JPS6116264B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing (+)-2-(6-methoxy-2-naphthyl)-propionic acid.

An object of the present invention is to provide a new compound useful as a new method for producing the above-mentioned compound.

The object of the method of the present invention (+)-2-(6-methoxy-2-naphthyl)-propionic acid is known as a drug that exhibits anti-inflammatory, analgesic, and antipyretic effects.

Various methods have been proposed to date for the synthesis of this compound, but all of them have drawbacks such as long reaction steps or the need to pass through complicated intermediates, and the yield is not always high enough. It's not something to be satisfied with.

As a result of intensive research into a manufacturing method suitable for industrial production of this compound, the inventors of the present invention have developed a process that is completely different from conventional methods, starting from easily available raw materials and passing through a new intermediate, and which is also gentle. The inventors succeeded in synthesizing the target product in high yield in a short reaction time under reaction conditions, leading to the completion of the present invention.

Part of the invention is the formula By dehydration condensation with 2-thioxo-4-oxo-thiazolidine and 2-acetyl-6-methoxy-naphthalene represented by the formula 2-thioxo-4-oxo-5- represented by
[1-(6-methoxy-2-naphthyl)-ethylidene]-thiazolidine, which is then hydrolyzed to produce the following formula: α-thioketo-β-methyl-β-(6
-Methoxy-2-naphthyl)-pyruvic acid is desulfurized and the formula β-methyl-β-(6-methoxy-2
-naphthyl)-pyruvic acid, which is oxidatively decarboxylated to give the formula (+)-2-(6-methoxy-2-naphthyl)-propionic acid, which is characterized in that it is a racemic 2-(6-methoxy-2-naphthyl)propionic acid represented by the formula, and then optically resolved. It is a manufacturing method.

The steps will be explained in order below.

<Dehydration condensation step> In this step, 2-thioxo-4 of the above formula
-Oxo-thiazolidine and 6-methoxy-2-acetylnaphthalene are dehydrated and condensed to form a new compound of the above formula 2-thioxo-4-oxo-5-[1
(6-methoxy-2-naphthyl)-ethylidene]-
Leads to thiazolidine.

This reaction is an addition/elimination reaction to a carbonyl compound using an active methylene compound as a carbanion source, and is carried out in a solvent or in the absence of a solvent, and is promoted in the presence of a suitable catalyst.

Any solvent can be used as long as it does not inhibit this reaction, but in order to carry out the reaction while continuously removing water produced as the reaction progresses from the reaction system, and to facilitate the recovery of the solvent, Solvents that do not dissolve water and are azeotropic with water are preferred.

As such a solvent, a hydrocarbon-based or halogenated hydrocarbon-based solvent is generally used,
Examples of the former include benzene, toluene, xylene, and cyclohexane, and examples of the latter include chloroform and ethylene dichloride. A mixture of these may be used. If desired, amines in the following catalysts may be used as a solvent to serve as a catalyst as well.

As the catalyst, when the reaction is carried out in a solvent, for example, an organic acid salt of an organic acid such as glacial acetic acid and ammonia or amines, or ammonia or amines is used.

Examples of the above amines include pyridine,
Examples include piperidine, piperazine, morpholine, triethylamine, diethylamine, aniline, and the like.

In addition, in the reaction without a solvent, the above-mentioned ammonia or organic acid salts of amines are used. Conditions such as reaction temperature and time are appropriately determined depending on the solvent, catalyst, etc. used.

The compound of the formula thus produced can be crystallized and isolated, for example, by distilling off the solvent from a solution of the above-mentioned solvent.

<Hydrolysis step> In this step, the 2-thioxo-4-oxo-5[1-(6-methoxy-2
-naphthyl)-ethylidene]-thiazolidine ()
was hydrolyzed to form the new compound α-thioketo-
β-Methyl-β-(6-methoxy-2-naphthyl)-pyruvic acid () is produced.

This hydrolysis reaction is carried out by bringing the compound () into contact with a base in an aqueous or alcoholic solution. Inorganic bases are generally used as bases, such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, alkaline earth metal hydroxides, sodium carbonate, potassium carbonate, barium carbonate, etc. Examples include carbonates of alkali and alkaline earth metals.

Conditions such as reaction temperature and time can be appropriately determined depending on the type and concentration of the solvent and base used.

For example, when hydrolyzing in a 10-20% sodium hydroxide aqueous solution at about 90-100℃, 1
The reaction proceeds sufficiently in about an hour.

