JP2740853B2 - Method for producing 2,2-diaryl glycolic acid - Google Patents

Description

The present invention relates to a novel method for producing 2,2-diaryl glycolic acid via diaryl ethylene glycol by oxidizing diaryl ethylene which is a simple hydrocarbon compound. Method.

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 known as benzylic acid)
It is a compound used as an intermediate for producing diphenine hydrochloride, benactidine hydrochloride, mebenzolate bromide, pipenzolate methyl bromide, etc. used as a parasympathetic nerve inhibitor.

[Related Art] Hereinafter, benzyl acid will be described as an example of 2,2-diaryl glycolic acid.

Benzic 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, the production method using benzylic acid rearrangement, which is also practiced industrially, is a method in which an alcoholic solution of caustic potassium or a concentrated aqueous solution is allowed to act on benzyl and heated (Or
ganic Synthesis, Vol. 1, 29 (1921)).

[Problems to be Solved by the Invention] Although the above-described method is a simple reaction itself, benzyl as a raw material is usually obtained by adding potassium cyanide to an ethanol solution of benzaldehyde, boiling to benzoin, and then further oxidizing. Is obtained by That is, toxic potassium cyanide is used.

As described above, the above method is dangerous because toxic potassium cyanide is used in the synthesis of the raw material, and the raw material itself is expensive, so that it cannot be said that it is still sufficient for an industrial production method.

Therefore, the present invention provides 2,2-diaryl glycolic acid, which is useful as an intermediate material for various agricultural chemicals and pharmaceuticals,
It is intended to produce a high yield from easily available inexpensive raw materials.

[Means for Solving the Problems] That is, the present invention provides a method for oxidizing
The present invention relates to a method for producing 2,2-diaryl glycolic acid via diaryl ethylene glycol.

 Hereinafter, the present invention will be described in detail.

Step (I) of the present invention is carried out by oxidizing diarylethylene glycol from 1,1-diarylethylene, which is easily available, in the presence of a specific oxidizing agent.

The raw material of the step (I) of the present invention is represented by the following formula (I):
1-diarylethylene.

Here, Ar ₁ or Ar ₂ in the above formula represents, for example, an aryl group which may have a substituent, such as a phenyl group, a naphthyl group, and a biphenylyl group, which 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. May be substituted with 1 to 3 substituents.

Specific 1,1-diarylethylenes include 1,1-diphenylethylene, 1,1-phenyltolylethylene, 1,1
-Ditolylethylene, 1,1-phenylbromophenylethylene, 1,1-bisbromophenylethylene, 1,1-bischlorophenylethylene, 1,1-bismethoxyphenylethylene, 1,1-bisfluorophenylethylene, 1 1,1-phenylnitrophenylethylene, 1,1-bisnitrophenylethylene, 1,1-phenyl- (3- (1-carboxyethyl) phenyl) ethylene, 1,1-phenylnaphthylethylene and the like.

The diarylethylene glycol produced by the step (I) of the present invention is represented by the following general formula (II).

Here, Ar ₁ and Ar ₂ are the same substituents as defined in the above formula (I).

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

Therefore, specifically, for example, 1,1-diphenylethylene glycol is obtained from 1,1-diphenylethylene, and 1,1-bischlorophenylethylene glycol is 1,1-bischlorophenylethylene from 1,1-bischlorophenylethylene. 1,1-phenyl- (3- (1-carboxyethyl) phenyl) ethylene glycol is derived from phenyl- (3- (1-carboxyethyl) phenyl) ethylene and 1,1-phenyl is derived from 1,1-phenylpyridylethylene. Phenylpyridyl ethylene glycol is obtained in each case.

In the step (I) of the present invention, the 1,1-diarylethylene of the above formula (I) is any oxidizing agent selected from the group consisting of permanganate, osmium tetroxide, cobalt triacetate and singlet oxygen. Is oxidized.

Specific examples of permanganate include potassium permanganate, barium, calcium, magnesium, and lead, and ammonium salts such as cetyltrimethylammonium.

In addition to oxidizing osmium tetroxide by adding an equimolar number or more to the reaction substrate, a method of oxidizing a catalytic amount of osmium tetroxide with a co-oxidizing agent such as a nitroso compound, an iodosyl compound, or a peroxide. Can also be employed. Specific examples of the nitroso compound include methylmorpholine N-oxide, and examples of the iodosyl compound include iodosyltoluene acetate and iodosylbenzene acetate.

Singlet oxygen consists of hydrogen peroxide and sodium hypochlorite,
According to a method based on a reaction with a hypohalite such as calcium hypochlorite or sodium hypobromite, or a method based on thermal decomposition of an organic peroxide, etc., it can be easily used.

