JPH04134078A - Production of 5-substituted oxazole - Google Patents

Abstract

PURPOSE:To obtain the subject compounds in a high yield with industrial advantage by heating and decarbonating a substituted oxazolecarboxylic acid in the presence of an aprotic amide containing a protic compound. CONSTITUTION:A 5-substituted oxazole-4-carboxylic acid (e.g. 5-methyloxazole-4- carboxylic acid) of formula I [R is 1-10C alkyl, (substituted)phenyl, furil, thienyl or naphthyl] is heated and decarbonated in the presence of an aprotic amide (preferably DMEF) containing one or more protic compounds selected from an alcohol (e.g. methanol), a carboxylic acid (e.g. formic acid), a phenol and water, thus obtaining the objective compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to an industrially advantageous method for producing 5-substituted oxazole, which is a decarboxylation product thereof, from 5-substituted oxazole-4-carboxylic acid. be.

BACKGROUND OF THE INVENTION 5-(4-pyridyl)oxazole, one of the 5-substituted oxazoles, is important as an intermediate for obtaining cephalosporin compounds. (For example, JP-A-61-7
280)) As a conventional technique for producing 5-(4-pyridyl)oxazole, there is a method of condensing 4-, lysine aldehyde, and tosylmethyl isocyanide (Che
m, Pharm, Bull,, 27.793 (
(1979)), a method for producing aminoisonicotinoylmethane from 4-acetylpyridine and then ring-closing it with ethyl orthoformate (J, Org, Chem, 2).
261 f19801) 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.

As a manufacturing route different from the above method, JP-A-63-
Publication No. 150280 describes 5-(4-pyridyl) obtained by hydrolyzing a reaction product of isocyanoacetate and activated isonicotinic acid (isonicotinic acid chloride, etc.).
A method is shown in which the target product, 5-(4-pyridyl)oxazole, is produced by using oxazole-4 carboxylic acid as a raw material and decarboxylating it in a solvent such as dimethylformamide in the presence of a catalyst. . In addition, as a catalyst in this decarboxylation reaction, metal powder (for example, Cu
(powder) and an organic base (eg pyridine).

Regarding 2-methyloxazole, which is one of the 5-substituted oxazole, there is the following literature.

i.e. J, Am, Chem, Sac, 6
9.96 f1947) describes a method for obtaining 2-methyloxazole by decarboxylating 2-methyloxazole-4-carboxylic acid in a quinoline solvent containing CuO.

Problems to be Solved by the Invention 5-(
The method for producing 4-pyridyl)oxazole has extremely high industrial value in that inexpensive and easily available raw materials can be used.

However, in this method, after the fat decarboxylation reaction is completed, insoluble matter and solvent are distilled off from the reaction mixture, and
When it is necessary to separate the target substance from the residue, the purity of the target substance in the residue is low, and it is necessary to separate the metals mixed in the residue (if the metal is expensive, it is also necessary to recover it). ), 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 (b) the yield of the target product is around 70%. However, there are problems such as the fact that the cost is not necessarily high, and further improvements are desired in order to implement it on an industrial scale.

J, Am, Chem, Soc,, 69.96
(The method for producing 2-methyloxazole described in 19471 also uses CuO as a catalyst, so insoluble matter and solvent are distilled off from the reaction mixture after the decarboxylation reaction is completed, and the target product is separated from the residue.) However, there are problems in that the purity of the target substance in the residue is low and CuO mixed in the residue must be separated, making the purification process complicated.

The present invention provides a method for producing 5-substituted oxazole from 5-substituted oxazole-4-carboxylic acid by decarboxylation reaction, which does not require the use of a special catalyst and can significantly improve the yield. The purpose is to

Means for Solving the Problems The method for producing a 5-substituted oxazole of the present invention is based on the formula (where R is an alkyl group having 1 to 10 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group, a thienyl group, a naphthyl group) In producing the 5-substituted oxazole represented by the formula by heating and decarboxylating the 5-substituted oxazole-4-carboxylic acid represented by (or pyridyl group),
It is characterized in that the reaction is carried out in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohol, carboxylic acid, phenol and water.

