JPH0662489B2 - Valproic acid manufacturing method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing valproic acid, which is useful for various purposes including pharmaceuticals.

[Prior Art] As a method for producing valproic acid, a 4-hydroxyheptane method, a cyanoacetic acid method, a malonic acid ester method and the like have been conventionally known. However, since the yields of all of these methods are about 70%, they are not always satisfactory when they are carried out on an industrial scale. In the above method, expensive reagents such as Grignard reagent and sodium cyanide, which require careful handling, must be used, or in the method, the reaction conditions are rather harsh,
The other method has drawbacks such as the need for expensive raw materials such as propyl halide.

As a means for improving the above means, the present applicant has previously filed Japanese Patent Application No.
No. 12297 (Japanese Patent Application Laid-Open No. 60-156638) is being applied for.

The application is (1) a step of reacting acetoacetic acid ester with allyl halide to obtain 2,2-diallylacetoacetic acid ester, (2) reacting 2,2-diallylacetoacetic acid ester with alcohol to obtain diallylacetic acid ester Step, (3) Hydrolyzing diallyl acetic acid ester to diallyl acetic acid and then reducing, or (3) 'Diallyl acetic acid ester is reduced to valproic acid ester and then hydrolyzing. It is characterized by.

[Problems to be Solved by the Invention] The above application has a great advantage in that an object can be obtained by using an inexpensive raw material and an easy method. However, when the present inventors further researched thereafter, in the method of the application, the step (3) or (3) ′, that is, “the hydrolysis of diallylacetic acid ester to diallylacetic acid followed by reduction”, It was found that α-propyl-β-ethyl-acrylic acid ester was produced as a by-product in the step of "reducing diallyl acetic acid ester to valproic acid ester and then hydrolyzing".
Although the amount produced is about several percent, it cannot be easily removed by ordinary purification treatment, and therefore the quality of the drug is greatly deteriorated. Therefore, the valproic acid obtained by this method needs a post-treatment to remove the by-product again in another step, which is a disadvantage in industrialization.

[Means for Solving Problems] However, as a result of further investigations by the present inventors to establish a more industrially superior process flow for producing valproic acid which does not have the above-mentioned drawbacks, the result is (I) acetoacetic acid ester Reacting allyl halide with 2,2-diallylacetoacetic acid ester, (II) reducing 2,2-diallylacetoacetic acid ester to obtain 2,2-dipropylacetoacetic acid ester, (III) ) 2,2-dipropyl acetoacetic acid ester is deacetylated with an alcohol to obtain a valproic acid ester, (IV) a step of hydrolyzing the valproic acid ester, in the case of producing valproic acid, the purpose is The inventors have found what can be achieved and have completed the present invention.

Hereinafter, the method of the present invention will be sequentially described.

Step (I): Reaction of acetoacetic acid ester with allyl halide 2,
2-Diallylacetoacetic acid ester is produced.

The reaction formula is Indicated by.

As the acetoacetic ester, methyl acetoacetate, ethyl acetoacetate or the like is used.

As the allyl halide, allyl bromide and allyl chloride can be used.

The reaction is usually carried out in the presence of a base catalyst, it is preferable to coexist a phase transfer catalyst, as such a catalyst, a quaternary ammonium salt, such as benzyltrimethylammonium chloride (or bromide), benzyltriethylammonium chloride (or bromide), Tetramethylammonium chloride (or bromide), tetraethylammonium chloride (or bromide), tetrapropylammonium chloride (or bromide), tetrabutylammonium chloride (or bromide), dodecyltrimethylammonium chloride (or bromide), dodecyltriethylammonium chloride (Or bromide), cetyltrimethylammonium chloride (or bromide), cetyltriethylammonium chloride (or bromide) ) And the like. Examples of the base catalyst include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alcoholates such as sodium alcoholate and potassium alcoholate, and other alkaline earth metal catalysts. Hydroxides, carbonates, alcoholates, etc. may be used, but they are tetrabutylammonium chloride (or bromide) and the above alkali metal hydroxides.
The combined use of (aqueous solution) is most preferable in terms of yield, easy handling and easy availability.

