JPH03123779A - Production of 5-(4-pyridyl)oxazole - Google Patents

Abstract

PURPOSE:To industrially advantageously obtaining using no catalyst the title compound useful as an intermediate for cephalosporin compounds by heating and decarboxylating a (pyridyl)oxazole-carboxylic acid in the presence of a protonic compound-contg. aprotic amide. CONSTITUTION:The objective compound can be obtained by heating pref. at 100-210 deg.C for 0.5-10hr of 5-(4-pyridyl)oxazole-4-carboxylic acid in the presence of an aprotic amide (pref. DMF) containing a protonic compound (pref. an alcohol, carboxylic acid or phenol) to effect the decarboxylation.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides 5-(4-pyridyl)oxazole-4-
The present invention relates to an industrially advantageous method for producing 5-(4-pyridyl)oxazole, which is a decarboxylation product of carboxylic acid, from carboxylic acid.

[Prior Art] 5-(4-pyridyl)oxazole is important as an intermediate for obtaining cephalosporin compounds. (For example, see JP-A-61-7280.) Conventional techniques for producing 5-(4-pyridyl)oxazole include a method of condensing 4-pyridine aldehyde and tosylmethyl isocyanide (Chew, Pharm,
Bull, 27.793 (1971))
4-7 A method of producing amine isonicotinoylmethane from cetylpyridine and then ring-closing it with orthoethyl (
J, Org, Cbem, 2261 (1980
) is known.

However, these methods have the problem that the raw material compounds used are expensive in the former case, and the reaction process is long in the latter case, and both are advantageous from an industrial standpoint. It was difficult to say.

Therefore, as a production route different from the method described in L, one of the present applicants proposed a reaction between isocyanoacetic ester and isonicotinic acid activated form (isonicotinic acid chloride, etc.) in JP-A-63-150280. 5-(4-pyridyl)oxazole-4 obtained by hydrolyzing
-Proposed a method for producing the target product, 5-(4-pyridyl)oxazole, by using 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] The method described in JP-A-63-150280 has extremely high industrial value in that inexpensive and easily available raw materials can be used.

However, this method has the following problems: After the decarboxylation reaction, it is necessary to distill off the insoluble matter and solvent from the reaction mixture, and also to separate the target product from the residue. The purity of the target product is low, and metals mixed in the residue must be separated (
If the metal is expensive, it must be recovered), and in order to reuse the distilled solvent, it may be necessary to remove the organic base mixed in the solvent, which complicates the purification process and makes it difficult to obtain the desired product. Since the yield is not necessarily high at around 70%, further improvements are desired in order to implement it on an industrial scale.

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

- [Means for Solving the Problems] The method for producing 5-(4-pyridyl)oxazole of the present invention includes heating and decarboxylating 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 a protic compound.

The present invention will be explained in detail below.

Starting material 5-(4-pyridyl)oxazole-4
- Carboxylic acid is the JP-A No. 63-15028 cited above.
As described in Publication No. 0, it is obtained by hydrolyzing a reaction product of isocyanoacetic acid ester and an activated isonicotinic acid (especially isonicotinic acid chloride).

The reaction between isocyanoacetate and activated isonicotinic acid is carried out in an appropriate solvent in the presence of an organic or inorganic base.
It is carried out under a temperature condition of about θ to 50°C. The hydrolysis reaction is carried out in water or hydroalcohol in the presence of an inorganic base.
The process is carried out at a temperature ranging from room temperature to about 50°C.

In the uninvented state, 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 a protic compound.

Here, the aprotic amides include N,N-dimethylformamide (boiling point 153°C), N,N-dimethylacetamide (boiling point 166°C), and N.

N-diethylformamide (boiling point 177-178°C).

, N, N, N', N'-tetramethylurea (boiling point 177
~178°C), N-methylpyrrolidone (boiling point 202°C)
, N-formylpiperidine (boiling point 166°C), etc. Among these, N,N-dimethylformamide is the most industrially viable, considering the boiling point, yield, cost, etc., if necessary. For example, other solvents may be used in combination without departing from the spirit of the present invention.

As the protic compound, alcohol, carboxylic acid, or phenol is preferably used, and
Alcohol is particularly preferred from the viewpoint of ease of isolation of the target product and cost.

Examples of alcohols include methanol, ethanol, n
−Property tools, Improper tools.

