JPH05255299A - Production of 4-hydroxycumarin - Google Patents

Abstract

PURPOSE:To provide the subject method capable of sufficiently producing 4- hydroxycumarin useful as an intermediate raw material for synthesis of medicines and agricultural chemicals even on an industrial scale. CONSTITUTION:(i) A malonic acid diester is reacted with (ii) magnesium chloride or magnesium oxide and (iii) acetylsalicylic chloride and the resultant 2-(2- acetoxybenzoyl)malonic acid dialkyl ester is subsequently cyclized by using an alkali.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 4-hydroxycoumarin which is useful as an intermediate raw material for medicines, agricultural chemicals, particularly rodenticides.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 4-hydroxycoumarin, 3-ethoxycarbonyl-4-hydroxycoumarin [Indian. Acetyl salicyl chloride, diethyl malonate, and magnesium ethylate obtained by reacting them in a benzene solvent] [Indian. J. Chem. Sect
B. 20B (6) 511 (1981)] is deacetylated with sulfuric acid or the like to produce 4-hydroxycoumarin.

[0003]

In such a method, however, the raw material magnesium ethylate is an expensive and difficult-to-handle chemical, and the reaction system becomes a slurry or blocks into a muddy state as the reaction proceeds, It has drawbacks such that smooth stirring becomes very difficult, and it is impossible to carry out production on an industrial scale.

[0004]

SUMMARY OF THE INVENTION However, the present inventor has conducted extensive studies to find a manufacturing method which can be industrially sufficiently manufactured using inexpensive and easy-to-handle raw materials, and as a result,
The present invention has been completed by finding that (i) malonic acid diester (ii) magnesium chloride or magnesium oxide (iii) acetylsalicylic acid chloride was used as a raw material, which met the purpose. That is, the present invention succeeded in preventing the reaction solution from becoming muddy or agglomerated by using magnesium chloride or magnesium oxide instead of magnesium ethylate, which is inexpensive and easy to handle. Hereinafter, the present invention will be described in detail.

In the present invention, (i) malonic acid diester (ii) magnesium chloride or magnesium oxide (ii)
i) reacting with acetylsalicylic acid chloride to give 2-
After obtaining (2-acetoxybenzoyl) malonic acid dialkyl ester, cyclization reaction is carried out with alkali to produce 4-hydroxycoumarin, and such steps will be sequentially described. First, in the first step, malonic acid diester, magnesium chloride or magnesium oxide, and acetylsalicylic acid chloride are supplied to a solvent to prepare 2- (2
-Acetoxybenzoyl) malonic acid dialkyl ester is prepared. This first step is based on the reaction mechanism,
As shown in, an intermediate (I) is first produced from malonic acid diester (i) and magnesium chloride or magnesium oxide (ii), and the intermediate (I) reacts with acetylsalicylic acid chloride (iii) to give 2 It is considered that-(2-acetoxybenzoyl) malonic acid dialkyl ester (iv) is produced.

[0006]

[Chemical 1]

[0007]

[Chemical 2]

When magnesium chloride is used in such a reaction, hydrogen chloride is produced as a by-product when intermediate (I) is produced. Therefore, triethylamine, pyridine, morpholine, piperazine or the like is added as an absorbent of such hydrogen chloride. There is a need to. The amount of addition is appropriately 1.0 to 2.0 mol, preferably 1.1 to 1.3 mol per mol of magnesium chloride. Examples of the malonic acid diester include dimethyl malonate, diethyl malonate, dipropyl malonate, diisopropyl malonate and the like, and the practical one is diethyl malonate. The amount of the drug used in such a reaction is 1.0 / 1.0 to 2.0 / 1.0 in terms of molar ratio of acetylsalicylic chloride / malonic acid diester / magnesium chloride or magnesium oxide.
To 2.0, preferably 1.0 / 1.0 to 1.2 / 1.0 to 1.0.
2 is appropriate. The reaction temperature is -10 to 20 ° C, preferably 0 to 10 ° C when magnesium chloride is used, and 50 to 100 ° C, preferably 70 when magnesium oxide is used.
-80 ° C is suitable, and the reaction time is preferably 5-20 hours.

Aromatic hydrocarbons, aliphatic nitriles, aliphatic ketones and the like are used as the solvent in the present invention. Toluene, benzene, xylene and the like are practical as the aromatic hydrocarbons, and acetonitrile is used as the aliphatic nitrile. , Propionitrile and butyronitrile are practically available. Further, as the aliphatic ketone, propanone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2
-Pentanone, 2-hexanone, 2-heptanone, 2-
Any ketone such as octanone can be used, preferably a ketone having 3 to 6 carbon atoms, more preferably 2-butanone (methyl ethyl ketone), 4-methyl-2
-Pentanone (methyl isobutyl ketone) is practical.