A solvent is not always necessary, but usually toluene, benzene, xylene, acetonitrile, dimethylformamide, dimethylsulfoxide and the like are used.

The amount of acetoacetate and allyl halide used is the former 1
The latter 2-10 mol is suitable for the mol.

The catalyst is 0.01 per mol of acetoacetic ester.
It is used in an amount of at least mol, preferably 0.05 to 0.5 mol.

It is practical to use the solvent in the same amount as the acetoacetate or in an amount up to about 50 times by weight.

The means for charging such a medicine is arbitrary, and any of batch charging, divided charging, continuous charging and the like can be carried out.

It is advantageous that the reaction temperature is 0 ° C. to the boiling point, preferably about 10 to 40 ° C., and the reaction time is 2 to 24 hours.

After completion of the reaction, the reaction mixture is cooled to remove undissolved components, and then the liquid is concentrated, or water is added to the reaction liquid, and the liquid is separated and concentrated to obtain the desired product. Purification is performed if necessary.

The yield of 2,2-diallyl acetoacetic acid ester is 90% or higher with respect to the charged acetoacetic acid ester.

Step (II): 2,2-diallylacetoacetic acid ester is reduced to 2,2
-Produce dipropyl acetoacetic acid ester.

The reaction formula is Indicated by.

The reduction can be carried out by any means such as a catalytic hydrogen reduction method and a reagent reduction method, but the catalytic hydrogen reduction method is industrially advantageous.

In the catalytic reduction, no solvent may be used, but water, a lower alcohol such as methanol, a lower aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid, etc., among which methanol, acetic acid, etc. are preferably used. The solvent is at least twice the amount of the raw material 2,2-diallylacetoacetic acid ester,
A suitable amount is 3 to 20 times.

In carrying out the catalytic hydrogen reduction, it is particularly preferable to use a nickel catalyst such as Raney nickel, but a palladium catalyst such as palladium carbon or a platinum catalyst can also be used. The amount added is 0.5% by weight or more, preferably 1 to 6% by weight, based on 2,2-diallylacetoacetic acid ester.

The reaction can be carried out under normal pressure or increased pressure, and the reaction temperature varies depending on the solvent, but is usually room temperature to 200 ° C., particularly 40 to 60.
C is preferred. The reaction time may be set to the end point when the absorption of hydrogen is stopped, but it is usually about 1 to 10 hours.

The yield of 2,2-dipropylacetoacetate with respect to 2,2-diallylacetoacetate is almost 100.
%, No reduction product of the acetyl group is produced.

Step (III): 2,2-Dipropylacetoacetic acid ester is deacetylated with alcohol to produce valproic acid ester.

As the alcohol, an alcohol having a carbon number of about 1 to 6 such as methanol, ethanol, propanol, butanol, and hexanol is used.

Since alcohol has a function as a solvent as well as a reaction agent, it is not necessary to use another solvent in this step.

In this step as well, the same basic solvent as used in the step (I) can be used, but sodium alcoholate and potassium alcoholate are particularly preferable.

The catalyst is used in an amount of 0.01 mol or more, preferably 0.05 to 1.0, based on 1 mol of 2,2-dipropylacetoacetic acid ester.
Used in the molar range.

The alcohol is used in the range of 3 to 50 mol per 1 mol of 2,2-propylacetoacetic acid ester.

Means for charging the drug is not particularly limited as in the step (I). Reaction time is 0.5 to 10 hours, reaction temperature is 50 ° C.
~ Boiling point is practical.

The yield of valproic acid ester is 95% or more based on 2,2-dipropylacetoacetic acid ester.

Step (IV): Valproic acid is produced by hydrolyzing valproic acid ester.

The reaction formula is Indicated by.

