%, purity 86%).

For reference, the comparative example was carried out by the method described in Japanese Laid-Open Patent Publication No. 04-368353, which was previously disclosed in the prior art.

[Nuclear Magnetic Resonance Spectrum Analysis]

NMR analysis of the 2- (4-formylphenyl) propionic acid compound obtained as the target material in Example 1 revealed that d 12.51 (s, 1H), 1H), 7.78 (d, 2H), 7.61 (d, 2H), 3.80 (m, 1H) and 1.39 (d, 3H). At this time, measurement conditions of nuclear magnetic resonance (NMR) are as follows.

1) Apparatus: Bruker AC NMR 200

2) Measuring range: -1.0 ~ 15 ppm

3) Number of scans: 16

From the nuclear magnetic resonance spectrum data of FIG. 1, it can be confirmed that the target substance prepared according to the present invention is pure 2- (4-formylphenyl) propionate. Further, from the results of the above Examples and Comparative Examples, it can be seen that the yield of the target substance is about 15% or more and the purity of the target substance is about 10 % ≪ / RTI > In addition, since no toxic carbon tetrachloride is used as the crystallization solvent, the working environment can be improved to a very environmentally friendly atmosphere.

Claims (6)

(a) dissolving 2- [4- (hydroxymethyl) phenyl] propionic acid in an ester solvent, adding thereto a 1N acid aqueous solution and a carbon catalyst selected from activated carbon, graphite or graphene;
(b) dropwise adding 1 to 1.5 equivalents of a 10% aqueous solution of sodium hypochlorite (NaOCl) to the 2- [4- (hydroxymethyl) phenyl] propionic acid at a temperature of 30 to 40 ° C and stirring Wow;
(c) filtering the carbon catalyst and washing the residue with an aqueous solution of sodium thiosulfate (Na ₂ S ₂ O ₃ ) to decompose and remove unreacted sodium hypochlorite (NaOCl);
(d) separating and concentrating the organic layer, and crystallizing with a mixed solvent of ethyl acetate and a saturated hydrocarbon solvent;
(4-formylphenyl) propionic acid using a carbon catalyst.
2. The method of claim 1, wherein the ester solvent used in step (a) is at least one selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate. Methylphenyl) propionic acid.
The method of claim 1, wherein the acid aqueous solution of step (a) is at least one selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and phosphoric acid. Methylphenyl) propionic acid.
delete delete The method according to any one of claims 1 to 3, wherein at least one selected from the group consisting of normal pentane, n-hexane, and n-heptane is used as the saturated hydrocarbon solvent in the step (d) - (4-formylphenyl) propionic acid.

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