JPH0414106B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 3-hydroxy-pyridones. 3-Hydroxy-pyridones are known to have various physiological activities, for example, as reported in the Journal
of Pharmaceutical Sciences, Vol. 69, p. 1074 (1980), it is reported that it exhibits high antitumor activity. However, 3-hydroxy-
The production of pyridones requires a multi-step reaction,
Until now, a major drawback was that it could not be easily synthesized. For this reason, many attempts to obtain 3-hydroxy-pyridones using 3-hydroxy-4-pyrones, which are easily available as raw materials, have been investigated for a very long time, but so far they have not been successful. I haven't seen any examples of this happening. For example, when 3-hydroxy-2-methyl-4-pyrone is reacted with ammonia, the addition only produces a weak salt, and the resulting salt immediately decomposes in the air and cannot be returned to its raw material. It has been reported. In addition, Yasue et al., Pharmaceutical Journal, Volume 90, 1223
(1970) 2-methyl-3-hydroxy-4
- It has been reported that 4-pyridone is not obtained even when pyrone is treated with ammonia. The present inventors have conducted intensive research on the reactivity of 3-hydroxy-4-pyrones. As a result, they surprisingly discovered that the reaction to obtain 3-hydroxy-pyridones from 3-hydroxy-4-pyrones and ammonia depends on the reaction conditions, leading to the completion of the present invention. That is, the present invention provides the general formula 3-hydroxy-4 (wherein R is a hydrogen atom alkyl group or substituted alkyl group)
-3-hydroxy- characterized by reacting pyrones and ammonia at a temperature of 35°C to 120°C
This is a method for producing 4-pyridones. The 3-hydroxy-pyridones of the present invention have the general formula

【formula】

[expression] or

The compound represented by the formula is described below as a representative of 3-hydroxy-4(1H)-pyrrolidone. According to the reaction of the present invention, 3-hydroxy-4
(1H)-pyrrolidone can be obtained in good yield through a one-step reaction. Although the mechanism of this reaction is not yet clear, the present inventors speculate as follows. It is thought that first, the -OH group at the 3-position of the pyrone ring and one molecule of ammonia are added to form a weak salt, and then the pyrone ring is converted to a pyridone ring by another ammonia molecule. 3-hydroxy-4- raw material used in the present invention
Pyron has the general formula (However, R is a hydrogen atom, an alkyl group, or a substituted alkyl group.) Since R in the general formula does not participate in the reaction of the present invention and remains as it is in the product after the reaction, it is not particularly limited. Generally, when R is an alkyl group, it is not particularly limited and can be selected as required, but from an industrial standpoint, for example, a methyl group, an ethyl group, a propyl group, a butyl group,
Lower alkyl groups such as cyclohexyl are preferred. Substituted alkyl groups are those in which the hydrogen atom of the alkyl group is substituted with another atom or group, and generally from an industrial standpoint, at least one of the hydrogen atoms is a halogen atom, an alkoxy group, a hydroxyl group, or a vinyl group. Substituted alkyl groups substituted with etc. are preferably used. Ammonia used in the present invention can be used without particular limitation in any of gaseous, liquid, or solution states dissolved in a solvent or the like. However, from the viewpoint of reaction operation, a solution state such as an aqueous solution is often advantageous. Furthermore, since the amount of ammonia affects the yield of the desired product, it needs to be appropriately selected depending on other conditions. Generally, the raw material 3-hydroxy-
It is best to use at least an equimolar amount to 4-pyrone.
Industrially, it is preferable that the amount is 1.1 times or more, preferably 1.5 times or more, and more preferably 2 times or more, since the yield of the reaction improves. The reaction of the present invention needs to be carried out under heating, and is generally preferably carried out at a temperature of 35°C or higher, preferably 40°C or higher. Further, a temperature of 60° C. or higher is more suitable because the reaction progresses more easily. However, in the reaction at low temperature, 3-hydroxy-4-
Pyridone and ammonia add to form a weak salt, but this reaction tends to be difficult to proceed and cannot be used. Also, the upper limit of the reaction temperature is
The temperature is 120℃. If the reaction temperature is higher than the above upper limit, the yield of the target product will be extremely reduced. Although the reaction of the present invention proceeds with or without a solvent, it is generally carried out in the presence of a solvent. The solvent may be used without any particular restriction as long as it does not react with the raw material and dissolves the raw material. It is preferable that the solvent forms a homogeneous phase with ammonia, but even if it forms a heterogeneous phase with ammonia, it can be used because the reaction proceeds by contacting and mixing the two phases. Typical solvents that are generally suitably used include: aliphatic hydrocarbon solvents such as n-hexane and pentane; aromatic hydrocarbon solvents such as benzene and toluene; halogenated hydrocarbon solvents such as chlorobenzene. Solvent: Ether solvent such as diethyl ether, tetrahydrofuran, diglyme; dimethyl sulfoxide,
Oxosulfur solvents such as sulfolane; nitrile solvents such as acetonitrile and benzonitrile;
These include amide solvents such as N,N-dimethylformamide and hexamethylphosphoramide; alcohol solvents such as methanol and ethanol; tertiary amines such as pyridine and triethylamine; and water. Of course, these solvents can be used alone or in combination. The reaction of the present invention may be carried out in a state in which the raw material compound and the solvent are charged, and may be carried out in the open to the atmosphere, or may be carried out under pressure in a sealed container such as an autoclave. However, it is usually preferable to carry out the reaction in a sealed container such as an autoclave, since it is possible to prevent loss of ammonia, which is a raw material, and to increase the ammonia concentration. The reaction time in the present invention varies depending on the type of solvent used, the reaction temperature, etc., and cannot be absolutely limited, but it is generally preferable to select it within the range of several minutes to several days, and if necessary, It is preferable to select other conditions so that the reaction time is on the order of hours. Examples are shown below to specifically explain the present invention, but the present invention is not limited to these Examples. The yield (%) is based on the weight of 3-hydroxy-4-pyrone used as a raw material, and the yield (%) is based on the weight of 3-hydroxy-4-pyrone used as a raw material.
The weight of the target product actually isolated is expressed as a ratio (%) to the weight of 4(1H)-pyridone. Example 1 1.26 g of 3-hydroxy-2-methyl-4-pyrone (common name: maltol) and 30 ml of 25% ammonia aqueous solution were placed in a 100 ml reaction container of a stainless steel autoclave, and the reaction container was heated while stirring the inside of the reaction container. was heated to 70°C. After 7 hours, the reaction vessel was cooled, and the contents were taken out from the reaction vessel and transferred to a 100 ml eggplant-shaped flask. Keep the 100ml eggplant-shaped flask at a reduced pressure of 1mmHg.
Water and low-boiling components were removed from the contents by heating to 70°C, yielding 1.21 g of a black solid. The black solid was washed three times with 30 ml of chloroform and then three times with 30 ml of methanol to remove raw maltol and trace amounts of by-products, yielding 1.18 g of a brown solid. The infrared absorption spectrum, ¹ H-NMR spectrum, mass spectrum and elemental analysis values of this product are 3-
A complete match was found under hydroxy-2-methyl-4(1H)-pyridone. The yield was 94%. Example 2 The same experimental procedure as in Example 1 was carried out except that the reaction temperature was changed to 40° C., and 3-hydroxy-2-methyl-4(1H)-pyridone was obtained. As a result, the yield of 3-hydroxy-2-methyl-4(1H)-pyridone was 58%. Further, for comparison, the reaction was carried out in the same manner as in Example 1 except that the reaction temperature was set to room temperature (10° C.). As a result, 3-hydroxy-2-methyl-4
Almost no formation of (1H)-pyridone was observed. Furthermore, the same procedure as in Example 1 was carried out except that the reaction temperature was changed to 150°C, and the result was 3-hydroxy-2-
The yield of methyl-4(1H)-pyridone was 23%;
When the temperature was changed to 180°C, it was only 8%, and a large amount of black tar-like substance was produced in both cases. The generation of this tar-like substance is thought to be due to the substitution reaction of hydroxyl groups with amino groups by ammonia, and the resulting amine derivative further reacted with the raw material. Example 3 3-Hydroxy-2-methyl-4(1H)-pyridone was obtained by carrying out the same experimental procedure as in Example 1, except that the amount of ammonia was changed. This result is the first
Shown in the table.

