JP2015063488A - Method of manufacturing 4-hydroxy-2-methylbenzoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing 4-hydroxy-2-methylbenzoic esters simply in a short time.SOLUTION: There is provided a method for manufacturing a 4-hydroxy-2-methylbenzoic acid derivative (1) by air oxidizing a 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (2) in a polyether-based solvent or an amide-based solvent in a presence of a platinum group catalyst. In the formula, Rrepresents hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group which may be substituted or a benzyl group which may be substituted, and Rrepresents an alkyl group having 1 to 6 carbon atoms or a benzyl group which may be substituted.

Description

  The present invention relates to a process for producing a 4-hydroxy-2-methylbenzoic acid derivative, and more particularly to a highly economical process for producing a 4-hydroxy-2-methylbenzoic acid derivative useful as a pharmaceutical intermediate.

4-hydroxy-2-methylbenzoic acid ester is used as an intermediate for drug candidates such as platelet aggregation inhibitors (fibrinogen receptor antagonists), and 4-hydroxy-2,6-dimethylbenzoic acid and its esters are Originally developed as an anti-adhesion agent for engine deposits, recently it was developed as a drug candidate substance such as airway hypersensitivity drug (PGD ₂ DP receptor antagonist), HIV infection drug (CCR-5 receptor antagonist), etc. Used as an important intermediate.

  Among the 4-hydroxy-2-methylbenzoic acid derivatives described above, 4-hydroxy-2-methylbenzoic acid esters having a substituent only at the 2-position are known to be obtained by various production methods. For example, the method by air oxidation of 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (Hagemann's ester) (Non-patent Documents 1 and 2), Reimer-Tiemann reaction with metatetrazole by carbon tetrachloride-copper-caustic soda (Patent Document 1, Non-Patent Document 3), a method of reacting Hagemann's ester with bromine in carbon disulfide (Non-Patent Document 4), cleavage reaction of acetophenone derivative with iodine / pyridine (Patent Document 2, Patent Document 3, Methods such as Patent Document 4 and Patent Document 5) are known.

  On the other hand, there are relatively few processes for preparing 4-hydroxy-2,6-dimethylbenzoates having substituents at the 6-position in addition to the 2-position, for example, Hagemann's ester with 2 equivalents of iodine in tert-butanol. Oxidation (Non-patent document 5), Grignard reaction of 4-bromo-3,5-dimethylphenol derivative (Non-patent document 6), Hagemann's ester reacted with bromine in carbon disulfide (Non-patent document 7), Hagemann's ester diethylene glycol A method such as a dehydrogenation reaction (Patent Document 6) refluxing with 3% palladium / chromium-alumina in butyl methyl ether is known.

  By the way, as described above, many methods for producing a 4-hydroxy-2-methylbenzoic acid derivative are known, but in practice, a 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (Hagemann's ester) Other than air oxidation and dehydrogenation reactions, there are drawbacks such as long reaction steps and low yields, and even in short steps, industrial methods such as using reagents with a large environmental impact such as carbon tetrachloride are used. As a problem.

  In contrast, 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivatives (Hagemann's ester) are easily produced by condensation and cyclization of methyl acetoacetate or other esters with aldehydes such as formaldehyde and acetaldehyde. Therefore, if these can be subjected to a dehydrogenation reaction or an air oxidation reaction to be aromatic cyclized, the corresponding 4-hydroxy-2-methylbenzoic acid derivative should be obtained, and the 4-hydroxy-2-methylbenzoic acid derivative As a raw material for the preparation of 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (Hagemann's ester) was expected to be preferable.

However, the dehydrogenation reaction generally requires a high temperature of 200 ° C. or higher. According to previous reports, ethyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate [in formula (2), R ₁ = CH ₃ , R ₂ = C ₂ H ₅ ] is refluxed with 5% palladium on charcoal in the absence of a solvent to cause a disproportionation reaction, and the desired 4-hydroxy-2-methylbenzoic acid derivative [the following formula (1), wherein R ₁ = CH ₃ , R ₂ = C ₂ H ₅ ] and a 1: 1 mixture of cyclohexanone derivatives in which the double bond of the starting compound is reduced. Therefore, using a special palladium catalyst, a solution of ethyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate in diethylene glycol butyl methyl ether (bp. 212 ° C.) is refluxed to obtain the target 4-hydroxy The only report was that a 2-methylbenzoic acid derivative was obtained (Patent Document 6). In this patent document, methyl 2-methyl-4-oxo-6-phenyl-2-cyclohexenecarboxylate [in formula (2) described below, R ₁ = Ph, R ₂ = CH ₃ ] is triethylene glycol dimethyl ether. A cyclohexanone derivative which caused a disproportionation reaction when heated to 220 ° C. with 5% palladium on charcoal and reduced the double bond of the starting compound together with the dehydrogenated 4-hydroxy-2-methylbenzoic acid derivative, which is the target product It has also been reported that a mixture of