Hydrolysis is after concentrating the reaction obtained in step (III),
It is carried out by heating the valproate ester in the presence of an alkali or an acid in an aqueous medium while heating at a temperature of 50 to 90 ° C. The reaction time is about 2 to 5 hours. After the reaction, pH 9-
Set to 10, and extract with toluene, benzene or the like. On the water layer side
After adjusting the pH to about 2, it is left to stand and the organic layer is separated.

The desired valproic acid is obtained by removing the solvent from the solution. Of course, a purification treatment can be performed if necessary.

[Effect] By the steps (I) to (IV), in the present invention, it becomes possible to avoid the generation of the by-product which is not easy to separate from valproic acid, and the post-treatment for industrialization is performed. It is extremely useful in that it makes it possible to significantly reduce the burden on the user. Of course, the yield of valproic acid is as high as 85% or more with respect to the acetoacetic acid ester as a raw material.

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

Example 1 Production of methyl 2,2-diallylacetoacetate: Step (I) A reactor equipped with a condenser and a stirrer was mixed with 64.4 g of tetrabutylammonium bromide, 140 g of 40% aqueous sodium hydroxide solution and 1530 g of allyl chloride. The liquid was stirred, and while maintaining the temperature at 20 to 30 ° C., 232.2 g of methyl acetoacetate was allowed to react dropwise for 3 hours. During this period, after 50 minutes and 110 minutes from the start of dropping, 140 g each of the same sodium hydroxide aqueous solution as above was additionally charged. After the total amount was charged, stirring was continued for an additional 1.5 hours, 100 g of water was added to separate the layers, and the organic layer was concentrated to 440
g yellow liquid was obtained.

After washing the concentrated liquid with water, the organic layer was further distilled under reduced pressure to obtain a main fraction (74 ° C./2.5 torr to 76 ° C./2.3 torr) 37
2.5 g was obtained.

Incidentally, the tetrabutylammonium salt was recovered at a rate of 95% by separately concentrating the aqueous solution layer.

As a result of quantitative analysis of the main fraction by gas chromatography, the content of methyl 2,2-diallylacetoacetate was 9
The yield was 7% and the yield based on methyl acetoacetate was 92%.

Production of Methyl 2,2-di-n-propylacetoacetate: Step (II) 372.5 g of a liquid mainly containing the methyl 2,2-diallylacetoacetate obtained above, 15 g of Raney nickel (50% water content product) ) And 800 g of methyl alcohol were charged into the autoclave and replaced with hydrogen.
The temperature was kept at 0 ° C., and the mixture was stirred and reduced under a hydrogen pressure of 1.1 kg / cm ² .

After about 5 hours, the reaction was terminated by stirring for another 30 minutes after the absorption of hydrogen stopped. After separating the catalyst from the reaction solution, methanol was distilled off and the main fraction (7
3 ° C / 1 Torr to 77 ° C / 2.5 Torr) 361.2g
Got

As a result of analysis by gas chromatography, the rate of change of methyl 2,2-diallylacetoacetate was 100%, 2,2-
The yield of methyl dipropylacetoacetate to methyl 2,2-diallylacetoacetate was 97%, and the presence of other reduction products was not recognized.

Production of methyl valproate: Step (III) In a reactor equipped with a condenser and a stirrer, 142.2 g of methyl 2,2-dipropylacetoacetate, 15.1 g of 28% sodium methylate-methanol solution, and methanol 2
2 g was charged and reacted under reflux for 2.5 hours.

The by-produced methyl acetate was distilled off for 2 hours and then concentrated under normal pressure to obtain 123.5 g of a blackish brown concentrated liquid.

As a result of analysis by gas chromatography, the content of methyl valproate was 87%, and the yield based on methyl 2,2-dipropylacetoacetate was 98%.

Production of valproic acid: Step (IV) 40% aqueous sodium hydroxide solution 106 was added to the above concentrated solution.
g and 44 g of water were added, the mixture was reacted at 71 to 88 ° C. for 2 hours, and then concentrated under normal pressure.