The amount of the oxidizing agent is not particularly limited, but may be, for example, 0.1 to 20 with respect to the raw material 1,1-diarylethylene.
Molar times, preferably 1.0 to 10 times, are suitable. When the amount of the oxidizing agent is less than the lower limit of this range, the reaction does not proceed sufficiently, and even when the amount of the oxidizing agent is more than the upper limit of the above range, it hardly contributes to the improvement of the reaction rate. Instead, it takes much time to recover the oxidizing agent, which is not preferable.

The reaction temperature depends on the oxidizing agent, but is generally -50.
-200 ° C, preferably 0-100 ° C. If the temperature is lower than −50, the reaction solvent or the reaction raw material is coagulated, or the reaction temperature is too low, so that the reaction rate is unfavorably reduced. When the temperature exceeds 200 ° C., side reactions such as thermal decomposition of the reaction product, diarylethylene glycol, occur.
Any of these is not preferred because the selectivity of the target product is significantly reduced. The reaction time varies depending on the reaction conditions such as the oxidizing agent and the reaction temperature, but is generally selected from the range of 10 minutes to 10 hours.

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

A solvent may be used to improve the contact efficiency between the 1,1-diarylethylene and the oxidizing agent.Examples of such a solvent include water, alcohols such as methanol or isopropanol, dioxane, acetone, acetonitrile, and isooctane. , Benzene, a single solvent such as chloroform or a mixed solvent thereof is used,
Preferably, water is used.

The reaction of step (I) can be performed, for example, as follows.

A reaction vessel is charged with 1,1-diarylethylene and a reaction solvent, and an oxidizing agent is added under predetermined conditions to allow the reaction to proceed. However, the order of addition is not particularly limited.

After the reaction, solids such as metals are separated by means such as filtration, and then benzene, ethyl acetate,
After extracting the reaction mixture with an organic solvent such as chloroform, diarylethylene glycol is obtained by ordinary distillation or recrystallization.

In the step (II), the compound represented by the general formula (II)
The 1-diarylethylene glycol is oxidized by molecular oxygen.

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

Here, Ar ₁ and Ar ₂ are the same substituents as defined in the above formula (I).

As 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 obtained from 1,1-diphenylethylene glycol, and 2,2-phenyltolylglycolic acid is obtained from 1,1-phenyltolylethylene glycol, respectively. can get.

In the reaction of the step (II), a catalyst is used for the purpose of accelerating the reaction. As the catalyst, a transition metal, 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 problem. 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. If the amount of the catalyst used is less than the lower limit of this range, the reaction will not proceed sufficiently. Further, if 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, and it takes much time to recover the catalyst, which is not preferable.

In step (II), 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.

In step (II), oxidation is performed by molecular oxygen. Oxygen may be diluted with a reaction inert gas such as nitrogen, carbon dioxide, helium, argon, methane, ethane, and 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., a side reaction such as thermal decomposition of the reaction product 2,2-diaryl glycolic acid occurs, and the selectivity of the target product is significantly reduced. Also,
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.

The pressure of the reaction system during the reaction can be appropriately selected because it does not affect the reaction of the present invention at all, 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. As such a solvent, for example, a single solvent such as water, dioxane, acetone, acetonitrile, isooctane, benzene, chloroform, or a mixed solvent thereof is used, and preferably water is used.

Step (II) can be performed, for example, as follows.

The 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, then acidified, and the reaction mixture is extracted with an organic solvent such as benzene, ethyl acetate or chloroform according to a conventional method. Pure 2,2-diaryl glycolic acid is easily obtained.

[Effects of the Invention] As described in detail above, according to the present invention, 1,1-diarylethylene is oxidized in the presence of a specific oxidizing agent, and is converted to 2,2-diarylglycolic acid via diarylethylene glycol. Can be produced in high yield.

EXAMPLES Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to only these examples.

-Step (I)-<Experimental example 1> Permanganic acid was prepared by diluting 10.0 g (50 mmol) of 1,1-diphenylethylene as 1,1-diarylethylene into ethanol to 120 ml while maintaining the temperature at -15 ° C. Potassium 1
A 160 ml aqueous solution of 2.0 g and 9.0 g of magnesium sulfate was added dropwise.
The dropwise addition was continued until a purple color due to potassium permanganate appeared in the mixture.

After stirring for 1 hour after the dropwise addition, manganese dioxide was filtered off from the reaction solution, and the filtrate was extracted with ether. After quenching the ether layer with sodium sulfite, it was dried and the solvent was further evaporated to obtain a crude product as a white solid. The crude product was recrystallized from benzene and n-hexane to obtain 5.2 g of a purified product. Analysis of the purified product by NMR and IR confirmed that it was 1,1-diphenylethylene glycol.

The crude product was subjected to liquid chromatography (column: ERMAERC-10
00, eluent: 75% methanol aqueous solution, detector: UV-225n
m), the conversion of the raw material was 85% and 1,1-
Diphenylethylene glycol was obtained with a yield of 72%.