On the other hand, air oxidation proceeds at a lower temperature than the dehydrogenation reaction and has the advantage of greatly reducing the environmental burden compared to the normal oxidation reaction. However, the conventional method requires a long reaction time using a complex system. It was. That is, as a method using air oxidation for the 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative, ethyl 2-methyl-4-oxo-2-cyclohexenecarboxylate [in formula (2), R ₁ = H, R ₂ = C ₂ H ₅ ] only has been reported, and this method is based on a palladium trifluoroacetate system using 2-dimethylaminopyridine as a ligand in p-toluenesulfone in dimethyl sulfoxide. Complex system such as heating in air with acid for 24 hours (Non-patent document 1) or heating in excess of tetrabutylammonium bromide-vanadium sulfate-trifluoroacetic acid in dimethyl sulfoxide for 14 hours (Non-patent document 2) For a long time, whereby ethyl 4-hydroxy-2-methylbenzoate [described below] (1) _was to obtain R _{1 =} H, the R _{2 =} C _{2 H 5]} in 79-89% yield.

  Further, for compounds having substituents at the 2-position and 6-position, such as 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylic acid derivatives, the corresponding 4-hydroxy-2,6-dimethylbenzoate An efficient production method for acid derivatives has not been reported.

JP 10-017469 A US5854245 WO9800134 EP481671 FR25000825 EP49848 JP 09-031023 WO060105964

Science, 333,209 (2011) Tetrahedron Lett., 50, 7385 (2009) Indian J. Chem., Section B, 30B, 800 (1991) Indian J. Chem., Section B, 26B, 679 (1987) ARKIVOC, (4), 104-124 (2010) J. Org. Chem., 50, 1867 (1985) Indian J. Chem., Section B, 19B, 191 (1980) J. Am. Chem. Soc., 113, 1614 (2011)

  Therefore, the present invention provides 4-hydroxy-2-methylbenzoic acid derivatives, particularly 4-hydroxy-2,6-dimethylbenzoic acid esters having a substituent at the 6-position in addition to the 2-position, in a simple and short time. It is an object of the present invention to provide a method that can be manufactured by the above method.

  The present inventors focused on the possibility of air oxidation in the production of 4-hydroxy-2-methylbenzoic acid derivatives, and have conducted extensive studies to solve the above problems. According to this method, a 4-hydroxy-2-methylbenzoic acid derivative can be efficiently produced from a 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative in a simple system using a solvent. It was found that a 4-hydroxy-2-methylbenzoic acid derivative having a substituent at the position can also be obtained efficiently, and the present invention was completed.

（式中、Ｒ_１は水素、炭素数１ないし６のアルキル基、置換されていても良いフェニル基、また
は置換されていても良いベンジル基を示し、Ｒ_２は、炭素数１ないし６のアルキル基または置
換されていても良いベンジル基を示す）
で表される２−メチル−４−オキソ−２−シクロヘキセンカルボン酸誘導体を、ポリエーテル系溶剤またはアミド系溶剤中、白金族触媒の存在下で空気酸化することを特徴とする一般式（１）

（式中、Ｒ_１およびＲ_２は前記した意味を有する）
で表される４−ヒドロキシ−２−メチル安息香酸誘導体の製法である。 That is, the present invention relates to the general formula (2)

(Wherein R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group,
Represents an optionally substituted benzyl group, and R ₂ represents an alkyl group having 1 to 6 carbon atoms or an optionally substituted benzyl group)
A general formula (1), characterized in that a 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative represented by the formula (1) is oxidized in air in the presence of a platinum group catalyst in a polyether solvent or an amide solvent:

(Wherein R ₁ and R ₂ have the above-mentioned meanings)
It is a manufacturing method of 4-hydroxy-2-methylbenzoic acid derivative represented by these.

