JPH0236178A - Production of 4-hyroxycoumarin - Google Patents

Abstract

PURPOSE:To obtain the subject compound which is an intermediate raw material for medicines, etc., in high yield without converting the reaction system into a muddy form by reacting an inexpensive acetoacetic acid ester as a raw material with an acetylsalicyloyl halide using a ketone as a solvent and subsequently carrying out cyclizing and deacetylating reaction. CONSTITUTION:An acetylsalicyloyl halide is reacted with an acetoacetic acid ester in an amount of preferably 1.2-2mol based in 1mol acetylsalicyloyl halide in the presence of an alkali, such as sodium hydroxide, using a ketone as a solvent at 0-50 deg.C to provide an alkali alpha-[2-hydroxybenzoyl]acetoacetate. A mineral acid is subsequently added to the above-mentioned reaction product solution to carry out cyclizing reaction and afford 3-acetyl-4-hydroxycoumarin, which is then subjected to deacetylating reaction in the presence of sulfuric acid (in 80-100% concentration) in a molar amount of 6-15 times based on the afore-mentioned reaction product to afford the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 4-hydroxycoumarin, which is useful as an intermediate raw material for pharmaceuticals, agricultural chemicals, and especially rodenticides.

[Prior Art] Conventionally, as a method for producing 4-hydroxycoumarin using acetylsalicylic acid halide as a raw material, Czechoslovak National Patent No. 153829 describes (I) acetylsalicylic acid halide and acetylsalicylic acid halide in the presence of an alkali in an aqueous solvent. Step of reacting acetoacetate to obtain alkali salt of α-[2-hydroxybenzoyl]acetoacetate (2) Step of obtaining alkali salt of α-[2-hydroxybenzoyl]acetoacetate from the reaction product solution by salting out (3) A production method consisting of a combination of steps to obtain 4-hydroxycoumarin by subjecting an alkali salt of α-[2-hydroxybenzoyl]acetoacetate to a cyclization reaction in the presence of sulfuric acid, and the desired product is obtained with a total yield of 79.2
There is a description that it can be obtained at ~85.0%.

Further, in the example of US Pat. No. 2,439,302, the desired product was obtained in a total yield of 53.4% by using a water solvent in step (I) and following the same process.

[Problems to be Solved by the Invention] However, in the above conventional method, water is used as the main solvent when reacting acetylsalicylic acid halide and acetoacetate in step (I), so the reaction system is The resulting slurry becomes highly slurry or blocks, making it extremely difficult to stir smoothly, and the filterability of the alkali salt of α-[2-hydroxybenzoyl] acetoacetate obtained in step (2) is poor. The disadvantage is that filtration takes a long time. In addition, in terms of yield, the present inventors' study results show that when ethyl acetoacetate is used as a raw material, the yield from acetylsalicylic acid chloride is 76% (literature value 78%).
．． 2%), but the yield from acetylsalicylic acid chloride is as low as 55% when cheaper methyl acetoacetate is used (no examples are described in the literature). Therefore, in the production of 4-hydroquine coumarin, it is necessary to smoothly produce and separate the alkali salt of α-[2-hydroxybenzoyl]acetoacetate, and to determine which ester is the raw material acetoacetate. However, it is a challenge to be able to obtain the target product in good yield, which is a problem that must be solved for industrialization.

[Means for Solving the Problems] Therefore, as a result of intensive research in order to solve the problems, the present inventors used a ketone solvent as a reaction solvent during the reaction in step (I), and In the step 2), it was discovered that the above object could be achieved when 3-acetyl-4-hydroxycoumarin, which is easily soluble in common organic solvents, is extracted, and the present invention was completed.

That is, the present invention involves reacting acetylsalicylic acid halide and acetoacetate in a (+)ketone solvent in the presence of an alkali to obtain
- Step of obtaining an alkali salt of [2-hydroxybenzoyl] acetoacetate, (II) Adding a mineral acid to the above reaction product solution to cause a cyclization reaction of the alkali salt of α-[2-hydroxybenzoyl] acetoacetate to produce 3-acetyl - A method for producing 4-hydroxycoumarin comprising a combination of the steps of obtaining 4-hydroxycoumarin and (■) deacetylating 3-acetyl-4-hydroxycoumarin in the presence of an acid to obtain 4-hydroxycoumarin. It is.