The present invention will be explained in detail below.

Specific examples of the 5-substituted oxazole-4-carboxylic acid represented by the formula [il include 5-methyloxazole-4-carboxylic acid, 5-ethyloxazole-4-carboxylic acid, and 5-propyloxazole-4-carboxylic acid. , 5-butyloxazole-4-
Carboxylic acid, 5-hexyloxazole-4-carboxylic acid, 5-octyloxazole-4-carboxylic acid, 5-
Phenyloxazole-4-carboxylic acid, 5-(p-tolyl)oxazole-4-carboxylic acid, 5-(p-chlorophenyl)oxazole-4-carboxylic acid, 5-(p-furyl)oxazole-4-carboxylic acid, Examples include 5-(2-thienyl)oxazole-4-carboxylic acid and 5-(β-naphdyl)oxazole-4-carboxylic acid.

The starting material, 5-substituted oxazole-4-carboxylic acid represented by formula (1), can be obtained by any method.

In the present invention, when the 5-substituted oxazole-4-carboxylic acid represented by the formula (il) is heated to decarboxylate, 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), NN-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, boiling point, yield, cost, etc. Considering comprehensively, N, N
-Dimethylformamide is the most industrially viable. If necessary, other solvents may be used in combination without departing from the spirit of the present invention.

Protic compounds include alcohols, carboxylic acids,
At least one selected from the group consisting of phenol and water is used, and alcohol is particularly preferred in terms of yield, ease of handling, ease of isolation of the target product, and cost.
Water is also preferred.

Examples of alcohols include methanol, ethanol, n
-propanol, isopropanol, n-butanol,
Isobutanol, 5eC-butatol, tert-butanol, n-amyl alcohol, isoamyl alcohol,
Aliphatic alcohols such as hexanol and octatool; alicyclic alcohols such as cyclopentazole and cyclohexanol; aromatic alcohols such as benzyl alcohol and β-phenylethyl alcohol; heterocyclic alcohols such as furfuryl alcohol; ethylene glycol and propylene. Aliphatic polyhydric alcohols such as glycol, butanediol, hexanediol, glycerin, trimethylolethane, trimethylolpropane, neopentyl alcohol,
Polyhydric alcohols containing ether bonds such as diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol (3-<2-pyridyl)
Examples include nitrogen-containing alcohols such as propatool, and alcohols having about 1 to 10 or more carbon atoms.

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-lytetraphenol, and the like.

The appropriate amount of aprotic amide to be used is about 5 to 20 parts by weight, especially about 10 parts by weight, per 1 part by weight of 5-substituted oxazole-4-carboxylic acid. Not limited.

The amount of the protic compound to be used varies greatly depending on the type, so it cannot be determined with certainty, but the amount of the aprotic amide 1
About 0.05 to 20 parts by weight, preferably 0
．． It is often 1 to 10 parts by weight, particularly preferably 0.1 to 5 parts by weight.

The above-mentioned starting materials, aprotic amide and protic compound may be charged in any manner, including a method of charging them all at once, a method of charging any or all three of them in portions, and a method of continuously charging at least one of them. etc. will be adopted.

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

After the reaction is completed, the aprotic amide and protic compound are removed by appropriate means such as distillation under reduced pressure. Concentrate (
Since the residue) is a 5-substituted oxazole containing some impurities, it is purified by recrystallization, washing, and other means.
get the object.

Function The reaction of the present invention is represented 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.

(i) Example Next, the present invention will be further explained with reference to Examples.

Example 1 A flask equipped with a reflux device was charged with 10.00 g of 5-phenyloxazole-4-carboxylic acid, 100 g of N,N-dimethylformamide, and 2.04 g of water, and heated under reflux (reflux temperature: 136°C). A decarboxylation reaction was carried out for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 7.71 g of concentrate.
I got it. This was distilled to obtain 7.04 g of a standard product.

