JPS581097B2 - Racemization method for optically active α-substituted aryl acetic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for racemizing optically active α-monosubstituted arylacetic acids having anti-inflammatory and analgesic effects.

More specifically, the present invention relates to optically active 2-(6-methoxy-
The present invention relates to an efficient racemization method for (2-naphthyl)-propionic acid.

Conventionally, as a racemization method of this type of optically active α-monosubstituted aryl acetic acid, a method using cinchonidine is known, which is described in Japanese Patent Publication No. 31981/1981.

However, it is well known that cinchona alkaloids such as cinchonine and quinine are easily isomerized and become toxins (Asakura Shoten, "Big Organic Chemistry", Vol. 17, "Heterocyclic Compounds Part 2", No. 121-123). (see page).

Therefore, even under the racemization reaction conditions described in Japanese Patent Publication No. 49-319814, there is a possibility that cinchonidine is isomerized, and because of this, expensive cinchonidine is consumed in each reaction, the prior art method described in the above publication is not economical. Considering gender, it cannot be said to be a good idea.

As a result of extensive research, the inventor has determined that d- or 1-2
-(6-methoxy-2-naphthyl)-propionic acid or a mixture of both in a non-reactive polar solvent at least once
It has been found that racemization easily occurs when heat treated with a compound of the formula MOR (wherein M represents sodium or potassium and R represents hydrogen or a lower alkyl group) at a temperature of 00° C. or higher.

Bases used in the method of the present invention include sodium metomeside, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium hydroxide, and sodium hydroxide.

The amount of such a base to be used needs to be at least twice the mole of the raw material, and in practice it is preferable to use an amount of about 2.0 to 2.5 times the mole.

The reaction temperature can range from 100°C to 200°C, but the reaction can be carried out at 110°C to 150°C without any problem.

The reaction time is affected by the reaction temperature, but at 110°
In the range of ~150°C, the racemization reaction can be almost completed in about 24 hours at the most.

Examples of the reaction medium include polar solvents having a boiling point of 100°C or higher, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethylene glycol, butanol, and water.

Even if a lower alcohol is mixed in these polar solvents, there will be no problem in the reaction as long as the boiling point of the reaction solution is 110° C. or higher.

Furthermore, when selecting a polar solvent, it should be selected so that it does not substantially react with the base used.

For example, when using a hydroxide such as potassium hydroxide or sodium hydroxide as a base, amide solvents such as dimethylformamide or dimethylacetamide are undesirable because they undergo hydrolysis; in this case, water or alcohol solvents are used. It is desirable to do so.

When water is used as a solvent, racemization will proceed rapidly if alkali hydroxide is also dissolved at a high concentration and the reaction temperature is raised to 110° C. or higher.

When the boiling point of the non-reactive polar solvent used in the method of the present invention is 100°C or lower, the racemization reaction can be carried out under pressurized conditions and the reaction temperature can be maintained at 100°C or higher.

The present invention is extremely excellent as an industrial method because the chemicals and solvents used are inexpensive, easily available, and easy to handle.

Conventionally, it has been known to use dilute alkali for racemization of amino acids, but in the case of the present invention, the intended purpose cannot be achieved with dilute alkali.

In the method of the present invention, the objective is achieved only by using a base, which is an alkali or alcoholate, at a high concentration, and in order to achieve such a high concentration, 100%
℃ or higher, it is surprising that the α-monosubstituted aryl acetic acid to be treated by the method of the present invention can be racemized under such high temperature and high concentration basic conditions without problems such as decomposition. I should say.

The raw material used in the method of the present invention can be produced, for example, by the following operation.

Specifically, 2-methoxynaphthalene is treated with acetyl chloride in the presence of aluminum chloride in nitrobenzene to give 6-methoxy-2-acetylnaphthalene, and this product is then treated with methyl chloroacetate in the presence of sodium methoxide. Dalzene condensation gives 3-methyl-3-(6
-Methoxy-2-naphthyl)-glycidate, and the glycidate ester is then treated with magnesium bromide to form methyl 2-hydroxy-3-(6-methoxy-2-naphthyl)-3-butenoate. The hydroxybutenoic acid ester is then treated with sodium methoxide, followed by hydrolysis and oxidation with hydrogen peroxide to yield dl-2-(6-methoxy-2-naphthyl)-monopionic acid.

