JP2847672B2 - Method for producing 4-hydroxycoumarin - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing 4-hydroxycoumarin, which is useful as an intermediate material for pharmaceuticals, pesticides, particularly rodenticides and the like.

[Prior art] Conventionally, acetylsalicylic acid halide was used as a raw material for 4-
As a method for producing hydroxycoumarin, Czechoslovak Patent No. 153829 describes (1) reacting acetylsalicylic halide with acetoacetate in an aqueous solvent in the presence of an alkali to obtain α.
-Step of obtaining alkali salt of [2-hydroxybenzoyl] acetoacetate (2) Step of obtaining α- [2-hydroxybenzoyl] acetoacetate by salting out from the above reaction product solution (3) α- [2-hydroxy Benzoyl] acetoacetate is subjected to a cyclization reaction in the presence of sulfuric acid to obtain 4-hydroxycoumarin.
There is a statement that it can be obtained at 5.0%.

Also, in the examples of US Pat. No. 2,439,302, the desired product was obtained in a total yield of 53.4% by using the aqueous solvent in the above step (1) in substantially the same manner.

[Problems to be Solved by the Invention] However, in the above-mentioned conventional method, water is used as a main solvent in the reaction of acetylsalicylic acid halide and acetoacetic ester in the first step (1), so that the reaction system is There is a drawback that the slurry is turned into a slurry or made into a muddy state, and smooth stirring becomes extremely difficult. In terms of the yield, the present inventors have found that when ethyl acetoacetate is used as a raw material, the yield from acetylsalicylic acid chloride is 76% (reference value: 78.2%), which is a relatively good yield. However, when using cheaper methyl acetoacetate, the yield from acetylsalicylic acid chloride is 55%.
(Examples are not described in the literature) and the yield is low. Therefore, in the production of 4-hydroxycoumarin, the production of the above-mentioned α- [2-hydroxybenzoyl] acetoacetic acid alkali salt can be carried out smoothly, and any of the starting acetoacetate esters can be used. The problem is that the desired product can be obtained with high yield, which is a problem to be solved for industrialization.

[Means for Solving the Problems] Accordingly, the present inventors have conducted intensive studies to solve the problems, and as a result, when using a ketone solvent as a reaction solvent during the reaction in the first step (1), The inventors have found that the object can be achieved, and have completed the present invention.

That is, the present invention provides: (I) reacting acetylsalicylic halide with acetoacetate in a ketone solvent in the presence of an alkali to obtain α
-A step of obtaining an alkali salt of [2-hydroxybenzoyl] acetoacetate; (II) a step of obtaining an alkali salt of α- [2-hydroxybenzoyl] acetoacetate from the reaction product by salting out; (III) α- [2 -Hydroxybenzoyl] acetoacetic acid in the presence of sulfuric acid in a cyclization reaction to obtain 4-hydroxycoumarin.

The feature of the present invention is that a ketone solvent is used as the reaction solvent in the step (I) as described above. By using this ketone solvent, mudification of the system at the time of the reaction is prevented, stirring becomes easy, and even when inexpensive methyl acetoacetate is used as a raw material, the desired product can be obtained with a good yield of 70 to 80%. This is very advantageous for industrialization.

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

Step (I) The reaction of acetylsalicylic halide with acetoacetate in a ketone solvent in the presence of an alkali to give α- [2
-Hydroxybenzoyl] acetoacetic acid alkali salt is produced.

This step (I) probably involves a reaction mechanism. First, from acetylsalicylic acid halide (i) and acetoacetate (ii), α- [2-acetoxybenzoyl] acetoacetate alkyl ester is formed, and then the ester is formed. Is considered to be hydrolyzed by an alkali to change to α- [2-hydroxybenzoyl] acetoacetic acid alkali salt (iii).

In any case, the step (I) is a step of producing a compound (iii) by reacting the compounds (i) and (ii) in the presence of an alkali. Indicated by

As the acetylsalicylic acid halide, acetylsalicylic acid chloride and acetylsalicylic bromide can be used. The compound is used without solvent or dissolved in an inert organic solvent.

As the acetoacetate, various alkyl esters such as methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, and butyl acetoacetate can be used, and economically inexpensive methyl acetoacetate is advantageous.

The amount of the acetoacetate used is 1 mol or more, preferably 1.2 to 2 mol per mol of acetylsalicylic halide.
Molar is appropriate.

Sodium hydroxide and potassium hydroxide can be used as the alkali. The alkali is added to the system as an aqueous solution, and the concentration of the alkali solution is suitably 20 to 50% by weight, preferably 40 to 50% by weight.