A feature of the present invention is that, as described above, a ketone solvent is used as the reaction solvent in step (I). The use of this ketone solvent prevents the system from becoming muddy or lumpy during the reaction, making stirring easier, and in the subsequent step (II), the ketone solvent can be used as it is as an extractant, so the product can be separated. Furthermore, even if inexpensive methyl acetoacetate is used as a raw material, the desired product can be obtained with a good yield of 70 to 80%, which is very advantageous in terms of industrialization.

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

Step (I) In a ketone solvent, in the presence of an alkali, acetylsalicylic acid halide and acetoacetate are reacted to produce α-[2-
Produce alkali salt of hydroxybenzoyl acetoacetate.

This step (I) probably involves acetylsalicylic acid halide (i) and acetoacetate (ii) in terms of reaction mechanism.
), an alkyl ester of α-[2-acetoxybenzoyl]acetoacetate is first produced, and then the ester is hydrolyzed with an alkali and converted to an alkali salt of α-[2-hydroxybenzoyl]acetoacetate (iii). It seems to be.

In any case, step (I) involves reacting compounds (i) and (ii) in the presence of an alkali to form compound (iii).
The reaction formula is (i) (ii)
(iii) (X; halogen, R; alkyl group 0M
;alkali metal).

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

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

The amount of acetoacetate used is 1 mol or more, preferably 1.2 to 1 mol, per 1 mol of acetylsalicylic acid halide.
2 moles is suitable.

As the alkali, sodium hydroxide and potassium hydroxide are economically advantageous. Alkali is added to the system as an aqueous solution, and the concentration of the alkaline solution is between 20 and 50.
% heavy debt, preferably 40-50% by weight is suitable.

Although the amount of the alkali to be used cannot be clearly defined because it varies depending on the nature of the acetylsalicylic acid halide, it is generally appropriate to use 2 to 5 moles per mole of acetoacetate.

Although the required amount of alkali may be charged in its entirety at the start of the reaction, it is advantageously supplied to the system continuously or intermittently during the reaction of compounds (i) and (ii).

Ketone solvents include propanone, 2-butanone, 2-
Any ketone can be used, such as pentanone, 3-pentanone, 4-methyl-2-pentanone, 2-hexanone, cyclohexanone, 2-heptanone, 2-octanone, and preferably a ketone having 4 to 8 carbon atoms. Practical examples include 2-butanone, 4-methyl-2-pentanone, and cyclohexanone. The amount of ketone solvent to be used is 0.
A suitable amount is 5 times by weight or more, preferably 0.8 to 10 times by weight.

In the present invention, the ketone solvent may not only be used alone, but may also be used in combination with a small amount of other solvent such as water, as long as the effect is not impaired. In this case, it is necessary that the ketone solvent be contained in the total reaction solvent in an amount of 10 to 85% by weight, preferably 20 to 70% by weight.

Any method can be used during the reaction, such as adding a solvent during the reaction as necessary.

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) A mineral acid is added to the above reaction product solution to cause a cyclization reaction of the alkali salt of α-[2-hydroxybenzoyl]acetoacetate.
-Acetyl-4-hydroxycoumarin is obtained.

The reaction formula is shown by the beam (iv).

Hydrochloric acid, sulfuric acid, phosphoric acid, etc. can be used as the mineral acid, and the mineral acid is added until the pH of the reaction product liquid reaches about 3 to 1. 3-acetyl-4-hydroxycoumarin is extracted from the acidic slurry using an oil agent, and after distilling off the extractant, crystalline 3-acetyl-4-hydroxycoumarin containing an oily component is extracted.
4-hydroxycoumarin is obtained. The oil agent used is preferably the ketone used as the reaction solvent, but general organic solvents such as toluene, benzene, and esters such as ethyl acetate can be used.

