JPH0586048A - Method for producing 3-alkoxycarbonyl-4-hydroxycoumarin - Google Patents

Abstract

PURPOSE:To produce a 3-alkoxycarbonyl-4-hydroxycoumarin on an industrial scale, useful as an intermediate for medicine, agricultural chemical, especially rodenticide by preventing thickening phenomena of reaction system by the use of a specific solvent. CONSTITUTION:A malonic diester of formula (i) (R is 1-2C alkyl) is reacted with magnesium ethylate of formula (ii) and acetylsalicylic acid chloride of formula (iii) to give a 2-(2-acethoxybenzoyl)malonic acid dialkyl ester of formula (iv), which is subjected to ring formation with a mineral acid to produce a 3-alkoxy-4-hydroxycoumarin of formula (v). In the production, an aliphatic nitrile (e.g. acetonitrile, propionitryl or butyronitrile) or an aliphatic ketone (preferably 3-6C ketone, especially methyl ketone or methyl isobutyl ketone) is used as a solvent and the amount of the solvent used is >=twice as much as, preferably 5-10 times as much as the amount of the compound of formula (iii) so that formation of muddiness and lump is prevented to produce the objective compound industrially.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 3-alkoxycarbonyl-4-hydroxycoumarin which is useful as an intermediate raw material for medicines, agricultural chemicals, particularly rodenticides.

[0002]

2. Description of the Prior Art Conventionally, 3-alkoxycarbonyl-4-
As a method for producing hydroxycoumarin, a method of reacting acetylsalicylic chloride, diethyl malonate and magnesium ethylate in a benzene solvent to obtain 3-ethoxycarbonyl-4-hydroxycoumarin [Indian.
J. Chem. Sect B. 20B (6) 511 (1981)] is known.

[0003]

However, in such a method, as the reaction progresses, the reaction system becomes a slurry or blocks to form a mud-like state, which makes smooth stirring extremely difficult, and therefore, on an industrial scale. Manufacturing implementation is absolutely impossible.

[0004]

However, the present inventors have
As a result of intensive research to find a manufacturing method that can be industrially sufficiently manufactured, 2- (2-acetoxybenzoyl) malonic acid dialkyl ester is obtained by reacting acetylsalicylic acid chloride, malonic acid diester, and magnesium ethylate. Then, in the production of 3-alkoxy-4-hydroxycoumarin by cyclization reaction with a mineral acid, it was found that the use of an aliphatic nitrile or an aliphatic ketone as a solvent meets the purpose, and the present invention is completed. Came to. That is, the present invention is characterized in that a specific solvent is used, and it is difficult to prevent the reaction solution from becoming muddy or agglomerated even if a solvent other than the one specified in the present application is used, and to achieve such an object. I can't. Hereinafter, the present invention will be described in detail.

In the present invention, as described above, 2- (2-acetoxybenzoyl) malonic acid dialkyl ester is obtained by reacting acetyl acid chloride, malonic acid diester and magnesium ethylate using aliphatic nitrile or aliphatic ketone as a solvent. And then cyclized with mineral acid to give 3-
Alkoxy-4-hydroxycoumarin is produced, and the steps will be sequentially described. First of all
In the process, malonic acid diester and magnesium ethylate are charged in a specified solvent, and then acetylsalicylic acid chloride is supplied to produce 2- (2-acetoxybenzoyl) malonic acid dialkyl ester. This first
In terms of reaction mechanism, as shown by the following formula, first, an intermediate (I) is produced from malonic acid diester (i) and magnesium ethylate (ii), and such intermediate (I) and acetylsalicylic acid chloride ( It is considered that iii) reacts to produce 2- (2-acetoxybenzoyl) malonic acid dialkyl ester (iv).

[0006]

[Chemical 1]

[Chemical 2]

Examples of the malonic acid diester include dimethyl malonate, diethyl malonate, dipropyl malonate and diisopropyl malonate, and the practical one is diethyl malonate. The amount of the drug used in this reaction is 1.0 / 1.0 in terms of molar ratio of acetylsalicylic chloride / malonic acid diester / magnesium ethylate.
~ 2.0 / 1.0-2.0, preferably 1.0 / 1.0-1.0.
2 / 1.0 to 1.2 is suitable. Reaction temperature is 50 to 10
The temperature is preferably 0 ° C, preferably 70 to 90 ° C, and the reaction time is suitably 0.5 to 50 hours.