The amount of the alkali used cannot be clearly defined because it varies depending on the amount of acetylsalicylic acid halide. However, generally, 2 to 5 mol is suitable for 1 mol of acetoacetate ester.

The alkali may be charged in a necessary amount at the beginning of the reaction, but is preferably supplied to the system continuously or intermittently during the reaction of the compounds (i) and (ii).

As the ketone solvent, propanone, 2-butanone, 2
Any ketone such as -pentanone, 3-pentanone, 4-methyl-2-pentanone, 2-hexanone, cyclohexanone, 2-heptanone and 2-octanone can be used, and preferably a ketone having 4 to 8 carbon atoms is suitable. And
More preferably, 2-butanone, 4-methyl-2-pentanone, and cyclohexanone are practical. The amount of the ketone solvent to be used is 0.1 to acetylsalicylic acid halide.
5 times by weight or more, preferably 0.8 to 3 times by weight is appropriate.

In the present invention, the ketone solvent may be used alone or in a mixture with a small amount of another solvent such as water, as long as the effect is not hindered. In this case, it is necessary that the ketone solvent be contained in the entire reaction solvent in an amount of 10 to 85% by weight, preferably 20 to 70% by weight.

At the time of the reaction, an optional method such as adding an additional solvent during the reaction as necessary can be employed.

The reaction temperature is suitably 0 to 50 ° C, preferably 10 to 30 ° C. The reaction time is about 1 to 5 hours.

Step (II) An α- [2-hydroxybenzoyl] acetoacetic acid alkali salt is obtained from the above reaction product solution by salting out.

As the kind of salt to be used, sodium chloride, potassium chloride and the like can be used, and salting out is carried out according to a conventional method.
To the reaction solution obtained in the step (I), the salt is added in an amount of about 0.08 to 0.2 times by weight based on the weight of the water in the system, and after sufficient stirring, 0 to 1%.
Cool to about 0 ° C. to precipitate the desired product.

 Subsequently, the precipitate is separated according to a conventional method.

Step (III) Alkyl α- [2-hydroxybenzoyl] acetoacetate is cyclized in the presence of sulfuric acid to produce 4-hydroxycoumarin.

The reaction formula is Indicated by

In the cyclization reaction, after drying the compound (iii) obtained in the step (II), sulfuric acid having a concentration of 80 to 100% is used in an amount of 6 to 15 times the molar amount of the compound (iii), and the reaction temperature is 80 to 100 ° C. For about 2 to 8 hours. After the completion of the reaction, the reaction solution is added to water, and the precipitate is removed.

4-Hydroxycoumarin can be obtained in an overall yield of 70-80% based on acetylsalicylic acid halide.

4-hydroxycoumarin obtained by the production method of the present invention is used as an intermediate material for pharmaceuticals, pesticides, especially rodenticides, etc.
It is an extremely useful compound in industry.

[Action] In the method of the present invention, in particular, the ketone solvent used in the step (I) is converted into a muddy reaction system during the reaction in the step (I),
It prevents agglomeration and improves the yield of 4-hydroxycoumarin when inexpensive methyl acetoacetate is used as a raw material.

[Examples and Comparative Examples] Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.

Example 1 Step (I) A mixture of 34.8 g (0.3 mol) of methyl acetoacetate and 80.0 g of methyl isobutyl ketone (4-methyl-2-pentanone) was stirred at a temperature of 15 to 20 ° C. while stirring at a concentration of 40% by weight. 45.4 g (0.454 mol) of a 1% aqueous sodium hydroxide solution were added at a constant rate over a period of 2 hours. While maintaining the temperature of the reaction solution at 15 to 20 ° C., 15 minutes after the start of the charging of the aqueous sodium hydroxide solution, a solution obtained by dissolving 39.7 g (0.20 mol) of acetylsalicylic acid chloride in 20 g of methyl isobutyl ketone was added.
The reaction was performed at a constant rate over time. Subsequently, 200 g of methyl isobutyl ketone was added, and the mixture was stirred at a concentration of 40 g.
A 38.2 g aqueous sodium hydroxide solution was charged over 1 hour, and the mixture was kept at 30 to 35 ° C. for 30 minutes with stirring.
0 g was added, the mixture was heated to 40 ° C., and kept for 30 minutes.

As a result, a slurry containing sodium α- [2-hydroxybenzoyl] acetoacetate was obtained.

Step (II) 35 g of sodium chloride was added to the above slurry liquid, stirred sufficiently, cooled to 10 ° C., and the liquid was passed through. The cake was washed with a small amount of saturated saline (10 ° C.). After drying, 49.45 g (crude yield 101%) of a white to ivory solid was obtained.