[Table] Example 4 The same experimental procedure as in Example 1 was performed except that the compounds shown in Table 2 were used in place of maltol used in Example 1. The results are shown in Table 2.

【table】

[Table] Example 5 12.6 g of maltol was placed in a 100 ml stainless steel autoclave reaction vessel, and the reaction vessel was cooled with dry ice-methanol. Separately, cool the pure ammonia from the ammonia cylinder with dry ice-methanol, transfer it to a pressure-resistant glass container, and store the ammonia in the liquid state at -78℃.
ml was trapped. Next, the autoclave and the pressure-resistant glass container in which the ammonia was trapped are connected with a stainless steel tube, and while both containers are cooled with dry ice-methanol, the air inside is removed using a vacuum pump, and the inside of the autoclave and the pressure-resistant glass container are separated. Both were placed in a reduced pressure state. By gradually returning the pressure-resistant glass container to room temperature, ammonia was transferred into the autoclave reaction container, and when all the ammonia had been transferred, the pressure-resistant glass container and the autoclave were shut off. Gradually return the autoclave reaction vessel to room temperature.
The mixture was further heated to 70°C and stirred for 5 hours. After the reaction is complete, remove the ammonia from the autoclave,
Approximately 12 g of reaction product was obtained. The target product, 3-hydroxy-2-methyl-4(1H), was obtained by washing the product with chloroform and then methanol.
- 11.8 g of pyridone were obtained. Example 6 12.6 g of maltol and 20 ml of various solvents listed in Table 3 were placed in a 100 ml stainless steel autoclave reaction vessel.
I put in. Subsequently, the same experimental operations as in Example 5 were carried out, and 2 ml of liquid ammonia (-
at 78°C) and then at 70°C with stirring.
By reacting for 10 hours, the desired 3-hydroxy-2-methyl-4(1H)-pyridone was obtained. The results are shown in Table 3.

[Table] Example 7 In a 100ml eggplant-shaped flask, add 1.26g of maltol and
15 ml of 25% ammonia aqueous solution was added thereto, and the mixture was stirred for 3 hours while heating to 60°C. Next, add 15 ml of 25% ammonia aqueous solution to the eggplant-shaped flask,
By reacting with continuous stirring while heating at 60°C for 3 hours, 3-hydroxy-2-methyl-4
0.72 g (yield 58%) of (1H)-pyridone was obtained.

Claims (1)

[Claims] 1. General formula (wherein, R is a hydrogen atom, an alkyl group, or a substituted alkyl group)
A method for producing 3-hydroxy-4-pyridones, which comprises reacting 4-pyrones and ammonia at a temperature of 35°C to 120°C. 2. The method according to claim 1, wherein the amount of ammonia is equal to or more than the amount of the 3-hydroxy-4-pyrones.