JPH02292283A - Production of 5-(4-pyridyl)oxazole - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the subject compound by heating 5-(4-pyridyl)oxazole-4-carboxylic acid in the presence of an aprotic amide containing water to carry out decarboxylation. CONSTITUTION:5-(4-Pyridyl)oxazole-4-carboxylic acid is heated (100 to 210 deg.C) in the presence of an aprotic amide (preferably N,N-dimethylformamide) with a water content of preferably 0.5 to 30wt.% for 0.5 to 10hr to carry out reaction, the amide is eliminated by the distillation in vacus and purified through recrystallization, etc., to afford the objective compound. The aprotic amide containing water is used in an amount of 5 to 20 pts.wt. based on 1 pt.wt. 5-(4-pyridyl)oxazole-4-carboxylic acid.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention... The present invention relates to an industrially advantageous method for producing 5-(4-pyridyl)oxazole, which is a decarboxylation product thereof, from 5-(4-pyridyl)oxazole-4-carboxylic acid. [Prior Art] 5-(4-pyridyl)oxazole is often needed as an intermediate for obtaining cephalosborin compounds. (For example, see Japanese Patent Application Laid-Open No. 1-72-2003.) As a conventional technique for producing 5-(4-pyridyl)ogisazole, there is a method of condensing 4-pyridine aldehyde and tosylmethyl isocyanide (Chew. Pharm.
Bull. , 27, 793 (+979))
, 4-7 A method of producing 7-minoisonicothimeylmethane from cetylpyridine and then ring-closing it with ethyl orthoformate (J. Org. Che+s., 22B+ (19
80)) is known.

However, these methods have the problem that the raw material compounds used in the former are expensive, and the latter have the problem that the reaction process is complicated, and both methods are not advantageous from an industrial standpoint. It was very difficult. Therefore, as a production route different from the method described in (A), one of the present applicants proposed in Japanese Patent Application Laid-open No. 150280/1983 a method of combining isocyanoacetic ester and innicotine liquor active substance (isonicotinic acid chloride, etc.). 5-(4-pyridyl)xazole obtained by hydrolyzing the reactant
They have proposed a method for producing the target product, 5-(4-pyridyl)oxazole, by using 4-carboxylic acid as a raw material and subjecting it to a decarboxylation reaction in a solvent such as dimethylformamide in the presence of a catalyst. Note that, as a catalyst in this decarboxylation reaction, a catalyst consisting of a metal powder (for example, copper powder) and an organic base (for example, pyridine) is used.

[Problems to be Solved by the Invention] 1. The method described in Japanese Unexamined Patent Publication No. 150280/1983 has extremely high industrial value in that it can utilize inexpensive and easily available raw materials.

However, this method has the following problems: After the decarboxylation reaction is complete, it is necessary to distill off the insoluble matter and solvent from the reaction mixture and to separate the 11 substances from the residue. , the purity of the target substance in the residue is low, the gold mixed in the residue must be separated (if it is an expensive metal, it must also be recovered), and the distilled solvent must be reused. In order to do this, it may be necessary to remove the organic base mixed in the solvent, which complicates the purification process, and the yield of the target product is not necessarily high at around 70%. Further improvements are desired in order to implement it on a large scale.

An object of the present invention is to provide a method that does not require the use of a special catalyst in the -L decarboxylation reaction and can significantly improve the yield.

[Efforts to Solve the Problems] The method for producing 5-(4-pyridyl)oxazole of the present invention is to produce 5-(4-pyridyl)oxazole by heating and decarboxylating 5-(4-pyridyl)oxazole-4-carboxylic acid. (4-pyridyl)
In producing oxazole, the reaction is carried out in the presence of an aprotic amide containing water.

The present invention will now be described in detail.

Starting material 5-(4-pyridyl)oxazole-4
- Carboxylic acid is the JP-A No. 63-15028 cited above.
As stated in Publication No. 0. It is obtained by hydrolyzing a reaction product of isocyanoacetic ester and isonicotine lli compound (especially isonicotinic acid chloride).

The reaction between the isocyanoacetic acid ester and the activated isonicotinic acid 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 hydroalcohol in the presence of an inorganic base at a temperature from room temperature to about 50°C. In the present invention, the 5-(4-
When decarboxylating pyridyl)oxazole-4-carboxylic acid by heating, the reaction is carried out in the presence of an aprotic amide containing water.

Examples of aprotic amides include N,N-dimethylformamide (boiling point: 9t 5 3°C), N,N dimethylacetamide (boiling point: 166°C). N,N-diethylformamide' (boiling 177-178°C). N. N,N'
．． N'-tetramethylurea (boiling point 177-178°C)
, N-methylpyrrolidone (boiling point 202°C), N-formylbiperidine, and the like. Among these, when considering boiling point, yield cost, etc., N. N-dimethylformamide has the highest T-performance. If necessary, other solvents may be used in combination without departing from the spirit of the present invention. The water content of the aprotic amide (proportion of water in the water-containing amide) is advantageously between 0.1 and 50,000%, particularly between 0.5 and 30% by weight; The most favorable result is shown in jII. The sewing using hydrous aprotic amide is 5-(4-pyridyl)oxazole-4-carboxylic acid 1-W? About 5 to 20 heavy items for part A, especially 10 ton early part 1i? It is appropriate to set it after j, but it is not necessarily limited to this range.

The method of charging the above-mentioned starting material and the above-mentioned amide is arbitrary, and a method of charging both at once, a method of charging either or both in portions, a method of charging either or both by DHL, etc. can be adopted.

