JP3008296B2 - Method for producing diaryl glycolic acid - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing 2,2-diaryl glycolic acid, which comprises oxidizing 1,1-diaryl ethylene glycol with oxygen. .

Among the diaryl glycolic acids, there are many compounds useful as raw materials for organic synthesis or intermediate raw materials for pharmaceuticals. For example, diphenyl glycolic acid (also called benzylic acid) is a compound used as an intermediate for producing diphenine hydrochloride, benactidine hydrochloride, mepenzolate bromide, pipenzolate methyl bromide, etc., which are used as parasympathetic nerve depressants.

[Prior Art] Among these compounds, benzyl acid will be described as an example.

Benzyl acid is very useful, and various production methods have been proposed. For example, methods such as benzylic acid rearrangement, electrolytic reduction carboxylation of benzophenone, oxidation of diphenylacetic acid, and oxidation of diphenylglycolaldehyde are known. Among them, a production method using benzylic acid rearrangement, which is also practiced by industrial enemies, is a method in which an alcohol solution of caustic potassium or a concentrated aqueous solution is applied to benzyl and heated [Organic Synthesis, Vol. 1, 29, (192)
1)].

[Problems to be Solved by the Invention] Although the reaction of the above method itself is simple, benzyl as a raw material is usually added with potassium cyanide to an ethanol solution of benzaldehyde, boiled to benzoin, and further oxidized. Manufactured. As described above, the synthesis of the raw material is dangerous using toxic potassium cyanide, and the raw material is expensive, so that it cannot be said that it is still sufficient for an industrial production method.

Further, there is no example of synthesizing benzylic acid directly by oxidation of glycol as in the present invention.

For example, there is a method for producing hydroxyacetic acid by oxidizing ethylene glycol in an alkaline aqueous solution in the presence of a platinum catalyst (Tetrahedron Letters, 9 , 67-75).
(1960)). However, when ethylene glycol is used as a substrate, the hydroxyl group of the obtained hydroxyacetic acid, which is the target substance, is easily oxidized, and eventually becomes oxalic acid, which is a higher oxide. For this purpose, the progress of the oxidation must be precisely controlled.

A method of oxidizing ethylene glycol under non-alkali conditions has also been proposed (JP-A-53-46916). However, in the case of oxygen oxidation of 1,1-diarylethylene glycol, the yield was extremely reduced under non-alkali conditions, and it was found from the experiments of the present inventors that the yield was not appropriate.

Therefore, the present invention relates to an easily available raw material
The present invention also provides a method for producing, for example, benzylic acid from diarylethylene glycol in high yield, and further provides a method for producing diarylglycolic acid, which is useful as an intermediate material for various agricultural chemicals and pharmaceuticals. .

[Means for Solving the Problems] The present invention is useful as an intermediate material for pharmaceuticals and the like.
The present invention relates to a method for producing 2-diaryl glycolic acid with high yield from easily available inexpensive raw materials.

That is, the present invention provides a mixture of 1,1-diarylethylene glycol and a sufficient amount of a base to make the reaction system basic at a temperature of 0 to 200 ° C. in the presence of a transition metal catalyst.
The present invention relates to a method for producing 2,2-diaryl glycolic acid, which is oxidized by molecular oxygen.

 Next, the present invention will be described in detail.

The raw material of the present invention is 1,1-diarylethylene glycol represented by the following general formula (I).

Here, Ar ₁ or Ar _{2 in the following} formula represents an aryl group which may have a substituent, such as a phenyl group, a naphthyl group, and a biphenylyl group, and may be the same or different. The aryl group is selected from the group consisting of halogen atoms such as chlorine, fluorine, bromine and iodine, lower alkyl groups such as nitro group, amino group, methyl group and ethyl group, and lower alkoxy groups such as methoxy group and ethoxy group. It may be substituted with 1 to 3 substituents.