If this dl-acid is treated with cinchonidine in methanol, dextrorotatory crystals can be obtained from the solution, and levorotatory crystals can be obtained from the filtrate.

These reactions can be expressed using formulas as follows.

Next, the present invention will be explained by examples.

However, the present invention is not limited to these Examples.

Example 1 (b) 9=-42.8° (1% chloroform)
6-Mell xy-2-naphthyl) monopropionic acid (mixture of 84.2% l and 15.8% d) 6,9
Add 50rul of ethylene glycol to
It was heated to 125°C to dissolve it.

Then 15 ml of 28% sodium methoxide/methanol solution was added and heated at 80-85°C for 10 minutes.

The reaction solution was concentrated under reduced pressure to remove most of the methanol.

It was heated at 135-140°C for 6 hours and the reaction solution was poured into water.

The mixture was made acidic with dilute hydrochloric acid and then extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to give dl-2-(6-methoxy-
6.1 g of 2-naphthyl)-probionic acid were obtained.

(α)■=0° (1% chloroform).

Example 2 2- of (α)■=+35.0° (1% chlorophonolem)
(6-Methoxy-2-naphthyl)-propionic acid (mixture of 78% d and 22% 1) 6.91 was dissolved in 50 ml of dimethylformamide, 15 ml of 28% sodium methoxide/methanol solution was added and 1
Heating and stirring were performed at 00 to 110°C for 24 hours.

The reaction solution was poured into water, acidified with dilute hydrochloric acid, and then extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to obtain 6.2 g of 2-(6-methoxy-2-naphthyl)-propionic acid.

(α)■=0° (1% chloroform).

Example 3 2-( of (α)■=-42.8° (1% chloroform)
6-methoxy-2-naphthyl)-propionic acid (mixture of 84.2% 1 and 15.8% d) 6.9 g
was dissolved in 50 ml of ethylene glycol, a solution of 5.67 ml of caustic soda dissolved in 10 ml of water was added thereto, and the mixture was heated in a sealed tube at 135-145° C. for 10 hours.

The reaction was poured into water, acidified with dilute hydrochloric acid and extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to obtain 6.0 g of dl-2-(6-methoxy-2-naphthyl)-propionic acid.

(α)■=+0° (1% chloroform). Example 4 2-( of (α)■=-42.8° (1% chloroform)
6,9 g of 6-methquine-2-naphthyl)-propionic acid (mixture of 84.2% 1 and 15,8% d)
56 g of potassium hydroxide dissolved in 10 ml of water was added to the solution, followed by stirring and refluxing for 22 hours.

After diluting the reaction solution with water, it was acidified with dilute hydrochloric acid and extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to obtain 6.11 dl-2-(6-methoxy-2-naphthyl)-probionic acid.

[α2}■=0° (1% chloroform). Example 5 2-(6-
methoxy-2-naphthyl)-propionic acid (1 unit 74
% and d 26% mixture) was dissolved in 50 ml of dimethyl sulfoxide, 7.0 g of potassium tert-butoxide powder was added to this solution, and 115-12
Heating and stirring were performed at 0° C. for 20 hours.

The reaction solution was poured into water, acidified with dilute hydrochloric acid, and then extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to obtain 6.1 g of dl-2-(6-methoxy-2-naphthyl)-propionic acid.

(α)■=O° (1% chloroform).

Example 6 2-( of (α)■=-63.5° (1% chloroform)
To 6.9 g of 6-methoxy-2-naphthyl)-propionic acid (100%), add 5.6 g of potassium hydroxide to 10 g of water.
ml solution was added and stirred and refluxed for 22 hours.

The reaction solution was diluted with water, acidified with dilute hydrochloric acid, and extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.

Ethyl acetate was distilled off under reduced pressure to obtain 6.0 g of dl-2-(6-methoxy-2-naphthyl)-propionic acid.

(α)■=0° (1% chloroform).

Claims (1)

[Claims] 1 d- or 1-2-(6-methoxy-2-naphthyl) monopropionic acid or a mixture of both in a non-reactive polar solvent at a temperature of at least 100°C or higher with the formula MOR (where M is a sodium or potassium atom). and R
represents hydrogen or a lower alkyl group) A method for producing d1-2-(6-methoxy-2-naphthyl)-propionic acid.