CH512505A - Anti-inflammatory analgesic antipyretic oxazole - Google Patents

Abstract

Oxazole derivatives - (I) Y = phenyl-, benzyl- which may be subst. by up to 2 hal- or CF3 - Z = -CR1R2R3 - R1 = H-, C1-3 alkyl- - R2 = H-, C1-3 alkyl-, C2-6 alkoxycarbonyl- - R3 = CO2R4 or -CONHR5 - R4 = H-, alkyl-, dialkylaminoalkyl-, benzyl-, phenyl-, R5 = H-, -OH, -NH2, dialkylaminoalkyl-, alkoxycarbonylalkyl-, carboxyalkyl-particularly aluminium 2-(4-chlorophenyl) oxazol-4-acetate. - Anti-inflammatory, analgesic, antipyretic. - A mixture of 2(4-chlorophenyl)-4-cyanomethyl-oxazole, dry ethanol and conc. H2SO4 is heated for 10 hours at 100 deg.C. The solution is poured into ice-water and the mixture filtered to yield solid ethyl 2-(4-chlorophenyl)oxazol-4-yl acetate.

Description

  

  Process for the production of oxazole derivatives The invention relates to a process for the production of new oxazole derivatives. anti-inflammatory, analgesic and antipyretic properties.



  According to the invention, oxazole derivatives of the formula:
EMI0001.0000
    and their salts prepared, where Y is a phenyl or benzyl radical, which may optionally be substituted in the benzene ring by one or two halogen atoms or the trifluoromethyl radical, and R 'is a hydrogen atom or an alkyl radical having at most 3 carbon atoms.



  The oxazole nucleus is numbered as follows:
EMI0001.0001
    It is readily apparent from the above formula that the group -CHR'-COOH is in the 4-position when Y is in the 2-position and in the 2-position when Y is in the 4-position.



  The substituents optionally present in Y can, for. B. can be selected from fluorine, chlorine and bromine atoms. If R 'represents an alkyl radical with a maximum of 3 carbon atoms, this can be B. be the methyl radical.



  Examples of salts are those with alkali metals or alkaline earth metals, or aluminum or ammonium salts or salts with organic bases which give non-toxic, pharmaceutically acceptable cations.



  The preferred oxazole derivatives obtainable by the process according to the invention are: 2- (4-chlorophenyl) oxazol-4-ylacetic acid, α-12- (4-chlorophenyl) -oxazol-4-yl propionic acid, 2- (4-trifluoromethylphenyl ) -oxazol-4-ylacetic acid and 244-bromophenyl) oxazol-4-ylacetic acid and the alkali metal, alkaline earth metal and aluminum salts thereof.



  The inventive method is characterized in that a compound of the formula
EMI0001.0006
    in which Y and R 'have the above meaning and R2 stands for an alkyl radical, treated with an inorganic base in the presence of water and in the heat.



  In this reaction, of course, both hydrolysis and decarboxylation occur. A suitable base is e.g. B. an alkali metal hydroxide.



  Example 1 A mixture of 1 part 2-methyl-4-phenyl-oxazole, 0.75 part sodium hydride and 10 parts diethyl carbonate is refluxed for 4 hours. The mixture is cooled, poured into 10 parts of water and acidified with 2N hydrochloric acid. The mixture is extracted twice with ether. The combined ethereal extracts are washed with water and then dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue consists of diethyl 2- (4-phenyloxazol-2-yl) malonate.



  This compound is refluxed for 1 hour together with 30 parts of 2N sodium hydroxide. The mixture is cooled and washed with 10 parts of ether. The aqueous layer is separated off and acidified with 2N hydrochloric acid at 0 C. The resulting precipitate is filtered off and washed with water and then with ethanol. This gives 4-phenyloxazol-2-ylacetic acid, melting point 132 ° C. with decomposition.



  In essentially the same way, 4- (4-bromophenyl) -2-methyloxazole gives diethyl 4- (4-bromophenyl) oxazol-2-ylmalonate and 4- (4-bromophenyl) oxazol-2-ylacetic acid, M.p. 111-112 C with decomposition.