The obtained 3-acetyl-4-hydroxycoumarin may be subjected to the next reaction as it is, but it usually has 1 carbon number.
After removing impurities by washing with lower alcohol of 4 to 4 or dissolving under reflux using the alcohol as a solvent, cooling and precipitation, etc., the product is subjected to the next reaction.

Step (Ill) 4-hydroxycoumarin is produced by deacetylating 3-acetyl-4-hydroxycoumarin in the presence of sulfuric acid.

The reaction formula is shown as (iv) (v).

The deacetylation reaction is performed on the compound obtained in step (II) (
Adding sulfuric acid at a concentration of 80 to 100% to the compound (iv)
) using 6 to 15 times the molar amount, reaction temperature 80 to 100
It is carried out at ℃ for about 3 to 8 hours. After the reaction is completed, the reaction solution is added to water and the precipitate is filtered off to obtain 4-hydroxycoumarin.

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 an extremely useful compound industrially as an intermediate raw material for medicines, agricultural chemicals, especially rodenticides, and the like.

[Function] In the method of the present invention, in particular, the ketone solvent employed in step (I) prevents the reaction system from becoming muddy and agglomerated during the reaction in step (I), and also serves as a raw material. To improve the yield of 4-hydroxycoumarin when using inexpensive methyl acetoacetate.

[Examples and Comparative Examples] The present invention will be described in more detail below with reference to Examples and Comparative Examples.

Example 1 Step (I) Methyl acetoacetate I 04.49 (0.9 mol) and methyl isobutyl ketone (4-methyl-2-pentanone) 2
Add 136.2 ml of an aqueous sodium hydroxide solution with a concentration of 40% by weight to 40 g of the mixed solution while stirring at 15-20°C.
g (I°362 mol) was added at a constant rate over a period of 2 hours. 15 minutes after the start of charging the sodium hydroxide aqueous solution, a solution of 125 g (0.6 mol) of acetylsalicylic acid chloride dissolved in methyl isobutyl ketone 601F was added at a constant temperature for 2 hours while maintaining the temperature of the reaction solution at 15 to 20°C. The reaction was carried out at a rapid rate. Next, add methyl isobutyl ketone 6009 and adjust to a concentration of 40 with stirring.
wt% sodium hydroxide aqueous solution 114.69C1,1
46 mol) was continuously charged at a constant rate over 1 hour. At this time, the temperature of the reaction solution rose to 35°C. 3 more
Stirring was continued for 0 minutes.

Step (If) Add 263 g of concentrated hydrochloric acid to the above reaction solution (PH1),
After stirring at ~30°C for 30 minutes, water 4709 and methyl isobutyl ketone 3009 were added, and the temperature was maintained at 50~55°C. After the precipitate was dissolved, the organic layer was separated. 2 more tanks left
After extraction with 50 g of methyl isobutyl ketone, the organic layer was combined and concentrated under reduced pressure to obtain crystals containing 152.59 brown oily components.

The crystals were further heated under Inonf-IIF vacuum at 45°C for 16
Dry for 1 hour to obtain a brown solid content of 124.39.

Step (III) Add the above solid content 1243 to 4779 sulfuric acid with a concentration of 97% by weight.
9 was added with stirring, and the reaction temperature was maintained at 90-95°C for 4 hours. After the reaction was completed, the reaction solution was added to 2.4 parts of ice water (9 parts), the precipitate was filtered, and the resulting cake was thoroughly washed with water and dried. As a result, 74.9 g of a white to slightly yellow solid was obtained.

As a result of analysis by high performance liquid chromatography (HPLC), the purity of 4-hydroxycoumarin was 97%.

As a result of analysis by 'H-NMR and IR, it was found to be 4-hydroquinocoumarin (m, p, = 213°C (decomposed)).

The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 74.7%.

Example 2 In Example 1, methyl acetoacetate was changed to ethyl acetoacetate117
．． 19, and the reaction was carried out in the same manner except that methyl isobutyl ketone was changed to methyl ethyl ketone (2-butanone).

The yield of 4-hydroxycoumarin based on the acetylsalicylic acid chloride used was 72.6%.