The aliphatic ketone solvent in the present invention may be any ketone such as propanone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, 2-hexanone, 2-heptanone, 2-octanone. Can be used, and a ketone having 3 to 6 carbon atoms is preferable, and 2-butanone (methyl ethyl ketone) and 4-methyl-2-pentanone (methyl isobutyl ketone) are more practical. As the aliphatic nitrile solvent, acetonitrile, propionitrile and butyronitrile are practically used. The amount of the specified solvent used is 2 times by weight or more, preferably 5 to 10 times by weight, based on acetylsalicylic chloride. During the reaction, if necessary, an additional solvent may be added during the reaction,
Any method can be adopted.

Next, as a second step, a mineral acid is added to the above reaction product solution, and a 2- (2-acetoxybenzoyl) malonic acid dialkyl ester is cyclized to give 3-alkoxy-.
4-hydroxycoumarin (V) is obtained. The reaction formula is shown by the following formula.

[Chemical 3]

As the type of mineral acid to be used, hydrochloric acid, sulfuric acid, phosphoric acid or the like can be used, and the reaction product solution is PH.
The mineral acid is added as an aqueous solution until it is 3 or less. The conditions in the cyclization reaction are to heat the system at 10 to 50 ° C. for 1.0 to 5.0 hours. The reaction solution is left to separate into two layers of water and an organic layer to separate the organic layer, and the organic layer is concentrated to isolate the desired product, 3-alkoxycarbonyl-4-hydroxycoumarin. Further, if necessary, it can be purified according to a well-known method such as a recrystallization method or an activated carbon treatment method. The 3-alkoxycarbonyl-4-hydroxycoumarin obtained by the production method of the present invention is a very industrially useful compound as an intermediate raw material for medicines, agricultural chemicals and the like.

[0011]

[Operation] In the present invention, the use of a specific solvent can prevent the reaction solution from becoming muddy or agglomerated, so that the production of 3-alkoxycarbonyl-4-hydroxycoumarin becomes industrially feasible. The significance is extremely large.

[0012]

EXAMPLES The present invention will be described in more detail below with reference to examples. Example 1 50 g of acetonitrile, magnesium ethylate 10.
3 g (0.09 mol) was charged, the temperature was raised to 80 ° C., and diethyl malonate 12.01 g (0.075 mol) was added dropwise. After the dropping was completed, the mixture was mixed at the same temperature for 2 hours, and then 9.93 g of acetylsalicylic acid dissolved in 15 g of acetonitrile
(0.05 mol) was added dropwise, mixed for 1 hour, and then aged for 1.0 hour. Next, the pH of the system was adjusted to 1 or less by adding 150.8 g of a 6.25% sulfuric acid aqueous solution to the above reaction solution,
After stirring at 60 ° C. for 60 minutes while heating, the cyclization reaction was performed, and the mixture was allowed to stand at room temperature to separate the organic layer. The organic layer was concentrated under reduced pressure to give 13.5 g of crystals. As a result of analyzing the crystals by high performance liquid chromatography (HPLC), 3
The purity of -ethoxycarbonyl-4-hydroxycoumarin was 99.0%. As a result of analysis by 1 H-NMR and IR, 3-ethoxycarbonyl-4-hydroxycoumarin [m. p. = 99 ° C. (decomposition)]. The yield of 3-ethoxycarbonyl-4-hydroxycoumarin based on acetylsalicylic chloride was 89.
It was 8%.

Example 2 The same reaction as in Example 1 was carried out except that acetonitrile was changed to methyl isobutyl ketone. 3-Ethoxycarbonyl-to acetylsalicylic chloride
The yield of 4-hydroxycoumarin is 88.0% (purity 97.
8%). Example 3 A similar reaction was performed except that acetonitrile was changed to methyl ethyl ketone in Example 1. 3-Ethoxycarbonyl-4-to acetylsalicylic chloride
The yield of hydroxycoumarin is 85.4% (purity 99.0).
%)Met. Example 4 The same reaction as in Example 1 was performed except that acetonitrile was changed to propionitrile. The yield of 3-ethoxycarbonyl-4-hydroxycoumarin based on acetylsalicylic chloride was 89.0% (purity 99.0%).
Met.

