KR101393010B1 - A process for preparing 2-(4-formylphenyl)propionic acid by using TEMPO catalyst - Google Patents

Abstract

The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid using a TEMPO catalyst, and more particularly, to a process for preparing 2- (4-formylphenyl) (4- (hydroxymethyl) phenyl] propionic acid, which is a starting material, is oxidized with an aqueous solution of sodium hypochlorite (NaOCl) to produce a high purity 2- - < / RTI > formylphenyl) propionic acid in high yield.

Description

[0001] The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid by using TEMPO catalyst,

The present invention relates to a process for preparing 2- (4-formylphenyl) propionic acid using a TEMPO catalyst, and more particularly, to a process for preparing 2- (4-formylphenyl) (4- (hydroxymethyl) phenyl] propionic acid, which is a starting material, is oxidized with an aqueous solution of sodium hypochlorite (NaOCl) to produce a high purity 2- - < / RTI > formylphenyl) propionic acid in high yield.

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.

In addition, the pellets of the final product, pellubiprofen, which have not been completely removed during the purification process, are reduced in purity. Further, since carbon tetrachloride used in the crystallization process is classified as a substance having high hepatotoxicity, Can not be guaranteed.

1. Patent Publication No. 04-368353

Accordingly, a problem to be solved by the present invention is to provide a process for preparing 2- (4-formylphenyl) propionic acid which is a production intermediate of felubipropene, wherein TEMPO (2,2,6,6-tetramethylpiperidinyloxy free radical) And to provide a new production method capable of producing a high purity target substance at a high efficiency at a low cost in an environment friendly environment using a catalyst.

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, 0.01 to 0.1 equivalent of TEMPO (2,2,6,6-tetramethylpiperidinyl oxy free radical) catalyst to 4- (hydroxymethyl) phenyl] propionic acid; (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 10 to 40 ° C and stirring Wow; (c) 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 preparation of 2- (4-formylphenyl) propionic acid by reacting 2- [4- (hydroxymethyl) phenyl] propionic acid as a starting material with 2,2,6,6-tetramethylpiperidinyl oxidation reaction with an aqueous solution of sodium hypochlorite (NaOCl) under an oxygen free radical catalyst enables the yield of the target material to be improved by about 15% or more and the purity of the target material by about 10% or more, 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 TEMPO 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.

Then, 0.01 to 0.1 equivalent of TEMPO (2,2,6,6-tetramethylpiperidinyl oxy free radical) catalyst is added to the 2- [4- (hydroxymethyl) phenyl] propionic acid. The TEMPO, which is a stable form of radical compound, is a sublimable red solid and is mainly used as an oxidation catalyst for alcohol. The aldehyde or carboxylic acid is produced according to the paired oxidizing agent and has an activity to selectively oxidize the primary alcohol.

If the amount of the TEMPO catalyst used is less than 0.01 equivalent, the reaction rate is slowed and the yield is reduced. On the other hand, if it is 0.1 equivalents or more, the reaction rate is increased and side reactants are produced, and the cost efficiency is reduced due to the nature of TEMPO having a high cost.

Next, a 10 wt% aqueous solution of sodium hypochlorite (NaOCl) is slowly added dropwise while maintaining the temperature at 10 to 40 ° C. If the reaction temperature is less than 10 ° C, the solid is precipitated in the course of the reaction and stirring and reaction progress are difficult. On the other hand, if the reaction temperature exceeds 40 ° C, side reactants are formed.

When an aqueous solution of sodium hypochlorite (NaOCl) is added, an exothermic reaction occurs. In order to maintain the reaction temperature, it is preferable to slowly drop the reaction mixture. When the reaction time is increased to 1 hour or more, Is easy to generate.

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 9]

15 g of 2- [4- (hydroxymethyl) phenyl] propionic acid was placed in a reaction vessel of 250 ml, and 150 ml of the ester solvent shown in Table 1 below was added. Then, a 10 wt% aqueous solution of sodium hypochlorite (NaOCl) was slowly added dropwise at a temperature of 10 to 40 ° C, and the mixture was stirred for 30 minutes. Then, an organic layer and a water layer Respectively.

The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a mixed solvent of ethyl acetate and a saturated hydrocarbon solvent was used as a crystallization solvent to obtain a white solid object compound. The yield and purity of the target material identified for each example are shown in Table 1 below.

Example TEMPO
Catalyst
(equivalent weight) reaction
menstruum NaOCl
(equivalent weight) reaction
Temperature Crystallization solvent yield water One 0.01 Ethyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate N-heptane 95.0% 99.0% 2 0.01 Ethyl acetate 1.0 30 ~ 40 ℃ Ethyl acetate N-heptane 93.3% 98.5% 3 0.01 Ethyl acetate 1.5 10 ~ 30 ℃ Ethyl acetate N-heptane 93.0% 98.0% 4 0.1 Ethyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate N-heptane 94.3% 99.0% 5 0.01 Methyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate N-heptane 93.0% 98.7% 6 0.01 Propyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate N-heptane 94.0% 98.8% 7 0.01 Isopropyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate N-heptane 93.8% 98.7% 8 0.01 Ethyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate Normal pentane 93.7% 98.5% 9 0.01 Ethyl acetate 1.0 10 ~ 30 ℃ Ethyl acetate Normal hexane 93.7% 98.6%

In Table 1, the equivalent of the TEMPO catalyst and sodium hypochlorite (NaOCl) represents the relative value to the mole of the starting material 2- [4- (hydroxymethyl) phenyl] propionic acid.

[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 12.50 (s, 1H), 1H), 7.58 (d, 2H), 7.53 (d, 2H), 3.83 (m, 1H) and 1.40 (d, 3H). At this time, measurement conditions of nuclear magnetic resonance (NMR) are as follows.

1) Apparatus: Bruker Model DRX NMR 400

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 carbon tetrachloride is used as a crystallization solvent, the working environment can be improved to a highly environmentally friendly atmosphere.

Claims (4)

(a) 2- [4- (hydroxymethyl) phenyl] propionic acid is dissolved in an ester solvent and thereto is added 0.01 to 0.1 equivalent of TEMPO ( 2,2,6,6-tetra methyl piperidinyl oxy free radical) catalyst;
(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 10 to 40 ° C and stirring Wow;
(c) 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 TEMPO catalyst.
The process according to 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.
delete The process according to claim 1 or 2, wherein the saturated hydrocarbon solvent in step (c) is at least one selected from the group consisting of n-pentane, n-hexane and n-heptane. Formylphenyl) propionic acid.

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