Example 3 The reaction was carried out in the same manner as in Example 1 except for the following two points.

(2) 300 g of 151.89 methanol was added to the brown oil-containing crystals obtained in step (II) and heated to 50°C, then cooled to 15-25°C and filtered with suction. The resulting cake was further washed with a small amount of methanol to obtain 115.29 prismatic light brown crystals (containing 16.4% by weight of methanol).

The crystals were used in step (III) without drying.

■ In the step (I[I), at the time of preparation, the prismatic light brown crystals are mixed with 115.29% sulfuric acid and 380% sulfuric acid with a concentration of 97% by weight.
9. The reaction was carried out in the same manner as in Step (I[I) of Example 1, except that 56 g of sodium hydrogen sulfate (I hydrate) was further added.

The yield of 4-hydroxycoumarin based on the acetylsalicylic acid chloride used was 74.4%.

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

In step (I), the system became muddy or lumpy, and stirring was difficult. As a result of continuing the reaction, the yield of 4-hydroxycoumarin based on the acetylsalicylic acid chloride used was 51%.

Control Example 2 A reaction was carried out according to Diekoslovakia National Patent No. 153829.

Step (I) Add 83.89 (0,645 mol) of ethyl acetoacetate to a mixture of ice water and osg for 40 minutes while stirring while keeping the temperature at 0 to 5°C.
Weight% sodium hydroxide aqueous solution 57g (0.57 mol)
added. Add to this 100 acetylsalicylic acid chloride
(0.5 mol) in 50 g of toluene (A
) was added at a constant rate over 30 minutes. Next 4
After adding 28.1 (0.28 mol) of 0% by weight aqueous sodium hydroxide solution over 10 minutes, 37.5% of the solution (A)
9 was added dropwise over 20 minutes at a reaction temperature of 0 to 5°C. Again at a reaction temperature of 0 to 5°C, add 40% sodium hydroxide aqueous solution 2 by weight.
After adding 8.09 for 10 minutes, solution (A) 37.59
dropwise over 20 minutes. After further stirring for 20 minutes at 0 to 5°C, 95.5 g (0,955 mol) of a 40% by weight aqueous solution was added and stirred for 30 minutes. Then add 809 ounces of water and add 3
Stirred for 0 minutes.

(Up to this point, the reaction system had become muddy or lumpy and stirring was extremely difficult.) Furthermore, 9 was added to 1 of water and heated to 80°C.

The following steps were carried out in accordance with the (■) and ([) steps of Example 1.

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

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

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

As in Control Example 2, the reaction system became muddy in step (I),
Stirring was extremely difficult.

The yield of 4-hydroquine coumarin based on the acetylsalicylic acid chloride used was 70%.

Control Example 4 In Control Example 3, ethyl acetoacetate was replaced with methyl acetoacetate 748
The reaction was carried out in the same manner except that ν was changed.

As in Control Example 2, the reaction system became muddy in step (I),
Stirring was extremely difficult.

The yield of 4-hydroxycoumarin based on the acetylsalicylic acid chloride used was 53%.

[Effects] As mentioned above, the production method of the present invention is characterized in that a ketone solvent is used as a reaction solvent particularly in step (I). , unlike the conventional method, the reaction system is prevented from becoming muddy and clumpy, and the stirring rI
! It also has the effect of improving the yield when inexpensive methyl acetoacetate is used as a raw material.

Claims (1)

[Claims] (I) Reacting acetylsalicylic acid halide and acetoacetate in the presence of an alkali in a ketone solvent,
Step of obtaining alkali salt of α-[2-hydroxybenzoyl]acetoacetate, (II) Adding a mineral acid to the above reaction product liquid to cause a cyclization reaction of the alkali salt of α-[2-hydroxybenzoyl]acetoacetate to 3- A method for producing 4-hydroxycoumarin comprising a combination of the steps of obtaining acetyl-4-hydroxycoumarin and (III) deacetylating 3-acetyl-4-hydroxycoumarin in the presence of sulfuric acid to obtain 4-hydroxycoumarin. .