Step (III) 49.45 g of the above solid was added to 160.7 g of sulfuric acid having a concentration of 97% by weight while stirring, and the reaction temperature was maintained at 90 to 100 ° C. for 4 hours. After completion of the reaction, the reaction solution was added to 800 g of ice water, the precipitate was removed, and the obtained cake was sufficiently washed with water and dried. This result 2
4.7 g of a white solid was obtained.

As a result of analysis by high performance liquid chromatography, 4
-Hydroxycoumarin purity was 98%.

As a result of analysis by H-NMR and IR, it was found to be 4-hydroxycoumarin [mp = 212 ° C. (decomposition)].

The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 75%.

Example 2 In Example 1, methyl acetoacetate was replaced with ethyl acetoacetate 39.0.
The same reaction was conducted except that g and methyl isobutyl ketone were changed to methyl ethyl ketone (2-butanone).

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 76%.

Comparative Example 1 A reaction was carried out in the same manner as in Example 1, except that methyl isobutyl ketone was changed to toluene.

In the step (I), the system was muddy or clumped, and stirring was difficult. As a result of continuing the reaction, the yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride used was 52%.

Comparative Example 2 The reaction was carried out according to Czechoslovak Patent No. 153829.

Step (I) To a mixed solution of 83.8 g (0.645 mol) of ethyl acetoacetate and 108 g of ice water, 57 g (0.57 mol) of a 40% by weight aqueous sodium hydroxide solution was added while stirring at 0 to 5 ° C. To this, 100 g (0.5 mol) of acetylsalicylic acid chloride and 50 g of toluene
Of the solution (A) dissolved in the above was added at a constant rate over 30 minutes. Next, 28.0 g of 40% by weight aqueous sodium hydroxide solution
(0.28 mol) in 10 minutes, and then 3
7.5 g was added dropwise at a reaction temperature of 0 to 5 ° C over 20 minutes. Again at a reaction temperature of 0 to 5 ° C., 28.0 g of 40% by weight aqueous sodium hydroxide solution
Is added over 10 minutes, and 37.5 g of the solution (A) is added dropwise over 20 minutes. After further stirring at 0 to 5 ° C for 20 minutes, 95.5 g (0.955 mol) of a 40% by weight aqueous solution was added, and the mixture was stirred for 30 minutes. Next, 80 ml of water was added and the mixture was stirred for 30 minutes. (Up to this point, the reaction system became muddy or clumpy, and stirring was extremely difficult.) Further, water 1 was added and the mixture was heated to 80 ° C.

The following steps were performed in accordance with the steps (II) and (III) of Example 1.

As a result of analysis by high performance liquid chromatography (using an internal standard), the purity was 97%.

The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 76%.

Comparative Example 3 The reaction was carried out in the same manner as in Control Example 2 except that the solvent for dissolving acetylsalicylic acid chloride was changed from toluene to acetone.

In the same manner as in Comparative Example 2, in the step (I), the reaction system was muddy, and stirring was extremely difficult.

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 72%.

Control Example 4 In Control Example 3, ethyl acetoacetate was replaced with methyl acetoacetate 74.8.
The reaction was carried out in the same manner except that g was changed.

In the same manner as in Comparative Example 2, in the step (I), the reaction system was muddy, and stirring was extremely difficult.

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 55%.

[Effects] As described above, the production method of the present invention is particularly characterized in that a ketone solvent is used as a reaction solvent in the step (I), and when the ketone solvent is used in the reaction in the step (I), Unlike the conventional method, the reaction system is effective in preventing the reaction system from becoming muddy and agglomerated, facilitating stirring, and improving the yield when inexpensive methyl acetoacetate is used as a raw material.

────────────────────────────────────────────────── ─── Continued on the front page (56) References US Patent 2439302 (US, A) Czechoslovak Patent 153829 (CS) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 311/42- 311/56 REGISTRY (STN) CA (STN)

Claims (1)

(57) [Claims] (I) a step of reacting an acetylsalicylic acid halide with an acetoacetate in a ketone solvent in the presence of an alkali to obtain an alkali salt of α- [2-hydroxybenzoyl] acetoacetate; (II) the above reaction Obtaining α- [2-hydroxybenzoyl] acetoacetic acid alkali salt from the product solution by salting out; (III) cyclizing the α- [2-hydroxybenzoyl] acetoacetic acid alkali salt in the presence of sulfuric acid to form 4- A method for producing 4-hydroxycoumarin, which comprises a combination of steps for obtaining hydroxycoumarin.