  The 4- (4-bromophenyl) -2-methyloxazole used as starting material can be represented as follows: 25 parts of acetamide are heated to 120 ° C., and 70 parts of 4-bromophenacyl bromide are added in part over the course of 1 hour with thorough stirring. After a further 90 minutes at 120-140 C, the mixture is cooled, whereupon 150 parts of water and 150 parts of chloroform are added. The mixture is shaken and then separated and the chloroform layer is evaporated to dryness in vacuo. The solid residue is recrystallized from 50% strength by volume aqueous ethanol.

   This gives 4- (4-bromophenyl) -2-methyloxazole, m.p. 98-99 C.



  Example 2 30 parts of dry dimethylformamide are added to 2 parts of a 50% strength dispersion of sodium hydride in oil. Then 6 parts of diethyl 4-phenyloxazol-2-ylmalonate (see Example 1) in 30 parts of dry dimethylformamide are added to this mixture. The mixture is stirred for 1 hour, after which 6 parts of methyljo- did are added over 10 minutes. The mixture is then stirred for a further 2 hours. Then the mixture is poured into 100 parts of water and 6 parts of acetic acid and 100 parts of ether. The ethereal layer is separated and washed with excess aqueous sodium bicarbonate. The ether is evaporated in a vacuum.

   Crude diethyl (4-phenyloxazol-2-yl) -2-methylmalonate is obtained.



  This diethyl derivative is mixed with 2 parts of sodium hydroxide, 15 parts of water and 15 parts of ethanol and the mixture is refluxed for 1 hour. The mixture is then cooled, diluted with 30 parts of water and washed with 30 parts of ether. The aqueous layer is cooled to 0 C and acidified with concentrated hydrochloric acid. The resulting mixture is filtered. The solid residue thus obtained is (4-phenyloxazol-2-yl) -2-propionic acid with a melting point of 126-127 (decomp.).



  Example 3 1 part of 2- (4-chlorophenyl) oxazol-4-ylacetic acid is dissolved in 20 parts of hot 5% strength aqueous ammonium hydroxide, whereupon 5 parts of 10N sodium hydroxide are added. The mixture is cooled and the precipitate is filtered off and recrystallized from water. Thus he holds sodium 2- (4-chlorophenyl) oxazo1-4-ylacetate of melting point over 200 C.



  2.6 parts of sodium 2- (4-chlorophenyl) oxazol-4-ylacetate are dissolved in 30 parts of boiling water, whereupon 2 parts of calcium chloride in 20 parts of water are added. The precipitate is filtered off, washed with water and dried. Calcium 2- (4-chlorophenyl) oxazol-4-ylacetate is thus obtained.



  2.6 parts of sodium 2- (4-chlorophenyl) oxazol-4-ylacetate are dissolved in 30 parts of boiling water, whereupon a solution of 2 parts of aluminum nitrate in 20 parts of water is added. After cooling, the precipitate is filtered off, washed with water and dried. Aluminum 2- (4-chlorophenyl) oxazol-4-ylacetate is thus obtained.

 

Claims (1)

PATENT CLAIM Process for the production of oxazole derivatives of the formula: EMI0002.0025 and their salts, in which Y is a phenyl or benzyl radical, which can optionally be substituted in the benzene ring by one or two halogen atoms or the trifluoromethyl radical, and R 'is a hydrogen atom or an alkyl radical with at most 3 carbon atoms, characterized in that that you can get a compound of the formula: EMI0002.0026 in which Y and R 'have the above meaning and R2 stands for an alkyl radical, treated with an inorganic base in the presence of water and in the heat. SUBClaims 1. The method according to claim, characterized in that the inorganic base is an alkali metal hydroxide. 2. Process according to claim or dependent claim 1, characterized in that the process products are converted into salts with alkali metals or alkaline earth metals, or in aluminum or ammonium salts or in salts with organic bases.