<Experimental Example 2> 1.0 g (5.6 mmol) of 1,1-diphenylethylene as 1,1-diarylethylene was mixed with cobalt triacetate (13.9 mmol).
1.5 ml of water and 40 ml of glacial acetic acid solution were dissolved and reacted.

The reaction was carried out at 70 ° C. for 8 hours without stirring under an argon atmosphere. The reaction solution was extracted with ether, and the ether layer was washed with an aqueous solution of sodium sulfite, further washed with water, and dried over magnesium sulfate. The ether was removed by distillation, leaving a crude product as a white solid.

Subsequent analysis or quantification was performed in the same manner as in Experimental Example 1, and diphenylethylene glycol was obtained at a conversion of the raw material of 66% and a yield of 46%.

<Experimental example 3> 1,1-phenyl- (3
-(1-carboxyethyl) phenyl) ethylene 5.0g
A solution of (20 mmol) in 300 ml of methanol is cooled to 10 ° C., and 6.6 g (60 mmol) of a 31% aqueous hydrogen peroxide solution are added thereto.
30.1 g of 10.0% aqueous sodium hypochlorite solution (5
0 mmol) was added dropwise over 2 hours with continued cooling and stirring. The reaction was stirred overnight at the same temperature. The reaction mixture was diluted with water and extracted with ether.

The ether layer was washed with an aqueous solution of sodium sulfite, further washed with water, and dried over magnesium sulfate. Removal of the ether by distillation gave a viscous liquid.

2.5% isopropanol sulfate solution per 1 g of crude product 2
0 ml was added, and the mixture was reacted at a reflux temperature for 3 hours. The reaction solution was made basic with an aqueous sodium hydroxide solution, extracted with ether, the ether layer was dried and concentrated, and the remaining solution was subjected to GC-MA
When analyzed by SS, the raw material conversion was 59.8%,
-Phenyl- (3- (1-isopropoxycarbonylethyl) phenyl) ethylene glycol was produced in a yield of 36%.

<Experimental example 4> Experimental example 1 using 50 mmol each of 1,1-ditolylethylene, 1,1-bischlorophenylethylene and 1,1-bismethoxyphenylethylene as 1,1-diarylethylene.
By performing the same operation as in 1, 1,1-ditolylethylene glycol, 1,1-bischlorophenylethylene glycol, and 1,1-bismethoxyphenylethylene glycol were obtained, respectively. Conversion and yield are 75% / 6 respectively
1%, 81% / 70% and 97% / 80%.

Comparative Example 1 After diluting 10.0 g (50 mmol) of diphenylethylene as 1,1-diarylethylene with t-butanol to 50 ml, 3.35 g of tungstosilicic acid (SiO ₂ .12WO ₂ .2H ₂ O)
(1 mmol) and 16.5 g (150 mmol) of 31% aqueous hydrogen peroxide were added, and the mixture was reacted for 16 hours under reflux.

After completion of the reaction, 100 ml of water was added, and the mixture was extracted with ether.
After washing the ether solution with water, it was dried and the ether was removed by distillation.

When analyzed in the same manner as in Experimental Example 1, the conversion of the raw material was 32%, but no diphenylethylene was detected, and instead, benzophenone was obtained in a yield of 23%.

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

The product was a liquid chromatograph (column: ERMAERC-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.

<Experimental Example 6> The reaction was carried out in the same manner as in Experimental Example 5 except that the reaction temperature was changed to 50 ° C. As a result, the conversion was only 42%.

<Experimental Example 7> A reaction was carried out in the same manner as in Experimental Example 5 except that 5% of platinum-carbon supported in Experimental Example 5 was changed to a transition metal catalyst shown in the following table. The results are summarized in the following table.

<Experimental Example 8> Experimental Example 5 was conducted 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 Experimental Example 5, the raw material diarylethylene glycol was completely consumed.

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

<Comparative Example 3> A reaction was carried out in the same manner as in Experimental Example 5, 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%.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 29/48 C07C 29/48 33/26 33/26

Claims (2)

(57) [Claims] 1. The method comprises the following steps (I) and (II)
Method for producing 2,2-diaryl glycolic acid, step (I): 1,1-diarylethylene represented by the following general formula (I) is converted to permanganate, osmium tetroxide,
Oxidizing in the presence of any oxidizing agent selected from the group consisting of cobalt triacetate and singlet oxygen, producing a 1,1-diarylethylene glycol represented by the following general formula (II), Step (II): oxidizing 1,1-diarylethylene glycol represented by the above formula (II) with molecular oxygen at a temperature of 0 to 200 ° C. in the presence of a transition metal catalyst and a base, the following general formula (III) A step of producing a 2,2-diaryl glycolic acid represented by In the formula, Ar ₁ and Ar ₂ are the same or different aryl groups. 2. The compound according to claim 1, wherein the aryl group of each formula has 1 to 3 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 2-diaryl glycolic acid.