  According to the present invention, the 4-hydroxy-2-methylbenzoic acid derivative (1), which is the target product, can be produced at a very high conversion rate even at a low reaction temperature and at a low oxygen concentration. Moreover, the formation of other by-products is suppressed.

  Therefore, the method of the present invention can produce a 4-hydroxy-2-methylbenzoic acid derivative (1) that is particularly useful as an intermediate of a pharmaceutical product safely and economically.

  In the present invention, as shown in the following reaction formula, 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (2) is oxidized in air in the presence of a platinum group catalyst in a polyether solvent or an amide solvent. And 4-hydroxy-2-methylbenzoic acid derivative (1).

（式中、Ｒ_１およびＲ_２は前記した意味を有する）

(Wherein R ₁ and R ₂ have the above-mentioned meanings)

  The 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (2), which is a raw material of the present invention, is represented by the following formula according to, for example, a known method (Patent Document 7, Non-Patent Documents 5, 8, etc.). The aldehyde compound of formula (3) and the acetoacetate ester represented by formula (4) are reacted at a molar ratio of 1: 2 in the presence of a base to give 2-oxocyclohexane-1 of formula (5) , 5-dicarboxylic acid ester, which is then further dehydrated and decarboxylated.

（式中、Ｒ_１およびＲ_２は前記した意味を有する）

(Wherein R ₁ and R ₂ have the above-mentioned meanings)

In the compound (2), the alkyl group having 1 to 6 carbon atoms in the groups R ₁ and R ₂ includes a methyl group, an ethyl group, a propyl group, an i-propyl group, a butyl group, an i-butyl group, 2 -Butyl group, pentyl group, 2-pentyl group, 2-methylbutyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, cyclopentyl group, hexyl group, 2-hexyl group, 3-hexyl group, 2-methylpentyl Group, 3-methylpentyl group, 4-methylpentyl group, 2-ethylpropyl group, cyclohexyl group, etc., as substituents for benzyl group or phenyl group in groups R ₁ and R ₂ , hydroxyl group, methoxyl group Nitro group, amino group, acetylamino group, formylamino group, benzoylamino group, methanesulfonylamino group, p-toluenesulfonyla Group, N-acetyl-N-methylamino group, N-formyl-N-methylamino group, N-benzoyl-N-methylamino group, N-methanesulfonyl-N-methylamino group, N-methyl-N- Examples include p-toluenesulfonylamino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group and the like.

  On the other hand, examples of the catalyst used in the present invention include a platinum group catalyst using a platinum group metal, that is, a platinum catalyst, a palladium catalyst, a ruthenium catalyst, and the like. Of these, a platinum catalyst and a palladium catalyst are preferably used, and more preferably a palladium catalyst. As this palladium catalyst, a commercially available palladium catalyst such as palladium black, palladium acetate, palladium chloride, palladium on charcoal and the like can be used.

  The amount of the catalyst used varies slightly depending on the type and the content of the platinum group metal in the catalyst. For example, when 10% palladium on charcoal is used as the catalyst, 0.01% of the compound (2) as the substrate is used. -20% by mass (hereinafter simply indicated as "%"), preferably 0.1 to 10%. The palladium charcoal used here can be either dry or hydrous palladium charcoal, and does not require any special pretreatment.

  Furthermore, in the present invention, good results can be obtained only by using a polyether solvent or an amide solvent (hereinafter sometimes referred to as “polar solvent”) as the solvent, and other solvents may be used. No result is obtained.

Among these polar solvents, examples of polyether solvents include ethylene glycol, diethylene glycol, triethylene glycol and their monoalkyl ethers, or dialkyl ethers and monoacetyl monoalkyl ethers. Preferred alkyl groups in these ethers include C ₁ -C ₆ linear, branched, or cyclic alkyl groups. Among these, specific examples of particularly preferred polyether solvents include ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, triethylene glycol monomethyl ether, and triethylene glycol dimethyl ether.

  On the other hand, preferred specific examples of the amide solvent include N, N-dimethylformamide and N, N-dimethylacetamide.

  In the reaction of the present invention, the compound (2) is air-oxidized in the polar solvent in the presence of a platinum group catalyst to form the compound (1). This can be done in a conventional manner.

  When the reaction is carried out continuously, a part of the catalyst may be continuously or intermittently removed from the reactor, regenerated, and then recycled to the reactor again. Further, when the reaction is carried out batchwise, the catalyst separated and recovered from the reaction product containing the compound (1) after the reaction may be regenerated in whole or in part and repeatedly used as a catalyst for the reaction. it can.