Specific examples of 1,1-diarylethylene glycol include 1,1-diphenylethylene glycol, 1,1-bischlorophenylethylene glycol, 1,1-phenylpyridylethylene glycol, 1,1-phenyltolylethylene glycol, Examples thereof include 1, -phenylmethoxyphenylethylene glycol, 1,1-phenylnitrophenylethylene glycol, and 1,1-phenylnaphthylethylene glycol.

The 2,2-diaryl glycolic acid that can be produced according to the present invention is represented by the following general formula (II).

In the formula, Ar ₁ and Ar ₂ represent the same substituent as in the above formula (I).

In the diaryl glycolic acid produced by the method of the present invention, the aromatic substituent of the above formula (I) is preserved as it is.

Specifically, for example, benzylic acid (2,2-diphenylglycolic acid) is derived from 1,1-diphenylethylene glycol, and 2,2-phenyltolylglycolic acid is derived from 1,1-phenyltolylethylene glycol. Obtained respectively.

In the present invention, a catalyst is used for the purpose of accelerating the reaction. Catalysts include transition metals, for example, platinum, palladium, rhodium, ruthenium, rhenium, iridium,
Nickel, iron, cobalt, copper and mixtures thereof are used, and their oxides, sulfides, chlorides and the like, and salts thereof are also used. The catalyst is preferably platinum. The transition metal is a transition metal of any oxidation number,
It can be used in the present invention without any problems. Further, the catalyst may be one supported on a suitable inert carrier such as activated carbon, diatomaceous earth, barium carbonate, alumina, silica gel, magnesia, titania, and zirconia.

Specific examples of the catalyst include platinum-carbon, platinum black, colloidal platinum, platinum oxide, palladium-carbon, palladium black, rhodium-carbon, rhenium black and the like.

The amount of the catalyst used is, for example, 0.01 to 20% by weight, preferably 0.1 to 10% by weight, based on 1,1-diarylethylene glycol as a raw material. When the amount of the catalyst used is less than the lower limit of this range, the reaction does not proceed sufficiently, and even when the amount of the catalyst used is larger than the upper limit of the above range, it hardly contributes to the improvement of the reaction rate. Instead, it takes time to recover the catalyst, which is not preferable.

In the reaction of the present invention, a base is used. As the base, an alkali metal salt such as sodium hydroxide, sodium carbonate, potassium hydroxide and lithium hydroxide, or an alkaline earth metal salt such as calcium hydroxide and barium hydroxide can be used. The amount of the base used is not particularly limited as long as the amount is sufficient to make the reaction system basic.

The oxidation in this reaction is performed with molecular oxygen. Oxygen may be diluted with an inert gas such as nitrogen, carbon dioxide, helium, argon, methane, ethane, or the like. Alternatively, air can be used.

The reaction temperature is 0 to 200 ° C, preferably 50 to 100 ° C. If the temperature is lower than 0 ° C., the reaction solvent such as water or the reaction raw materials is coagulated, and the reaction rate is too low to lower the reaction rate, which is not preferable. At a high temperature exceeding 200 ° C., by-products such as thermal decomposition of the reaction product 2,2-diarylglycolic acid are generated, and the selectivity of the target product is remarkably reduced.

The reaction time varies depending on the reaction conditions such as the reaction temperature, but is generally selected from the range of 10 minutes to 10 hours.

Since the pressure of the reaction system during the reaction does not affect the reaction of the present invention at all, it can be appropriately selected, but normal pressure is usually sufficient.

A solvent may be used to improve the contact efficiency between 1,1-diarylethylene glycol and oxygen or a base.Examples of such a solvent include water, dioxane, acetone, acetonitrile, isooctane, benzene, and chloroform. Or a mixed solvent thereof, and preferably water.

This reaction can be performed, for example, as follows.

A reaction vessel is charged with 1,1-diarylethylene glycol, a transition metal catalyst and a reaction solvent, and the reaction is allowed to proceed under an oxygen atmosphere under predetermined conditions. However, the order of addition is not particularly limited.

After the reaction, the transition metal catalyst is separated by means of filtration or the like and then made acidic, and the reaction mixture is extracted with an organic solvent such as benzene, ethyl acetate, chloroform, etc. according to a conventional method, and then purified by ordinary recrystallization or the like. 2,2-diaryl glycolic acid can be easily obtained.