The reaction temperature is suitably about 100 to 210"C, and the reaction is usually carried out to reflux F-"F. Reaction time is 0.5-10
It is often about an hour.

After the reaction is completed, the amide is removed by means such as vacuum distillation. Since the concentrate is 5-(4-pyridyl)oxazole containing some impurities, it is purified by recrystallization, washing, and other means to obtain the desired product.

[Function] The uninvented reaction is expressed by the following formula. The aprotic amide containing water plays the role of a catalyst that promotes the decarboxylation reaction, as well as the role of a solvent. ! It is considered to be 4 plus. [Example] Next, the present invention will be further explained with reference to Examples.

Example 1 5-(4-pyridyl) was added to a flask equipped with a reflux device.
Oxazole-4-carboxylic acid e. 5 eJg of N,N-dimethylformamide and 1.15 g of water (moisture content: about 2%) were charged and heated to carry out a carbonic acid reaction under a stream of water for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 4.66 g of concentrate.
I got it.

As a result of analysis by gas chromatography (quantitative analysis by internal standard method), this e-condensate was 93.8 iT. :♀〜
% of 5-(4-pyridyl)oxazole. The yield was 94.6%. Example 2 Example 1 was repeated except that the amount of ice added was 0.57 g (water content approximately 1%). The IJ of 11 compounds in the concentrate is 90. The yield was 91.2%.

Example 3 Example 1 was repeated except that the water addition value was changed to 2.30 g (water content approximately 4 tonne %). The content of the target product in the concentrate was 90.2%, and the yield was 86.3%.

Example 4 NN in place of 58.8 g of N,N-dimethylformamide
-dimethylacetamide 5ta. Example 1 was repeated, except that 8 g was used and the amount of water added was 1.15 g (moisture content about 2 times 45%). The content of the target product in the concentrate was 77.9% by weight, and the yield was 80%.
．． It was 1%.

Example 5 N- in place of 58.8 g of N,N-dimethylformamide
Except that 81.1 g of formylbiperidine was used and the amount of water was 1.22 g (water content approximately 20%),
Example 1 was repeated several times. The content of the target substance in the reaction solution was approximately f3.09% by weight, and the yield was 8.
It was 7.5%. Example 6 47.3 g of N,N-dimethylformamide and 189 g of water
(Water content: approximately 3.8% by weight) and 2.5-(4-pyridyl)xazole 4-carboxylic liquor. A total of 10.0 g of Og was added 5 times every 1 hour, and then the mixture was further heated under a light flow for 4 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a concentrated 1h product of 8.02
I got g. Analysis by gas chromatography showed that this concentrate contained 94.1% by weight of 5-(4-pyridyl)oxazole. The yield was 98.2%.

Example 7 Addition of 5.75 g of water (moisture content approximately 9.2%
), Example 1 was repeated. 11 in concentrate
The target content 11 was 90.7% by weight, and the yield was 83.8%. Comparative Example 1 Example 1 was repeated except that the addition of water was omitted. (However, the water content in N,N-dimethylformamide is 0.0
1 East;,}%. ) After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 4.43 g of a concentrate.

The concentration of the target product in the concentrate is 53.0% by weight, and the yield is 50%.
．． It was 8%.

Comparative Example 2 5-(4-pyridyl)oxazole-4-carvone
．． oog, 56.4 g of N-dimethylformamide. 0.28 g of copper powder and 1.98 g of pyridine were added, and the mixture was heated to carry out a decarboxylation reaction under erosion for 5 hours.

After 7' of chewing, the insoluble matter was separated by filtration after cooling on ice, and then the solvent was distilled off under reduced pressure to obtain a condensate of 5.25 1
I got j.

The content of the target product in the concentrate is B2.2%, and the yield is 7.
It was 0.8%.

<Summary of Results> The results of Examples 1 to 7 and Comparative Examples 1 to 2 are summarized as follows. Danmachi 1 animal n ± Example 1 94.8% Example 2 91.2 g Example 3 8G. 3 2 Example 4 80.1% Example 5 87.5 2 Example 6 98.2 2 Example 7 83.8 2 Comparative example 1 50.8 2 Comparative example 2 70.8 2 [Effect of the invention] k In the old QI method, the desired product, 5-(4-pyridyl)oxazole, can be obtained in good yield simply by carrying out the reaction in the presence of an ice-containing aprotic amide. It is not necessary to use catalysts such as Kinku powder or organic bases, and the water-containing aprotic amide can be easily removed from the reactants, and the purity of the target product in the reactants is extremely high, so it can be easily removed after the reaction is completed. tp of [] target from the reactant. ! The purification process is much simpler than conventional methods.

Therefore, without the invention, 5-(4-pyridyl)oxazole can be produced advantageously in terms of T industry.

4v revised consultant 4′? fraudulent applicant representative person Megi Synthetic Chemical T-gyo Co., Ltd. Daiichi Pharmaceutical Co., Ltd.

Claims (2)

[Claims] (1) In producing 5-(4-pyridyl)oxazole by heating and decarboxylating 5-(4-pyridyl)oxazole-4-carboxylic acid, in the presence of an aprotic amide containing water. A method for producing 5-(4-pyridyl)oxazole, which comprises carrying out a reaction. (2) The production method according to claim 1, characterized in that the reaction is carried out in the presence of an aprotic amide having a water content of 0.1 to 50% by weight.