  As the oxygen source for air oxidation in the present invention, oxygen and oxygen-containing gas can be used in addition to air. For example, high-purity oxygen gas with an oxygen concentration of 100% by volume or close thereto may be used, but this is diluted with a gas inert to the reaction, such as nitrogen, helium, argon, carbon dioxide, etc., and supplied to the reaction system It is preferable to do this. However, in this reaction, not only is it very economically advantageous, but it is also possible to effectively oxidize the substrate by using air as an oxygen source, which can reduce the risk of explosion occurring in the case of industrialization. it can.

  The oxygen concentration in the oxygen source is, for example, about 5 to 100% by volume, preferably about 5 to 20% by volume. The air oxidation of the present invention proceeds effectively even at a low oxygen concentration. The reaction pressure may be increased, but is preferably atmospheric pressure.

  When supplying molecular oxygen into the reaction vessel, after supplying sufficient molecular oxygen in advance, the reaction may be performed in a closed system, or the molecular oxygen may be continuously circulated. Good.

  In the present invention, the concentration of the compound (2) as a substrate in the reaction system is about 10 to 75%, preferably 15 to 50%. Since the oxidation reaction can be performed even at such a high concentration, it is extremely useful industrially.

  In addition, the air oxidation reaction proceeds at a temperature of about 100 to 200 ° C., but a condition around 110 to 160 ° C. is particularly preferable.

  In the above-described method of the present invention, water is generated by air oxidation, but if this water is stored in the reaction system as it is, not only the reaction is inhibited but also a by-product may be generated. For this reason, in order to advance reaction smoothly, it is preferable to remove | eliminate the produced | generated water continuously. For the removal of the produced water, it is preferable to use an apparatus / apparatus that does not return the distilled liquid to the reaction system, such as a distillation apparatus. Further, the reflux liquid may be dehydrated by passing it through a hygroscopic agent such as molecular sieves or zeolite.

  The 4-hydroxy-2-methylbenzoic acid derivative (1) produced by the above reaction of the present invention can be purified as necessary to have a higher purity. Examples of the purification means include conventional separation means, for example, separation means such as filtration, concentration, distillation, extraction, crystallization, recrystallization, column chromatography, etc., or a combination means in combination of these. The compound (1) can be easily separated and purified from the remaining raw materials and by-products.

  In particular, in the present invention, the conversion rate from the raw material compound (2) to the target compound (1) is very high, and the by-product of other by-products is remarkably suppressed. The filtrate after being filtered off is dropped into an aqueous solution of an inorganic salt such as sodium chloride, or the aqueous solution of an inorganic salt is dropped into the filtrate so that the high-purity compound (1) is crystallized or powdered. The efficiency is very high because it is obtained.

  In the case of sodium chloride, the concentration of the inorganic salt in the aqueous solution used in the crystallization or pulverization step is preferably about 1 to 25%, particularly preferably 3 to 10%. The amount of the inorganic salt aqueous solution is about 5 to 20 times the volume of the reaction solution, and it is particularly preferable to use 7 to 15 times the inorganic salt aqueous solution. The temperature of the aqueous inorganic salt solution during crystallization or pulverization is not particularly limited, but is preferably 0 to 70 ° C.

Of the 4-hydroxy-2-methylbenzoic acid derivative (1) obtained as described above, methyl 4-hydroxy-2-methylbenzoate in which R _{1 at} the 6-position is a hydrogen atom and R ₂ is a methyl group (Compound (1a)) can be made into an amidinophenylisoindoline compound represented by formula (7) by, for example, modifying its hydroxyl group to (6) and further chemical conversion. The compound is a platelet aggregation inhibitor candidate substance having a fibrinogen receptor antagonistic action (see Patent Document 1).

Of 4-hydroxy-2-methylbenzoic acid derivative (1), methyl 4-hydroxy-2,6-dimethylbenzoate (compound (1b)) in which R ₁ and R _{2 at the} 6-position are methyl groups The compound represented by the formula (9) can be synthesized by converting the hydroxyl group into a hydrogen atom, 4-pyridyl group or the like to obtain a compound (8), and further amidating. This compound is an HIV infection drug candidate substance having a selective CCR-5 receptor antagonistic action (Patent Document 8).