The resulting compound () is generally soluble in an aqueous alkaline reaction mixture, but its solubility decreases in acidic conditions, so the reaction mixture is
For example, the compound () can be precipitated as crystals by adding it to an aqueous solution of a strong acid such as hydrochloric acid or sulfuric acid.

<Desulfurization process> The compound () produced above is then desulfurized to β
-Methyl-β-(6-methoxy-2-naphthyl)-
Obtain pyruvic acid ().

The reaction is carried out in an ammonia alkaline aqueous solution or an alcoholic solution.

The reaction is usually completed in a relatively short time under heating. The temperature and time can be determined experimentally by considering other conditions. When the aqueous reaction mixture is made acidic, compound () can be precipitated as crystals.

<Oxidative decarboxylation step> In this step, the compound () produced in the above step is oxidatively decarboxylated to obtain racemic 2-(6-methoxy-2-naphthyl)propionic acid ().

This reaction is carried out by heating the compound () or treating it with an oxidizing agent.

The desired product can be produced even if compound () is heated to a high temperature of about 180°C or higher, but in order to improve the yield, milder conditions are generally desirable, and for this purpose it is better to use an oxidizing agent.

As the oxidizing agent, for example, lead tetraacetate, hydrogen peroxide, etc. can be used. Hydrogen peroxide is preferably used because it is easy to operate and has a good yield.

Hydrogen peroxide is used in acetic acid or formic acid solution, in alkali carbonate or caustic solution, in nitric acid or sulfuric acid solution, etc. When using nitric acid, it may be combined with, for example, 30% hydrogen peroxide. Hydrogen peroxide is added to a mixed solution containing these acids or alkalis and the compound ().

Water is usually used as the solution for the reaction, but when using an alkali, methanol,
Etal, acetone, etc. may also be used.

When using an oxidizing agent, the reaction proceeds even at low temperatures. For example, when hydrogen peroxide is applied to a compound () dissolved in an aqueous caustic solution, 0
The reaction can also be carried out at around ℃. However, the reaction temperature and time are controlled by conditions such as the type and concentration of the oxidizing agent, alkali, acid, etc., and can be determined experimentally.

The racemic 2-(6-methoxy-2-naphthyl)propionic acid () produced in the reaction mixture can be precipitated as crystals from an aqueous solvent under acid conditions.

<Optical resolution step> In this step, the compound () produced in the previous step is optically resolved to obtain (+)-2-(6-methoxy-2-naphthyl)-propionic acid.

It is known to optically resolve the compound () as a cinchonidine salt, for example.

The present inventors discovered that L-tyrosine hydrazide or α
It has been found that diastereomeric salts are formed when -phenylethylamine and compound () are reacted, and due to the difference in solubility in alcoholic solvents, optical isomers can be resolved in higher yields than when using ciconidine.

One embodiment of the optical resolution of the present invention is racemic 2-
(6-Methoxy-2-naphthyl)propionic acid is reacted with L-tyrosine hydrazide or L-α-phethynylethylamine under heating in an alcoholic solvent, and then the reaction mixture is cooled to remove the precipitated diastereomeric salt. (+)-2-(6-methoxy-2-
(naphthyl)-propionic acid.

In this embodiment, racemic 2-(6-methoxy-2-naphthyl)-propionic acid is reacted with L-tyrosine hydride or L-α-phenylethylamine.

This reaction is carried out in an alcoholic solvent such as methanol, ethanol, or isopropyl alcohol. If the reaction is carried out under refluxing alcohol, diastereomeric salts are formed in a relatively short time.

Then, when the reaction mixture is cooled, (+)-2-
(6-methoxy-2-naphthyl)-propionic acid.
L-tyrosine hydrazide salt or (+)-2-(6-
methoxy-2-naphthyl)-propionic acid L-
α-Phenylethylamine salt precipitates. After separating this precipitate, it is decomposed with a strong acid such as hydrochloric acid or sulfuric acid. and these acids and ethyl acetate,
By treating with a mixed solvent with an organic solvent such as ether, diastereomeric salts are decomposed and optically active (+)-2-(6-
Methoxy-2-naphthyl)-propionic acid can be extracted and collected in the organic layer. Of course, decomposition and extraction may be performed separately.

Although a part of the present invention includes the several types of reaction steps described above, the intermediate compounds produced in each step do not necessarily need to be isolated, and may be subjected to the next reaction as a crude product if necessary. It's okay.

