JP2892401B2 - Method for producing 5- (4-pyridyl) oxazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 5- (4-pyridyl) oxazole-4-
The present invention relates to a method for industrially and advantageously producing 5- (4-pyridyl) oxazole, which is a decarboxylation product thereof, from a carboxylic acid.

[Prior art] 5- (4-pyridyl) oxazole is important as an intermediate for obtaining a cephalosporin compound. As a conventional technique for producing 5- (4-pyridyl) oxazole, a method of condensing 4-pyridinealdehyde with tosylmethyl isocyanide (Chem. Pharm. Bull., 27 , 79
3 (1979)), a method of producing aminoisonicotinoylmethane from 4-acetylpyridine and then closing the ring with ethyl orthoformate (see J. Org. Chem., 2261 (1980)).

However, these methods have a problem in that the former is expensive in the raw material compound to be used, and a problem in the latter is that the reaction step is long, and both are advantageous from an industrial point of view. Was hard to say.

Therefore, as a production route different from the above-mentioned method, one of the present applicants disclosed in Japanese Patent Application Laid-Open No. 63-150280 a reaction product of an isocyanoacetate ester and an active isonicotinic acid (such as isonicotinic chloride). 5- (4-pyridyl) oxazole-4- obtained by hydrolysis of
A method has been proposed in which carboxylic acid is used as a raw material, and this is subjected to a decarboxylation reaction in the presence of a catalyst in a solvent such as dimethylformamide to produce 5- (4-pyridyl) oxazole, which is the target product. As a catalyst in this decarboxylation reaction, a catalyst composed of a metal powder (for example, copper powder) and an organic base (for example, pyridine) is used.

[Problems to be Solved by the Invention] The method described in JP-A-63-150280 described above has an extremely high industrial value in that inexpensive and easily available raw materials can be used.

However, this method has the following problems,
That is, after completion of the decarboxylation reaction, it is necessary to distill off the insolubles and the solvent from the reaction mixture and to separate the target substance from the residue, so that the purity of the target substance in the residue is low and mixed into the residue. Metal must be separated (the expensive metal must also be recovered), and in order to reuse the distilled solvent, it may be necessary to remove the organic base mixed in the solvent. Further, since the purification step becomes complicated, and the yield of the target product is not always high, around 70%, it is desired to further improve the method for carrying out on an industrial scale.

An object of the present invention is to provide a method for remarkably improving the yield without using a special catalyst in the above decarboxylation reaction.

[Means for Solving the Problems] The method for producing 5- (4-pyridyl) oxazole of the present invention comprises heating 5- (4-pyridyl) oxazole-4-carboxylic acid to decarbonate 5- (4-pyridyl) oxazole-4-carboxylic acid. In producing (4-pyridyl) oxazole, the reaction is carried out in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohols, carboxylic acids and phenols. It is.

 Hereinafter, the present invention will be described in detail.

Starting material 5- (4-pyridyl) oxazole-
As described in JP-A-63-150280, 4-carboxylic acid hydrolyzes a reaction product of an isocyanoacetic acid ester and an isonicotinic acid activator (particularly, isonicotinic acid chloride). It is obtained by doing.

The reaction between the isocyanoacetate and the isonicotinic acid activator is carried out in the presence of an organic or inorganic base in a suitable solvent at a temperature of about 0 to 50 ° C. The hydrolysis reaction is carried out in water or aqueous alcohol in the presence of an inorganic base at room temperature to about 50 ° C.

In the present invention, the thus obtained 5- (4
(Pyridyl) oxazole-4-carboxylic acid is heated and decarboxylated in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohols, carboxylic acids and phenols. I do.

Here, as the aprotic amide, N, N-dimethylformamide (boiling point: 153 ° C.), N, N-dimethylacetamide (boiling point: 166 ° C.), N, N-diethylformamide (boiling point: 17 ° C.)
7 to 178 ° C), N, N, N ', N'-tetramethylurea (boiling point 177
-178 ° C), N-methylpyrrolidone (boiling point 202 ° C), N-
And formyl piperidine (boiling point 166 ° C.).
Among these, N, N-dimethylformamide is the most industrial, considering the boiling point, yield, cost, and the like. If necessary, other solvents may be used in combination as long as the purpose of the present invention is not impaired.

As the protic compound, alcohol, carboxylic acid or phenol is used, and alcohol is particularly preferable in terms of yield, handleability, ease of isolation of the target substance, and cost.

Examples of alcohol include methanol, ethanol,
n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol,
Aliphatic alcohols such as hexanol and octanol; alicyclic alcohols such as cyclopentanol and cyclohexanol; aromatic alcohols such as benzyl alcohol and β-phenylethyl alcohol; heterocyclic alcohols such as furfuryl alcohol; ethylene glycol and propylene Glycol, butanediol, hexanediol, glycerin, trimethylolethane, trimethylolpropane, aliphatic polyhydric alcohols such as neopentyl alcohol, diethylene glycol, triethylene glycol,
Polyhydric alcohols containing ether bonds such as polyethylene glycol, dipropylene glycol, tripropylene glycol, and polypropylene glycol; nitrogen-containing alcohols such as 3- (2-pyridyl) propanol; and about 1 to 10 or more carbon atoms. Alcohol.