（式中、Ｒ_３は水素原子、ピリジル基等を示し、Ｒ_４は水素原子、低級アルコキシ基を示す）

(Wherein R ₃ represents a hydrogen atom, a pyridyl group or the like, and R ₄ represents a hydrogen atom or a lower alkoxy group)

  Thus, the compound (1) obtained by the method of the present invention is useful as an intermediate for various pharmaceuticals.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples. In the following examples, the reaction and product were traced by high performance liquid chromatography (HPLC), and the production rate and purity were indicated by area percentage (area%). The separation column was Inertsil ODS-2 (5 μm, 6.4 × 150 mm; manufactured by GL Science), and the UV wavelength of the detector was measured at 254 nm. Elution was performed at a flow rate of 1 mL / min, water (0.1% phosphoric acid) was used as the solution A as the solvent, acetonitrile was used as the solution B, and a linear gradient of 30 to 90% by volume of the solution B from 0 to 20 minutes was obtained. Up to -25 minutes was performed with 90% by volume of B liquid.

Example 1
Synthesis of methyl 4-hydroxy-2-methylbenzoate:
The title compound was synthesized by air oxidation using a personal organic synthesizer ChemStation PPS-2511 (manufactured by Tokyo Rika Kikai Co., Ltd.) as a reaction device.

Raw material compound, methyl 2-methyl-4-oxo-2-cyclohexenecarboxylate [in formula (2), R ₁ = H, R ₂ = CH ₃ ] (730 mg) of N, N-dimethylacetamide (DMA; (bp. 165 ° C.) solution (4 mL) was placed in the reactor, and 10% palladium on charcoal (water 50%; 100 mg) was added. This reaction system was reacted at 150 ° C. with heating and stirring for 2 hours, and then the amount of methyl 4-hydroxy-2-methylbenzoate (target compound (1)) and the amount of raw material (2) in the reaction mixture. Was analyzed by HPLC. As a result, the yield of the target compound (1) was 94.8%, and the residual ratio of the raw material compound (2) was 0.1%.

  In this example to Example 11 and the comparative example, the air oxidation is performed by performing the reaction in an open system when the raw material compound is 1 g or less, and when the raw material compound exceeds 1 g, the air oxidation is performed. In order to make it proceed smoothly, excess air was blown onto the surface of the reaction mixture using a small blower, or was blown into the reaction mixture. Furthermore, when the raw material compound was 1 g or less, water produced in the reaction was refluxed at the top of the reaction vessel and did not return to the reaction system, so it was not particularly removed, but in the reaction when the raw material compound exceeded 1 g. The produced water was continuously removed with a distillation apparatus.

Example 2
The reaction was conducted in the same manner as in Example 1 except that the solvent of methyl 2-methyl-4-oxo-2-cyclohexenecarboxylate was changed to diethylene glycol monomethyl ether (DEGM; bp. 194 ° C.). As a result, the yield of the target compound (1) was 89.0%, and the residual ratio of the raw material compound (2) was 0.4%.

Example 3
The same as Example 1 except that the solvent of methyl 2-methyl-4-oxo-2-cyclohexenecarboxylate was changed to N, N-dimethylformamide (DMF; bp. 153 ° C.) and the reaction time was 7.5 hours. The reaction was performed. As a result, the yield of the target compound (1) was 87.6%, and the residual ratio of the raw material compound (2) was 7.0%.

Examples 4-7
As a raw material compound, methyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate [in formula (2), R ₁ = CH ₃ , R ₂ = CH ₃ ] was used in the same weight as in Example 1, and the solvent used The air oxidation was performed in the same manner as in Example 1 except that the reaction time was changed as shown in the table below. The yield of the target compound (1) and the residual ratio of the raw material compound (2) in the reaction product obtained as a result are also shown in the same table.

Examples 8 and 9
As a raw material compound, ethyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate [in formula (2), R ₁ = CH ₃ , R ₂ = C ₂ H ₅ ] was used in the same weight as in Example 1, Air oxidation was performed in the same manner as in Example 1 except that the solvent used and the reaction time were changed as shown in the table below. The yield of the target compound (1) and the residual ratio of the raw material compound (2) in the reaction product obtained as a result are also shown in the same table.