The melting point was 37°C, and the results of NMR analysis were as follows.

NMR(fcDsl 1co): δ7.50.
7.75 (5H, H of phenyl group) 7.55 (18
, 4th position of oxazole ring) 8.20 flH, 2nd position of oxazole ring) Example 2 In a flask equipped with a reflux device, 5.0 Hg of 5-phenyloxazole-4-carboxylic acid, 50 g of N,N-dimethylformamide and 1 water were added. .02 g was charged and heated to perform a decarboxylation reaction under reflux (reflux temperature 139°C) for 5 hours. As a result, 54.64 g of reaction liquid was obtained.

As a result of analysis by gas chromatography (quantitative analysis by internal standard method, same hereinafter), it was found that this reaction solution contained 6.67% by weight of 5-phenyloxazole. The yield was 96.6%.

Example 3 A flask equipped with a reflux device was charged with 5.00 g of 5-phenyloxazole-4-carboxylic acid, 50 g of N,N-dimethylformamide, and 1.02 g of ethanol, and heated under reflux (reflux temperature 142°C). A decarboxylation reaction was carried out for 5 hours. As a result, 54.77 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 6.86% by weight of 5-phenyloxazole. The yield was 99.6%.

Example 4 In a flask equipped with a reflux device, 4.00 g of 5-phenyloxazole-4-carboxylic acid, 40 g of N,N-dimethylformamide and 1.32 g of ethylene glycol were added.
5g and heated under reflux (reflux temperature 142°C).
The decarboxylation reaction was carried out for an hour. As a result, the reaction solution 44.01
g was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 6.88% by weight of 5-phenyloxazole. The yield was 994%.

Example 5 4.5-phenyloxazole-4-carboxylic acid was added to a flask equipped with a reflux device. 40 g of OOg, N, N-dimethylformamide and 2.87 g of acetic acid were charged, and the mixture was heated to undergo a decarboxylation reaction under reflux (reflux temperature: 141°C) for 5 hours. As a result, 45.52 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 5.74% by weight of 5-phenyloxazole. The yield was 90.0%.

Comparative Example 1 A flask equipped with a reflux device was charged with 5-phenyloxazole-4-carboxylic acid s,oo g and 50 g of N,N-dimethylformamide, and heated and desorbed under reflux (reflux temperature 137°C) for 5 hours. A carbonic acid reaction was carried out. As a result, 54.22 g of one reaction solution was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 3.60% by weight of 5-phenyloxazole. The yield was 51.7%.

Example 6 A flask equipped with a reflux device was charged with 5.00 g of 5-(p-tolyl)oxazole-4-carboxylic acid, 50 g of NN-dimethylformamide, and 1.02 g of ethanol, heated under reflux (reflux temperature 139° C.) for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 4.39 g of concentrate.
I got it. This was distilled to obtain 3.34 g of a standard product.

The melting point was 64°C, and the results of NMR analysis were as follows.

NMR((CDsliCO): δ2.35(
3H,CH,-)? , 25 7.60 (4H, toluyl group) 7.45
(IH, 4th position of oxazole ring) 8.10 +i11. Oxazole ring 2nd position) Example 7 In a flask equipped with a reflux device, 5.00 g of 5-(p-tolyl)oxazole-4-carboxylic acid, 50 g of N,N-dimethylformamide and 1.02 g of ethanol were added.
was charged and heated to perform a decarboxylation reaction under reflux (reflux temperature 139°C) for 5 hours. As a result, 54.77 g of reaction liquid
was gotten.

Analysis by gas chromatography revealed that this reaction solution contained 7.06% by weight of 5-(p-tolyl)oxazole. The yield was 98.8%.