Examples of carboxylic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, adipic acid, benzoic acid, cyclohexanecarboxylic acid and the like.

Examples of phenol include phenol, cresol,
Xylenol, o-chlorophenol, and the like.

The amount of the aprotic amide used is 5 to 1 part by weight of 5- (4-pyridyl) oxazole-4-carboxylic acid.
It is appropriate to use about 20 parts by weight, especially about 10 parts by weight, but it is not necessarily limited to this range.

The amount of the protic compound to be used cannot be specified unconditionally because it varies greatly depending on the type, but it is often about 0.005 to 20 parts by weight, especially about 0.01 to 2 parts by weight per 1 part by weight of the aprotic amide. .

The method of charging the above-mentioned starting materials, aprotic amides and protic compounds is arbitrary, including a method of charging them all at once, a method of splitting one or two of them, a method of continuously charging at least one of them, and the like. Are both adopted.

The reaction temperature is suitably about 100 to 210 ° C, and the reaction is usually carried out under reflux. The reaction time is often about 0.5 to 10 hours.

After completion of the reaction, the aprotic amide and the protic compound are removed by an appropriate means such as distillation under reduced pressure. Since the concentrate (residue) is 5- (4-pyridyl) oxazole containing some impurities, it is purified by recrystallization, washing, or other means to obtain the desired product.

[Operation] The reaction of the present invention is represented by the following formula. alcohol,
The aprotic amide containing at least one protic compound selected from the group consisting of carboxylic acids and phenols is considered to play a role as a solvent as well as a catalyst for promoting the decarboxylation reaction.

[Examples] Next, the present invention will be further described with reference to examples.

Example 1 In a flask equipped with a reflux device, 5- (4-pyridyl)
6.00 g of oxazole-4-carboxylic acid, 56.6 g (60 ml) of N, N-dimethylformamide and 2.9 g of ethanol were charged, and the mixture was heated and subjected to a decarboxylation reaction under reflux (reflux temperature 122 ° C.) for 5 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 4.71 g of a concentrate.

Analysis by gas chromatography (quantitative analysis by the internal standard method, hereinafter the same) revealed that this concentrate contained 97.3% by weight of 5- (4-pyridyl) oxazole. The yield was 99%.

The concentrate was dissolved in ethyl acetate at a 20-fold weight ratio, and no insolubles were observed.

Example 2 A flask was charged with 5- (4-pyridyl) oxazole-4.
-4.00 g of carboxylic acid, 37.7 g of N, N-dimethylformamide
(40 ml) and 1.3 g of ethylene glycol, and the mixture was heated and subjected to a decarboxylation reaction under reflux (reflux temperature: 136 ° C.) for 5 hours.

After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 6.97 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 41.3% by weight of 5- (4-pyridyl) oxazole. The yield was 94%.

Example 3 A flask was charged with 5- (4-pyridyl) oxazole-4.
-4.00 g of carboxylic acid, 37.7 g of N, N-dimethylformamide
(40 ml) and 37.8 g of n-hexanol were charged, and heated to carry out a decarboxylation reaction under reflux (reflux temperature 140 ° C.) for 6 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3.20 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 95.1% by weight of 5- (4-pyridyl) oxazole. The yield was 99%.

Examples 4 to 5 The charged amount of n-hexanol was 6.7 g (Example 4), 36
Example 3 was repeated except that 0 g (Example 5) was used.

 The yield was 91% in Example 4 and 89% in Example 5.

Example 6 A flask was charged with 5- (4-pyridyl) oxazole-4.
-4.00 g of carboxylic acid, 37.7 g of N, N-dimethylformamide
(40 ml) and 12.6 g of cyclohexanol were charged and heated to carry out a decarboxylation reaction under reflux (reflux temperature: 157 ° C.) for 6 hours.

After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3.48 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 80.6% by weight of 5- (4-pyridyl) oxazole. The yield was 91%.

Example 7 A flask was charged with 5- (4-pyridyl) oxazole-4.
-Carboxylic acid 6.00 g, N, N-dimethylformamide 56.6 g
(60 ml) and 3.8 g of glacial acetic acid, and the mixture was heated and subjected to a decarboxylation reaction under reflux for 6 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 8.01 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 54.0 g% by weight of 5- (4-pyridyl) oxazole. The yield was 94%.

Example 8 A flask was charged with 5- (4-pyridyl) oxazole-4.
-Carboxylic acid 4.00 g, N, N-dimethylformamide 75.5 g
(80 ml) and 25.0 g of cyclohexanol, and the mixture was heated and subjected to a decarboxylation reaction under reflux for 5 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3.52 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 83.0% by weight of 5- (4-pyridyl) oxazole. The yield was 95%.