130 ml of water was added to the concentrate, and the concentrate was washed twice with the same amount of toluene. After liquid separation, the aqueous layer was added with a 30% sulfuric acid solution 194
The separated oil layer formed by the addition of g was separated, magnesium sulfate was added thereto, and the mixture was sufficiently stirred and filtered to obtain 105 g of a liquid.

As a result of analysis by gas chromatography, the content of valproic acid was 92.6%, and the yield based on methyl valproate was 9
It was 7%.

Fractionation of 87 ° C./3 mmHg was collected from the liquid by rectification to obtain valproic acid having a purity of 99.9%. α-propyl-β
-Ethyl-acrylic acid or its ester was not contained in the product at all.

Examples 2 to 4 Valproic acid was produced according to Example 1 except that the conditions of Steps (I) to (III) were changed as shown in the attached table.

In any of the examples, formation of by-products that would make isolation of valproic acid difficult was not observed in the reduction step and other steps.

The results are summarized in the table on the next page.

In the table, AAM means methyl acetoacetate and AAE means ethyl acetoacetate.

Example 5 Step (I) A reactor equipped with a condenser and a stirrer was charged with 11.6 g of methyl acetoacetate, 100 ml of dimethylformamide, 23.0 g of allyl chloride and 29.0 g of potassium carbonate, and the mixture was heated at 50 ° C. for 1 hour. The mixture was stirred and reacted at 60 ° C. for 1 hour and 90 ° C. for 3 hours.

After cooling the reaction solution to room temperature, the excess lump was washed with acetone and mixed with the solution to obtain 50 g of a concentrated solution at 30 mmHg and about 70 ° C. (bath temperature).

Water (250 ml) was added to the solution, and the mixture was extracted three times with 50 ml of benzene each. The benzene layer was washed twice with 100 ml of water. 21.0 by removing benzene from the washing solution
g of a light brown liquid was obtained.

As a result of quantitative analysis by gas chromatography, this liquid contained 85% of methyl 2,2-diallylacetoacetate. (Yield 91% to methyl acetoacetate) Step (II) 21.0 g of the light brown liquid obtained in Step (I), 63 g of methyl alcohol, 0.84 g of Raney nickel (water content 50%)
Was charged into an autoclave, catalytically reduced according to Example 1, and distilled under reduced pressure to obtain 18.4 g of a colorless liquid. As a result of analysis by gas chromatography, 95% of 2,2
-Contains methyl dipropylacetoacetate. (Yield 96% to methyl acetoacetate) Step (III) and Step (IV) 28% sodium methylate-methanol solution in 18.4 g of methyl 2,2-dipropylacetoacetate obtained in Step (II) 2.5 g and 3 g of methanol were added,
Reaction is carried out according to the step (III), and 15.9 g of a brown liquid.
Got

To this liquid, 13 g of 40% sodium hydroxide aqueous solution, 6 parts of water
ml was added, and valproic acid was obtained according to the following step (IV) of Example 1. As a result of analysis by gas chromatography,
The content rate of the target product was 95.7%.

The overall yield based on methyl acetoacetate was 85%.
No α-propyl-β-ethyl-acrylic acid or its ester was contained in the product.

Claims (4)

[Claims] 1. A step of reacting (I) acetoacetic acid ester with allyl halide to obtain 2,2-diallylacetoacetic acid ester, (II) 2,2-diallylacetoacetic acid ester is reduced to give 2,2-diallylacetoacetic acid ester. Of valproic acid, which comprises the step of obtaining propylacetoacetic ester, (III) deacetylating 2,2-dipropylacetoacetic ester with alcohol to obtain valproic acid ester, and (IV) hydrolyzing valproic acid ester. Manufacturing method. 2. The method according to claim 1, wherein the step (II) is carried out by a catalytic hydrogen reduction method. 3. The method according to claim 1, wherein the step (II) is carried out in the presence of a Raney nickel catalyst.
The manufacturing method described in the item. 4. The production method according to claim 1, wherein the step (I) is carried out in the presence of a quaternary ammonium salt catalyst.