The amount of such a solvent to be used is 2 times by weight or more, preferably 5 to 10 times by weight, based on acetylsalicylic chloride. At the time of the reaction, any method such as additionally charging a solvent during the reaction may be adopted. Next, as a second step, alkali is added to the above reaction product, and 2- (2-acetoxybenzoyl) malonic acid dialkyl ester is cyclized to obtain 4-hydroxycoumarin (V). The reaction formula is shown in Chemical formula 3.

[0011]

[Chemical 3]

As the type of alkali, potassium hydroxide,
Sodium hydroxide and the like are suitable. The amount used is practically 4 to 8 times mol based on acetylsalicylic chloride. The conditions in the cyclization reaction are to heat the system at 10 to 70 ° C. for 1.0 to 5.0 hours. The reaction solution is cooled and crystallized, and then filtered and washed with water to isolate the desired product, 4-hydroxycoumarin. If necessary, recrystallization method,
It is also possible to purify according to a well-known method such as an activated carbon treatment method. The 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.

[0013]

In the present invention, since it is possible to prevent the reaction solution from becoming muddy or agglomerated by using magnesium chloride or magnesium oxide which is inexpensive and easy to handle, the production of 4-hydroxycoumarin becomes industrially feasible, and its significance is Extremely large.

[0014]

EXAMPLES The present invention will be described in more detail below with reference to examples. Example 1 Acetonitrile 77.6 g (1.89 mol) and magnesium chloride 9.52 g (0.10 mol) were charged, cooled to 0 ° C., and diethyl malonate 16.02 g (0.10 mol) was added. Triethylamine 20.24 g (0.20 mol)
After addition of 19.86 g (0.10 mol) of acetylsalicylic acid chloride dissolved in 25 g of acetonitrile, the mixture was added dropwise and aged at 0 ° C. for 1 hour. When the reaction solution was evaporated to dryness at a vacuum of 30 Torr and a temperature of 80 ° C., 65.9 g of an evaporated dry matter was obtained.

Next, 100 g of methanol and 33.6 g of potassium hydroxide were added to the above dried solid, and the mixture was heated at 50 ° C. for 3 hours with stirring to carry out a cyclization reaction, then cooled to room temperature and crystallized. The cake obtained by precipitation and then filtration was washed with water and dried to obtain 16.46 g of crystals. The crystals were analyzed by high performance liquid chromatography (HPLC), and the purity of 4-hydroxycoumarin was 87.32%.
Met. As a result of 1 H-NMR and IR analysis, it was found to be 4-hydroxycoumarin. The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 77.4%.

Example 2 Toluene 150 g (1.63 mol), magnesium oxide 8.0 g (0.20 mol), diethyl malonate 20.82
g (0.13 mol), acetylsalicylic acid chloride 1
Charge 9.86 g (0.10 mol) and heat to 80 ° C.
After mixing for an hour, 100 g of methanol and 23.2 g of sodium hydroxide were added and heated at 70 ° C. for 2 hours with stirring to carry out a cyclization reaction, and then cooled to room temperature for crystallization,
Then, the cake obtained by filtration was washed with water and dried to obtain 20.20 g of crystals. As a result of analyzing these crystals by high performance liquid chromatography (HPLC), 4-
The purity of hydroxycoumarin was 92%. H-NM
As a result of analysis by R and IR, it was found to be 4-hydroxycoumarin. The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 77.0%.

Example 3 The same reaction as in Example 1 was carried out except that acetonitrile was changed to methyl isobutyl ketone. The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 74.2% (purity 90.0%). Example 4 A similar reaction was performed except that acetonitrile was changed to benzene in Example 1. The yield of 4-hydroxycoumarin based on acetylsalicylic chloride is 65.2.
% (Purity 88.5%).

Comparative Example 1 A reaction similar to that in Example 4 was carried out except that magnesium chloride was replaced with magnesium ethylate. When the reaction system was charged with acetylsalicylic acid chloride, the viscosity of the reaction system increased and the reaction system was agglomerated. did.

[0019]

INDUSTRIAL APPLICABILITY According to the present invention, since it is possible to prevent the reaction solution from becoming muddy or agglomerated by using magnesium chloride or magnesium oxide which is inexpensive and easy to handle, 4-hydroxycoumarin can be industrially produced. ..

Claims (1)

[Claims] (1) Malonic acid diester (ii) Magnesium chloride (iii) Acetylsalicylic acid chloride is reacted to obtain 2- (2-acetoxybenzoyl) malonic acid dialkyl ester, which is then cyclized with an alkali. And a method for producing 4-hydroxycoumarin