Example 9 A flask was charged with 5- (4-pyridyl) oxazole-4.
-Carboxylic acid 4.00 g, N, N-dimethylformamide 75.5 g
(80 ml) and 4.9 g of n-butanol, and the mixture was heated and subjected to a decarboxylation reaction under reflux for 5 hours.

After cooling, the reaction solution was analyzed by gas chromatography and found to contain 3.08% by weight of 5- (4-pyridyl) oxazole. The yield was 83%.

Examples 10 to 11 Instead of N, N-dimethylacetamide, 81.5 g of N-methylpyrrolidone (Example 10), N-formylpiperidine 8
Example 9 was repeated except that 1.5 g (Example 11) was used.

 The yield was 84% in Example 10 and 90% in Example 11.

Comparative Example 1 5- (4-pyridyl) oxazole-4 was added to a flask.
-Carboxylic acid 6.00 g and N, N-dimethylformamide 5
6.6 g (60 ml) was charged, and the mixture was heated and subjected to a decarboxylation reaction under reflux for 5 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 4.43 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 53.0 g% by weight of 5- (4-pyridyl) oxazole. The yield was 51%.

Ethyl acetate 20 times in weight ratio was added to the above concentrate and stirred, but undissolved components remained. After filtration, 0.9 g of an undissolved component was obtained.

Comparative Example 2 5- (4-pyridyl) oxazole-4 was added to a flask.
-4.00 g of carboxylic acid and 40.0 g of ethylene glycol were charged, heated and subjected to a decarboxylation reaction at 135 to 140 ° C for 5 hours.

After cooling, the reaction solution (42.4 g) was analyzed by gas chromatography. As a result, 4.28% by weight of 5- (4-pyridyl) was analyzed.
It was found to contain oxazole. 59% yield
Met.

Comparative Example 3 5- (4-pyridyl) oxazole-4 was added to a flask.
-4.00 g of carboxylic acid and 40.0 g of n-hexanol were charged, and heated to carry out a decarboxylation reaction under reflux for 5 hours.

After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3.94 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 16.8% by weight of 5- (4-pyridyl) oxazole. Yield was 22%.

Ethyl acetate at a weight ratio of 20 times was added to the above concentrate and stirred, but hardly dissolved, and 3 g of a solid content was recovered after filtration.

Comparative Example 4 5- (4-pyridyl) oxazole-4 was added to a flask.
-Carboxylic acid 6.00 g, N, N-dimethylformamide 56.6 g
(60 ml), 280 nm of copper powder and 1.96 g (2.0 ml) of pyridine were heated and subjected to a decarboxylation reaction under reflux for 5 hours.

After completion of the reaction, the mixture was cooled on ice, and the insolubles were separated by filtration. Then, the solvent was distilled off under reduced pressure to obtain 5.25 g of a concentrate.

The content of the target compound in the concentrate is 62.2% by weight, and the yield is 70.8%
Met.

When 20% by weight of ethyl acetate was added to the above concentrate and stirred, there was 0.94 g of undissolved matter.

 On the other hand, the concentrate contained 42 mg of copper.

Table 1 summarizes the conditions and results of Examples 1 to 11 and Comparative Examples 1 to 4.

Example 12 A flask was charged with 5- (4-pyridyl) oxazole-4.
-Carboxylic acid 4.00 g, N, N-dimethylformamide 48.0 g
And 4.0 g of phenol, and heated to carry out a decarboxylation reaction under reflux (reflux temperature: 152 ° C.) for 5 hours.

After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 8.16 g of a concentrate.

Analysis by gas chromatography revealed that the concentrate contained 32.1% by weight of 5- (4-pyridyl) oxazole. The yield was 85%.

Examples 13 to 22 Example 12 was repeated except that another protic compound was used instead of phenol. The conditions and results are shown in Table 2 and its footnotes.

[Effects of the Invention] In the present invention, the reaction is carried out only in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohols, carboxylic acids and phenols. Certain 5- (4-pyridyl)
Oxazole can be obtained in good yield.

The use of catalysts such as metal powders and organic bases becomes unnecessary, and
Since the removal of the aprotic amide containing a protic compound from the reaction product is easy, and the purity of the product in the reaction product is extremely high, the isolation and purification steps of the product from the reaction product after the reaction is completed It becomes much simpler than the conventional method.

Therefore, according to the present invention, 5- (4-pyridyl) oxazole can be industrially advantageously produced.

Continuation of the front page (72) Inventor Yusuke Yukimoto 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Production Research Laboratory (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 413/04 CA (STN)

Claims (2)

(57) [Claims] (1) 5- (4-pyridyl) oxazole-4-
By heating the carboxylic acid and decarboxylating it,
In the production of (pyridyl) oxazole, the reaction is carried out in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohols, carboxylic acids and phenols.
A method for producing-(4-pyridyl) oxazole. 2. The method according to claim 1, wherein the aprotic amide is N, N-dimethylformamide.