Example 8 In a flask equipped with a reflux device, 2.00 g of 5-(p-chlorophenyl)oxazole-4-carboxylic acid, N,N
-20 g of dimethylformamide and 0.4 g of ethanol
1 g of the solution was charged, and the mixture was heated to perform a decarboxylation reaction under reflux (reflux temperature: 146° C.) for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to concentrate, and this was purified by recrystallization to obtain 1.19 g of a sample.

The melting point was 66.2°C, and the results of NMR analysis were as follows.

NMR((CDm)*CO): δ7.40.7
．． 70 (411, H of phenyl group) 7.55 tl)
1. (4th position of oxazole ring) 8.20 (IH, 2nd position of oxazole ring) Example 9 In a flask equipped with a reflux device, 200 g of 5-(p-chlorophenyl)oxazole-4-carboxylic acid, N,N-
20 g dimethylformamide and 0.41 ethanol
5 g and heated under reflux (reflux temperature 146°C).
The decarboxylation reaction was carried out for an hour. As a result, the reaction solution 21.39
g was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 7.16% by weight of 5-(p-chlorophenyl)oxazole.

The yield was 95.3%.

Example 1O In a flask equipped with a reflux device, 5.00 g of 5-(2-thienyl)oxazole-4-carboxylic acid, 50 g of N,N-dimethylformamide and 1.02 g of ethanol.
was charged and heated to perform a decarboxylation reaction under reflux (reflux temperature 147°C) for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 4.05 g of concentrate.
I got it. This was distilled to obtain 3.00 g of standard product.

The results of NMR analysis were as follows.

NMR(fcos)2col: δ7.10 (
IH, 4th position of chenyl group) 7.35 (IH, 4th position of oxazole ring) 7.50 (
2H, 3.5th position of thienyl group) 8.10 (IH, 2nd position of oxazole ring) Example 11 In a flask equipped with a reflux device, 5.00 g of 5-(2-thienyl)oxazole-4-carboxylic acid, N, 60 g of N-dimethylformamide and 1.02 g of ethanol were charged, and the mixture was heated to undergo a decarboxylation reaction under reflux (reflux temperature: 147° C.) for 5 hours. As a result, 54.70 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 5.79% by weight of 5-(2-thienyl)oxazole. The yield was 80.6%.

Example 12 A flask equipped with a reflux device was charged with 5.20 g of 5-(2-furyl)oxazole-4-carboxylic acid, 52 g of NN-dimethylformamide, and 1.06 g of ethanol, and heated under reflux (reflux temperature: 149 g). ℃) for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 3.13 g of concentrate.
I got it. This was distilled to obtain 2.83 g of standard product.

The results of NMR analysis were as follows.

NMR (fcD, 1ffico): δ6.45
(IH, furyl group position 4) 6.60 (IH, furyl group position 3) 7.25 (IH, oxazole ring position 4) 7.45 (
l)1. Furyl group (5th position) 7.85 (IH, oxazole ring 2nd position) Example 13 In a flask equipped with a reflux device, 5.20 g of 5-(2-furyl)oxazole-4-carboxylic acid, 52 g of NN-dimethylformamide, and 1.06 g of ethanol was charged and heated under reflux (reflux temperature 149° C.) for decarboxylation reaction for 5 hours. As a result, 56.78 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 5.84% by weight of 5-(2-furyl)oxazole. The yield was 84.8%.

Example 14 A flask equipped with a reflux device was charged with 2.0 g of 5-(β-naphthyl)oxazole-4-carboxylic acid, 20 g of N,N-dimethylformamide, and 0.41 g of ethanol, and heated under reflux (refluxing). A decarboxylation reaction was carried out at a temperature of 147° C. for 5 hours.

After the reaction is complete, water is added to the reaction solution to form 5-(β-naphthyl).
Isolated by precipitation of oxazole, 1.16
A specimen of g was obtained.

The results of NMR analysis were as follows.