Example 5 In Example 1, 12.01 g (0.0) of diethyl malonate was used.
(75 mol) was changed to 9.9 g (0.075 mol) of dimethyl malonate, and the same reaction was performed except that acetonitrile was changed to butyronitrile, to obtain 13.1 g of crystals. As a result of analysis by 1 H-NMR and IR, it was found to be 3-methoxycarbonyl-4-hydroxycoumarin. The yield of 3-methoxycarbonyl-4-hydroxycoumarin based on acetylsalicylic acid was 89.0% (purity 99.0%).

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that benzene was used as the solvent instead of acetonitrile. When the reaction system was charged with acetylsalicylic chloride, the viscosity of the reaction system increased and the reaction was agglomerated. I canceled it.

[0016]

INDUSTRIAL APPLICABILITY In the present invention, the use of a specific solvent can prevent the thickening phenomenon of the reaction system, so that the industrial production of 3-alkoxycarbonyl-4-hydroxycoumarin becomes possible.

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[Procedure amendment]

[Submission date] March 11, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0005

[Correction method] Change

[Correction content]

The present invention uses an aliphatic nitrile or an aliphatic ketone as a solvent as described above, and uses acetylsalicylic acid
Since lolide , malonic acid diester and magnesium ethylate are reacted to obtain 2- (2-acetoxybenzoyl) malonic acid dialkyl ester, cyclization reaction with a mineral acid produces 3-alkoxy-4-hydroxycoumarin. However, such steps will be sequentially described. First, as a first step, malonic acid diester and magnesium ethylate are charged in a specified solvent, and then acetylsalicylic acid chloride is supplied to produce 2- (2-acetoxybenzoyl) malonic acid dialkyl ester. In the first step, the reaction mechanism is represented by the following formula: first, the intermediate (I) is produced from the malonic acid diester (i) and the magnesium ethylate (ii), and the intermediate (I) and acetyl are formed. It is considered that salicylic acid chloride (iii) reacts to produce 2- (2-acetoxybenzoyl) malonic acid dialkyl ester (iv).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0012

[Correction method] Change

[Correction content]

[0012]

EXAMPLES The present invention will be described in more detail below with reference to examples.
To do. Example 1 50 g of acetonitrile, magnesium ethylate 10.
Charge 3 g (0.09 mol) and raise the temperature to 80 ° C.
Diethyl acid 12.01 g (0.075 mol) was added dropwise.
did. After dripping, mix at the same temperature for 2 hours, then add acetonite
Dissolved in 15 g of rilAcetylsalicylic acid chloride
Charge 9.93 g (0.05 mol) dropwise and mix for 1 hour.
After aging, it was aged for 1.0 hour. Next, add 6.2 to the above reaction solution.
The pH of the system was adjusted to 1 or less by adding 150.8 g of a 5% sulfuric acid aqueous solution.
And heat at 70 ° C for 60 minutes with stirring to cyclize
Then, the mixture was left to stand at room temperature to separate the organic layer. Reduce the organic layer
Concentration under pressure gave 13.5 g of crystals. Such crystals
Analyzed by high performance liquid chromatography (HPLC)
As a result, 3-ethoxycarbonyl-4-hydroxy bear
The phosphorus purity was 99.0%. For H-NMR and IR
As a result of analysis, 3-ethoxycarbonyl-4-hydro
Xycoumarin [m. p. = 99 ° C (decomposition)]
There was found. 3 for acetylsalicylic chloride
-Ethoxycarbonyl-4-hydroxycoumarin yield
Was 89.8%.

Claims (1)

[Claims] 1. A reaction between acetylsalicylic acid chloride, malonic acid diester and magnesium ethylate.
After obtaining (2-acetoxybenzoyl) malonic acid dialkyl ester, cyclization reaction with a mineral acid is performed to give 3-alkoxy-4.
-A method for producing 3-alkoxycarbonyl-4-hydroxycoumarin, which comprises using an aliphatic nitrile or an aliphatic ketone as a solvent in producing hydroxycoumarin