[Effects of the Invention] As described above, according to the present invention, 1,1-diarylethylene glycol is oxidized by molecular oxygen at a temperature of 0 to 200 ° C in the presence of a transition metal catalyst and a base. As a result, 2,2-diaryl glycolic acid useful as an intermediate material for pharmaceuticals and the like can be produced in a high yield.

[Examples] Hereinafter, the present invention will be further described with reference to Examples.

<Example 1> A mixture of 2.14 g (10 mmol) of 1,1-diphenylethylene glycol as a 1,1-diarylethylene glycol, 0.4 g of 5% -supported platinum-carbon, and 350 ml of a 0.33N aqueous sodium hydroxide solution was heated at 85 ° C. With vigorous stirring
Pure oxygen was introduced at a rate of 6 / hr for 4 hours. After cooling to room temperature, the catalyst was filtered off from the reaction solution, acidified with hydrochloric acid, and extracted with ether. After drying the ether layer, it was concentrated by distillation.

The product is a liquid chromatograph (column: ERMA ERC-100
0, eluent: 70% methanol aqueous solution, detector: UV-225 nm)
And analysis by NMR and IR gave benzylic acid in 88% yield. Note that all the 1,1-diphenylethylene glycol was consumed.

<Example 2> The reaction was carried out in the same manner as in Example 1 except that the reaction temperature was changed to 50 ° C, and the conversion was only 42%.

<Example 3> The reaction was carried out in the same manner as in Example 1 except that 5% of the supported platinum-carbon in Example 1 was replaced with a transition metal catalyst shown in the following table. The results are summarized in the following table.

<Example 4> Example 1 was performed using 10 mmoles of 1,1-ditolylethylene glycol, 1,1-bischlorophenylethylene glycol, and 1,1-bismethoxyphenylethylene glycol as 1,1-diarylethylene glycol. When the same operation as described above was performed, 1,1-ditolyl glycolic acid,
1,1-bischlorophenyl glycolic acid and 1,1-bismethoxyphenyl glycolic acid were 81%, 79% and 89%, respectively.
% Yield. Further, as in Example 1, all of the raw material diarylethylene glycol was consumed.

<Comparative Example 1> When a reaction was carried out in the same manner as in Example 1 without adding 5% -supported platinum-carbon as a reaction catalyst, the conversion of the raw material was only 2%, and the target product, benzylic acid, Did not produce any.

<Comparative Example 2> A reaction was carried out in the same manner as in Example 1 except that the same amount of water was added instead of 350 ml of a 0.33N aqueous sodium hydroxide solution.

Analysis of the reaction product showed that benzyl acid was obtained in a low yield of 8%. In addition, 1,1-diphenylethylene glycol was consumed by 10%.

Claims (5)

(57) [Claims] 1. A mixture of a 1,1-diarylethylene glycol represented by the following general formula (I) and a base in an amount sufficient to make a reaction system basic, is heated at a temperature in the presence of a transition metal catalyst. 2,2 represented by the following general formula (II), characterized by being oxidized by molecular oxygen at 0 to 200 ° C.
-A method for selectively producing diaryl glycolic acid, In the formula, Ar ₁ and Ar ₂ are the same or different aryl groups. 2. The aryl group of the above formula has one to three substituents selected from the group consisting of a halogen atom, a nitro group, an amino group, a lower alkyl group and a lower alkoxy group. A method for producing the 2,2-diaryl glycolic acid according to the above. 3. The method according to claim 1, wherein any one transition metal selected from platinum, palladium, rhodium, ruthenium, rhenium, iridium, nickel, iron, cobalt and copper is used as a reaction catalyst. A method for producing 2-diaryl glycolic acid. 4. The process for producing 2,2-diaryl glycolic acid according to claim 1, wherein the base is an alkali metal salt or an alkaline earth metal salt. 5. The method for producing 2,2-diaryl glycolic acid according to claim 1, wherein the base is sodium hydroxide or potassium hydroxide.