N M R ((CD3) acOl δ7.50 (
2H, naphthalene ring position 7.8) 7.65 (IH, oxazole ring position 2) 7.8-8.0 (4H, naphthalene ring position 3,4,69) 8.20 (2)1. oxazole ring position 4, naphculene ring position 1) Example 15 In a flask equipped with a reflux device, 1.8 g of 5-(β-naphthyl)oxazole-4-carboxylic acid, 18 g of N,N-dimethylformamide, and 0.37 g of ethanol. was charged and heated to perform a decarboxylation reaction under reflux (reflux temperature 147°C) for 5 hours. As a result, 19.31 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 6.16% by weight of 5-(β-naphthyl)oxazole. The yield was 81.2%.

Example 16 A flask equipped with a reflux device was charged with 4.0 g of 5-(n-butyl)oxazole-4-carboxylic acid, 40 g of NN-dimethylformamide, and 082 g of ethanol, and heated under reflux (reflux temperature 145°C). A decarboxylation reaction was carried out for 5 hours.

After concentrating the reaction solution after the completion of the reaction, extraction was performed using a water-ethylene dichloride system, and 5-(
A sample of 1.63 g of n-butyl)oxazole was obtained.

The results of NMR analysis were as follows.

NMRNcM, col: δ 0.95 (3H, CHs-) 1.50 (4H, -CHzCHs-) 2.60 (2
+1. -CH2-) 6.60 (18, 4th position of oxazole ring) 7.60 (
IH, 2nd position of oxazole ring) Example 17 A flask equipped with a reflux device was charged with 4.0 g of 5-(n-butyl)oxazole-4-carboxylic acid, 40 g of NN-dimethylformamide, and 082 g of ethanol.
The mixture was heated under reflux (reflux temperature 145°C) for 5 hours to perform a decarboxylation reaction. As a result, 43.29 g of reaction liquid was obtained.

Analysis by gas chromatography revealed that this reaction solution contained 5.61% by weight of 5-(n-butyl)oxazole. The yield was 808%.

Effects of the Invention In the present invention, the desired 5-substituted oxazole can be obtained in good yield simply by carrying out the reaction in the presence of an aprotic amide containing a protic compound.

Not only does it not require the use of catalysts such as metal powders or organic bases, it is easy to remove aprotic amides containing protic compounds from the reactants, and the purity of the target product in the reactants is extremely high, so the reaction is easy. separation of the target product from the reaction product after completion;
The refining process becomes much simpler.

Therefore, according to the present invention, 5-substituted oxazole can be industrially advantageously produced.

Patent Applicant: Nippon Gosei Kagaku Kogyo Co., Ltd. Procedural Amendment (Voluntary) August 9, 1991 1990 Patent Application No. 253320 Name of the Invention Case involving a person amending the manufacturing method of 5-substituted oxazole Relationship Patent Applicant Address 9-6 Nozaki-cho, Kita-ku, Osaka-shi, Osaka Name (
410) Masaru Ohashi, Representative of Nippon Gosei Chemical Industry Co., Ltd.

Claims (1)

[Claims] (1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (i) (Here, R is an alkyl group having 1 to 10 carbon atoms, phenyl group, substituted phenyl group, furyl group, thienyl group) By heating and decarboxylating 5-substituted oxazole-4-carboxylic acid represented by Hits the,
1. A method for producing a 5-substituted oxazole, characterized in that the reaction is carried out in the presence of an aprotic amide containing at least one protic compound selected from the group consisting of alcohol, carboxylic acid, phenol and water. (2) The method according to claim 1, wherein the aprotic amide is N,N-dimethylformamide. (3) The method according to claim 1, wherein the amount of the aprotic amide used is 5 to 20 parts by weight per 1 part by weight of the 5-substituted oxazole-4-carboxylic acid. (4) Claim 1, wherein the amount of the protic compound used is 0.05 to 20 parts by weight per 1 part by weight of the aprotic amide.
Manufacturing method described. (5) The production method according to claim 1, wherein the reaction is carried out at 100°C or higher.