Aliphatic alcohols such as n-butanol, isobutanol, 58C-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, hexanol, octatool; Alicyclic alcohols such as cyclopentanol and cyclohexanol; benzyl alcohol, β −
Aromatic alcohols such as phenylethyl alcohol: Heterocyclic alcohols such as furfuryl alcohol: ethylene glycol, propylene glycol, butanediol, hexanediol, glycerin, trimethylolethane,
Aliphatic polyhydric alcohols such as trimethylolpropane and neopentyl alcohol, polyhydric alcohols containing ether bonds such as diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, and polypropylene glycol: 3-(2-pyridyl) ) Nitrogen-containing alcohols such as propatool: Examples include alcohols with carbon atoms of about 1 to 10 or more.

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

Examples of phenols include phenol, cresol, xylenol, O-chlorophenol, and the like.

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

The amount of the protic compound to be used varies greatly depending on the type, so it cannot be absolutely specified, but the amount of the aprotic amide 1
About 0.005 to 4 parts by weight, especially 0.005 to 20 parts by weight.
The amount is often about 1 to 2 parts by weight.

The method of charging the starting materials, aprotic amide, and protic compound listed in L is arbitrary; a method of charging them all at once, a method of charging one or both of them in parts, and a method of charging at least one of them continuously. All methods are adopted.

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

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

[Function] The reaction of the present invention is expressed by the following formula. The aprotic amide containing a protic compound is thought to play a role as a catalyst that promotes the decarboxylation reaction as well as a solvent.

[Example] Next, the present invention will be further explained with reference to Examples.

Example 1 In a flask equipped with a reflux device, 5-(4-pyridyl)oxazole-4-carboxylic acid e.g. oog, N. 56.8 g of N-dimethylformamide (EiOml) and 2.8 g of ethanol were charged, and the mixture was heated to perform a decarboxylation reaction under fast waves (radio wave temperature: 122° C.) for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 4.71 g of concentrate.
I got it.

As a result of analysis by gas chromatography (constant analysis using internal standard method, hereinafter the same), it was found that this concentrate contained 97.3% by weight of 5-(4-pyridyl)oxazole. The yield was 99%. The concentrate in L was dissolved in 20 times the weight of ethyl acetate, and no insoluble matter was observed.

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

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 6.97 g of concentrate.
I got it.

Analysis by gas chromatography showed that this concentrate contained 41.3% heavy wall 5-(4-pyridyl)oxazole. The yield was 94%.

Example 3 Into a flask, 5-(4-pyridyl)oxazo-Jl/
-4-carvone Iv 4.00 g, N, N-cy/' + lformamide 37.7 g (4 (1 ml)
and 37.8 g of n-hexanol were added thereto, and the mixture was heated to undergo a decarboxylation reaction under reflux (reflux temperature: 140°C) for 6 hours.

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

Analysis by gas chromatography showed that this concentrate contained 95.1% by weight of 5-(4-pyridyl)oxazole. The yield was 98%. Examples 4 to 5 The amount of n-hexanol charged was 6.7 g (Example 4)
, 380 g (Example 5), Example 3 was repeated.

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

Example 6 In a flask, 5-(4-pyridyl)oxazole-4-
4.00 g of carboxylic acid, 37.7 g (40 ml) of N,N-dimethylformamide, and 12.8 g of cyclohexanol were charged and heated under reflux (reflux temperature 1
The decarboxylation reaction was carried out at 57°C for 6 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a concentrate of 3.48%
I got g.

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

Example 7 In a flask, 5-(4-pyridyl)oxazole-4-
Carboxylic acid e, oOg, N,N-dimethylformamide 5e, I3g (f30ml) and unacetic acid 3
．． 8 g was charged, and the mixture was heated and decarboxylated under reflux for 6 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 8.01 g of concentrate.
I got it.

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

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

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

Analysis by gas chromatography revealed that this 'C condensate contained 83.0% by weight of 5-(4-pyridyl)oxazole. The yield was 95%.

Example 9 In a flask, 5-(4-pyridyl)oxazole-4-
Carboxylic acid 4. 75.5 g (80 ml) of QQg, N, N-dimethylacetamide and 4.8 g of n-butanol were charged, 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 was found to contain 3.08% by weight of 5-(4-pyridyl)oxazole.

The yield was 83%.

Examples 1O to 11 Example 9 was repeated except that 81.5 g of N-methylpyrrolidone (Example 10) and 81.5 g of N-formylpiperidine (Example 11) were used in place of N,N-dimethylacetamide. Ta.

The yield was 84% for Example 10 and 90% for Example 5.