Examples 10 and 11
As a raw material compound, methyl 2-methyl-4-oxo-6-phenyl-2-cyclohexenecarboxylate [in formula (2), R ₁ = Ph, R ₂ = CH ₃ ] was used in the same weight as in Example 1. Air oxidation was performed in the same manner as in Example 1 except that the solvent and reaction time were changed as shown in the table below. The yield of the target compound (1) and the residual ratio of the raw material compound (2) in the reaction product obtained as a result are also shown in the same table.

Comparative Example 1
The reaction was conducted in the same manner as in Example 1 except that methyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate was used as a starting compound, no solvent was used, and the reaction time was 17 hours. It was. As a result, the yield of the target compound (1) was 26.0%, and the residual ratio of the raw material compound (2) was 31.3%.

Comparative Example 2
Using methyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate as a raw material compound, using 4-methyl-2-pentanone (MIBK; bp. 117 ° C.) as a solvent, the reaction temperature is 115 ° C., The reaction was conducted in the same manner as in Example 1 except that the reaction time was 24 hours. As a result, the yield of the target compound (1) was 1.3%, and the residual ratio of the raw material compound (2) was 85.7%.

Comparative Example 3
The reaction was performed in the same manner as in Comparative Example 2 except that acetic acid was used as the solvent. As a result, the yield of the target compound (1) was 5.0%, and the residual ratio of the raw material compound (2) was 53.1%.

Example 12
Production of methyl 4-hydroxy-2,6-dimethylbenzoate:
DMF (11 mL) was added to methyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate (2.00 g), and 10% palladium on charcoal (water 50%; 273 mg) was further added to this solution. The mixture was heated and stirred at 150 ° C. for 24 hours while blowing excess air onto the surface of the reaction mixture with a small blower.

The reaction mixture was filtered, and the filtrate was added dropwise to 5% brine (90 mL), followed by stirring at room temperature to 10 ° C. for 2 hours. The precipitate was filtered and dried to obtain a light brown powder of methyl 4-hydroxy-2,6-dimethylbenzoate [in formula (1), R ₁ = R ₂ = CH ₃ ] at a yield of 90% (purity 90 0.7%).

Example 13
Production of methyl 4-hydroxy-2,6-dimethylbenzoate:
The same treatment as in Example 12 was carried out except that DMA was used in place of DMF and the reaction time was 7.5 hours to obtain the title compound in 85% yield (purity 99.4%).

Example 14
Production of methyl 4-hydroxy-2,6-dimethylbenzoate:
The same treatment as in Example 12 was conducted, except that DEGM was used instead of DMF as the solvent and the reaction time was 23 hours, whereby the title compound was obtained in a yield of 78% (purity 99.4%).

Example 15
Production of methyl 4-hydroxy-2-methylbenzoate:
DMF (4 mL) was added to methyl 2-methyl-4-oxo-2-cyclohexenecarboxylate (730 mg), and 10% palladium on charcoal (water 50%; 100 mg) was further added to this solution. This was heated and stirred at 150 ° C. for 7.5 hours while blowing excess air onto the surface of the reaction mixture with a small blower.

The reaction mixture was filtered, and the filtrate was added dropwise to 5% brine (50 mL), followed by stirring at room temperature to ice cooling. The precipitate was filtered and dried to give a light brown powder of methyl 4-hydroxy-2-methylbenzoate (in formula (1), R ₁ = H, R ₂ = CH ₃ ) in a yield of 43% (purity 97 0.9%).

Example 16
Production of methyl 4-hydroxy-2-methylbenzoate:
The title compound was obtained in 50% yield (purity 97.0%) by conducting the same treatment as in Example 15 except that DMA was used instead of DMF and the reaction time was 2 hours.

Example 17
Production of methyl 4-hydroxy-2-methylbenzoate:
The same treatment as in Example 15 was performed, except that DEGM was used instead of DMF as the solvent and the reaction time was 2 hours, to give the title compound in 52% yield (purity 93.0%).

Example 18
Preparation of methyl 4-hydroxy-2-methyl-6-phenylbenzoate:
To methyl 2-methyl-4-oxo-6-phenyl-2-cyclohexenecarboxylate (730 mg) was added DMF (4 mL), and 10% palladium on charcoal (water 50%; 100 mg) was further added to this solution. This was heated and stirred at 150 ° C. for 24 hours while excess air was blown onto the reaction mixture surface with a small blower.

The reaction mixture was filtered, and the filtrate was added dropwise to 5% brine (50 mL), followed by stirring at room temperature to ice cooling. The precipitate was filtered and dried to obtain 96% yield of methyl 4-hydroxy-2-methyl-6-phenylbenzoate [in formula (1), R ₁ = Ph, R ₂ = CH ₃ ] as a light brown powder. (Purity 73.5%).