For example, the ammonia alkaline reaction mixture obtained in the desulfurization process is used as a raw material for the next oxidative decarboxylation process without being purified. It is also possible to add caustic alkali to this and react with hydrogen peroxide.

In addition, compound () can be prepared by reacting compound () with hydroxylamine in a methanol solution to form the oxidation compound of the following formula. It can also be produced by hydrolyzing this with an inorganic acid such as hydrochloric acid and formaldehyde.

The method of the present invention is much easier to react than the conventionally known method for producing (+)-2-(6-methoxy-2-naphthyl)-propionic acid, and the yield in each step is also very good. -6-Methoxy-naphthalene gives almost quantitative yields of the compounds of formula and formula, and the total yield of formula through formula
It reached 80% or more and was extremely good in terms of optical resolution, so it can be said to be an industrially excellent method.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1 16.8 g of toluene was placed in a reactor equipped with a Dean & Stark distillation apparatus, and 140 g of 2-acetyl-6-methoxy-naphthalene, 9.3 g of 2-thioxo-4-oxothiazolidine, 1.2 g of ammonium acetate, and acetic acid were added. Add 3.4g and heat to boil and reflux to cause a condensation reaction. The water produced by condensation is azeotropically distilled with toluene and
It is stored in the separator at the bottom of the reflux vessel of the Stark distillation equipment and separated. The reaction continues until water production is complete.
The reaction is completed in about 8 hours.

After washing the reaction mixture with warm water, toluene is distilled off to give 2-thioxo-4-oxo-5[1-
(6-methoxy-2-acetyl)-ethylidene]-
Thiazolidine precipitates as crystals, which are separated and washed with water.

Yield 16.8g, melting point 171.5-172.0℃ Elemental analysis device C ₁₆ H ₁₃ NO ₂ S ₂ Calculated value C; 60.93, H; 4.15 Experimental value C; 60.88, H; 4.13 Example 2 2- obtained in Example 1 Thioxo-4-oxo-5-
Add 5 g of [1-(6-methoxy-2-naphthyl)-ethylidene]-thiazolidine and 15% (W/W) to 25 ml of an aqueous sodium hydroxide solution, and gradually heat from room temperature while stirring. As heating progresses, the crystals dissolve, forming a reddish-orange solution. Hydrolysis is completed by heating at 90-95°C for about 1 hour.

When 62.5 ml of 2N hydrochloric acid was cooled to 0°C and the above hydrolyzed solution was added dropwise to it while stirring and cooling, orange-yellow α-thioketo-β-methyl-β-(6-methoxy-2-naphthyl)-pyruvic acid was obtained. Since it precipitates as crystals, separate them and wash with water.

Yield 3.4g Melting point 167-168℃ Elemental analysis value C ₁₅ H ₁₄ O ₃ S Calculated value C; 65.67, H; 5.14 Experimental value C; 65.63, H; 5.08 Example 3 α-thioketo obtained in Example 2 β-methyl-β-
(6-methoxy-2-naphthyl)-pyruvic acid 30g
Dissolve in 1500ml of 0.5N ammonia water. This solution is filtered and the solution is heated to 70-75°C while stirring to react. The desulfurization reaction is completed in about 45 minutes. After cooling to room temperature, neutralize with 6N hydrochloric acid to Congolese acidity, and the oil will separate. Extract this oil with ether. Wash the ether layer thoroughly with water. After drying, distill off the ether to obtain a pale yellow oil. . When this oil is crystallized from benzene-hexane, pale yellow needle-like crystals of β-methyl-β-(6-methoxy-2-naphthyl)-pyruvic acid are obtained.

Yield 25.0g Melting point 106-107.5℃ Elemental analysis value C ₁₅ H ₁₄ O ₄ Calculated value C; 63.89, H; 5.46 Experimental value C; 63.88, H; 5.41 Example 4 β-Methyl-β- obtained in Example 3 (6-methoxy-
25.0 g of 2-naphthyl)-pyruvic acid was suspended in 120 ml of 1N aqueous sodium hydroxide solution, cooled to 0°C, and 20 ml of 30% hydrogen peroxide was gradually added dropwise with stirring. After the addition is complete, the temperature is gradually raised to room temperature while stirring is continued. The reaction is completed in about 5 hours. After the reaction is complete, the mixture is acidified using 6N hydrochloric acid while cooling and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried, and the ethyl acetate was distilled off to give 2-(6-methoxy-2
-White needle-like crystals of naphthyl)propionic acid are obtained.