Comparative Example 1 In a flask, 5-(4-pyridyl)oxazole-4-
8.00 g of carboxylic acid and 56.13 g (80+sl) of N,N-dimethylformamide were charged, heated, and decarboxylated under radio waves for 5 hours.

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

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

]: Ethyl acetate was added to the above concentrate in a weight ratio of 20 times, and the mixture was stirred, but an undissolved portion remained. After filtering, 0.8 g of undissolved matter was obtained.

Comparative Example 2 In a flask, 5-(4-pyridyl)oxazole-4-
4.00 g of carboxylic acid and 40 g of ethylene glycol
．． Og was charged and heated to perform a decarboxylation reaction at 135 to 140°C for 5 hours.

After cooling, the reaction solution (42.4 g) was analyzed by gas chromatography and found to contain 4.28% 5-(4-pyridyl)oxazole. Convergence was 59%.

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

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 3.94 g of concentrate.
I got it.

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

Ethyl acetate of 20 times the weight ratio was added to the concentrate in L and stirred, but it did not dissolve at all, and 3 g of solid content was recovered by filtration.

Comparative Example 4 In a flask, 5-(4-pyridyl)oxazole-4-
Carboxylic acid 8. OOg, N, N-dimethylformamide 58.8 g (80ml), copper powder 280ml
1.98 g (2.0 ml) of pyridine was charged, heated and decarboxylated under reflux for 5 hours.

After the reaction is complete, cool on ice and remove insoluble matter by filtration.
The solvent was then distilled off under reduced pressure to obtain 5.25 g of a concentrate.

The content of the target product in the concentrate was 62.2% by weight, and the yield was 70%.
．． It was 8%.

When 20 times the weight ratio of ethyl acetate was added to the concentrate of 1- and stirred, 0.94 g of undissolved matter was found.

On the other hand, the Toki concentrate contained 42B of copper.

Table 1 The conditions and results of Examples 1 to 11 and Comparative Examples 1 to 4 are summarized in Table 1.

Bl: N,N-dimethylformamide B2: N,N-dimethylacetamide 83: N-methylpyrrolidone B4: N-formylpiperidine C1: Ethanol C2: n-but/-ol C3: n-hexanol C4: Cyclohexanol C5: Ethylene glycol C6: Glacial acetic acid Note: Example 12 was repeated except that 280 g of copper powder and 1.9111 g of pyridine were used.
Shown in the table and its footnotes.

Table 2 Example 12 In a flask, 5-(4-pyridyl)oxazole-4-
Carboxylic acid 4. 48.0 g of OOg, N, N-dimethylformamide and 4.0 g of phenol were charged, and a decarboxylation reaction was carried out under heating and reflux (fast flow temperature: 152°C) for 5 hours.

After the reaction, the solvent was distilled off under reduced pressure and the concentrate s, teg
I got it.

As a result of analysis by gas chromatography, it was found that this e-condensate contained 5-(4-pyridyl)oxazole with a weight of 32.1% by V. The yield was 85% - Examples 13-22 Using other protic compounds in place of phenol Carboxylic acid Bl: N,N-dimethylformamide C7:0-cresol C8: Xylenol C9:0-chlorophenol C10 : β-phenylethyl alcohol (:11:
3-(2-Pyridyl)propatol C12: Propionic acid C13: Valeric acid C14: Adipine acid C15: Benzoic acid 018: Cyclohexanecarboxylic acid [Effects of the invention] In the present invention, an aprotic amide containing a protic compound The target product, 5-(4-pyridyl)oxazole, can be obtained in good yield simply by carrying out the reaction in the presence of .

There is no need to use catalysts such as metal powders or organic bases. (1) It is easy to remove the aprotic amide containing a protic compound from the reactant, and the purity of the target product in the reactant is extremely high, so the reaction is easy. Isolation of the target product from the reaction product after completion,
The purification process is much simpler than conventional methods.

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

Claims (3)

[Claims] (1) Presence of an aprotic amide containing a protic compound when producing 5-(4-pyridyl)oxazole by heating and decarboxylating 5-(4-pyridyl)oxazole-4-carboxylic acid. A method for producing 5-(4-pyridyl)oxazole, characterized in that the reaction is carried out below. (2) The production method according to claim 1, wherein the protic compound is at least one compound selected from the group consisting of alcohol, carboxylic acid, and phenol. (3) The method according to claim 1, wherein the aprotic amide is N,N-dimethylformamide.