Example 19
Preparation of methyl 4-hydroxy-2-methyl-6-phenylbenzoate:
The same treatment as in Example 18 was carried out, except that DEGM was used instead of DMF as the solvent and the reaction time was 6.5 hours, whereby the title compound was obtained in a yield of 97% (purity: 93.3%).

Example 20
Production of methyl 4-hydroxy-2,6-dimethylbenzoate:
DEGM (2 mL) was added to methyl 2,6-dimethyl-4-oxo-2-cyclohexenecarboxylate (730 mg), and 10% palladium on charcoal (water 50%; 50 mg) was further added to the solution. Air in which oxygen concentration was adjusted to 10% with nitrogen was put into an air bag, and this was heated and stirred at 150 ° C. for 4 hours while blowing excess air onto the reaction mixture surface with a small blower. The amount of methyl 4-hydroxy-2,6-dimethylbenzoate (target compound (1)) and the amount of raw material (2) in the reaction mixture were analyzed by HPLC. As a result, the yield of the target compound (1) was 90.2%, and the residual ratio of the raw material compound (2) was 0.3%.

  According to the present invention, the 4-hydroxy-2-methylbenzoic acid derivative (1), which is the target product, is suppressed from producing other byproducts even at a low reaction temperature and at a low oxygen concentration. It is produced at a very high conversion rate.

  And since the compound (1) obtained by this method can be used as an intermediate for the production of pharmaceuticals such as platelet aggregation inhibitors and HIV infection agents, the present invention is widely used in the field of pharmaceutical production. It can be done.

Claims (10)

The following general formula (2)

(In the formula, R ₁ represents hydrogen, an alkyl group having 1 to 6 carbon atoms, an optionally substituted phenyl group, or an optionally substituted benzyl group, and R ₂ represents an alkyl having 1 to 6 carbon atoms. Group or an optionally substituted benzyl group)
A general formula (1), characterized in that a 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative represented by the formula (1) is oxidized in air in the presence of a platinum group catalyst in a polyether solvent or an amide solvent:

(Wherein R ₁ and R ₂ have the above-mentioned meanings)
A process for producing a 4-hydroxy-2-methylbenzoic acid derivative represented by the formula:   The method for producing a 4-hydroxy-2-methylbenzoic acid derivative according to claim 1, wherein the air oxidation is performed in an atmosphere of oxygen diluted with air or an inert gas or in an air flow thereof.   3. The 4-type solvent according to claim 1, wherein the polyether solvent is a solvent selected from the group consisting of ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, triethylene glycol monomethyl ether and triethylene glycol dimethyl ether. A method for producing a hydroxy-2-methylbenzoic acid derivative.   The process for producing a 4-hydroxy-2-methylbenzoic acid derivative according to claim 1 or 2, wherein the amide solvent is N, N-dimethylformamide or N, N-dimethylacetamide.   The process for producing a 4-hydroxy-2-methylbenzoic acid derivative according to any one of claims 1 to 4, wherein the platinum group catalyst is a palladium catalyst selected from palladium black, palladium acetate, palladium chloride and palladium charcoal.   The process for producing a 4-hydroxy-2-methylbenzoic acid derivative according to any one of claims 1 to 5, wherein the reaction temperature is 110 to 160 ° C.   The method for producing a 4-hydroxy-2-methylbenzoic acid derivative according to any one of claims 1 to 6, wherein an oxygen concentration of an oxygen source used for air oxidation is 5 to 20% by volume.   The 4-platinum catalyst is used in an amount of 0.1 to 10% by mass based on the 2-methyl-4-oxo-2-cyclohexenecarboxylic acid derivative (2). A method for producing a hydroxy-2-methylbenzoic acid derivative.   Furthermore, the platinum group catalyst is removed after completion of the air oxidation reaction, and the resulting reaction solution is diluted with an aqueous inorganic salt solution to obtain 4-hydroxy-2-methylbenzoic acid derivative (1) as crystals or powder. A process for producing a 4-hydroxy-2-methylbenzoic acid derivative according to any one of claims 1 to 8. The process for producing a 4-hydroxy-2-methylbenzoic acid derivative according to claim 1, wherein water produced by the air oxidation reaction is continuously removed.