Yield: 20.0g Melting point: 154-156°C Elemental analysis: C ₁₄ H ₁₄ O ₃ Calculated value: C; 73.03, H; 6.13 Experimental value: C; 72.98, H; 6.08 Example 5 The 2-(6- Add 1.15 g of methoxy-2-naphthyl)propionic acid to 10 ml of methanol and heat on a water bath to completely dissolve. In this solution L
- Add 0.49 g of tyrosine hydrazide and continue heating to reflux the methanol.

When the crystals of L-tyrosine hydrazide are completely dissolved and a homogeneous solution is obtained, the heating is stopped and the solution is allowed to stand still. After a while, crystals will precipitate, so filter them and wash with methanol. The obtained crystals were recrystallized with methanol to obtain 0.6 g of (+)-2-(6-methoxy-2-naphthyl)-propionic acid/L-tyrosine hydrazide salt. Melting point: 165°C [α] ²⁰ _D = +35° (C=1, methanol).

Diastereomeric salt obtained as above 0.6
g to a stirred mixed solution of 2N hydrochloric acid and ethyl acetate. After stirring for 1 hour, the mixture was left still for a while and the ethyl acetate layer was separated. After washing the organic layer with water and drying,
Ethyl acetate is distilled off to obtain crystals. By recrystallizing these crystals with ethyl acetate, white needle-like crystals of (+)-2-(6-methoxy-2-naphthyl)-propionic acid are obtained.

Yield 0.3g, melting point 155-156℃ [α] _D = +65゜ (C = 1, chloroform) Elemental analysis value As C ₁₄ H ₁₄ O ₃ , calculated value C; 73.03, H; 6.13 Experimental value C; 73.98, H ;6.10 Example 6 1.2 g of 2-(6-methoxy-2-naphthyl)propionic acid obtained in Example 4 is dissolved in 10 ml of warm methanol. This solution was heated and stirred to produce L-α.
- Add phenylethylamine dropwise to make the liquid neutral. Crystals will precipitate if left at 0° C. for about 7 hours, and are separated and washed with methanol.
The obtained crystals were re-crystallized with methanol to give (+)-2-
(6-methoxy-2-naphthyl)-propionic acid.
0.6 g of L-α-phenylethylamine salt is obtained.

Melting point 170.5-171.5℃ [α] ²⁰ _D = -8.3 (C = 1, methanol) Diastereomeric salt obtained as above 0.6
g to a stirred mixed solution of 2N hydrochloric acid and ethyl acetate. After stirring for 1 hour, the ethyl acetate layer was separated, washed with water, and dried. When ethyl acetate is distilled off, (+)-2-(6-methoxy-
2-naphthyl)-propionic acid is obtained.

Yield 0.3g Melting point 155.5-156℃ [α] _D = +65゜ (C = 1, chloroform) Elemental analysis value As C ₁₄ H ₁₄ O ₃ Calculated value C; 73.03, H; 6.13 Experimental value C = 73.98, H; 6.10

Claims (1)

[Claims] 1 formula 2-thioxo-4-oxothiazolidine represented by the formula is dehydrated and condensed with 2-acetyl-6-methoxy-naphthalene to form the formula 2-thioxo-4-oxo-5-[1
-(6-methoxy-2-naphthyl)-ethylidene]
− Lead to thiazolidine, then hydrolyzed to produce Formula α-thioketo-β-methyl-β-(6
-Methoxy-2-naphthyl)-pyruvic acid is desulfurized and the formula β-methyl-β-(6-methoxy-2
-naphthyl)-pyruvic acid, which is oxidatively decarboxylated to give the formula (+)-2-(6-methoxy-2-naphthyl)-propionic acid, which is characterized by preparing racemic 2-(6-methoxy-2-naphthyl)propionic acid represented by and then optically resolving this. Manufacturing method. 2 Optical resolution is racemic 2-(6-methoxy-2
- naphthyl) propionic acid with L-tyrosine hydrazide or L-α under heating in an alcoholic solvent.
- Phenylethylamine is reacted on the reaction mixture, the reaction mixture is then cooled to separate the precipitated diastereomeric salt, and this is decomposed with a strong acid to (+)-2-(6-
The method according to claim 1, which is carried out by obtaining methoxy-2-naphthyl)-propionic acid.