5-Methyl-3-isoxazole carboxylic acid

Eqn. (a) shows the interaction between benzaldehyde and 5-methyl-3-isoxazole carboxylic acid hydrazide in the presence of ethanol at 4°C to 3neld l-benzylidene-2 (5-methyl-3-isoxazolylcarbonyl) hydrazine (I) with the elimination of one mole of water as indicated above. 

Chemicals Required. Benzaldehyde 80 g Ethanol [95% (v/v)] 750 ml 5-Methyl-3-isoxazole-carboxylic acid hydrazide 72 g l-Benzylidene-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine 11.5 g Anhydrous Solvent Ether 500 ml Pure LiAlH 1.85 g Ethyl acetate 25 ml Benzene 20 ml Methanol q.s. 

AMPA (= 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid)] (isoxazole carboxylic acid)... 

APA is duly acylated with 3-(o-chlorophenyl)-5-methyl-4-isoxazole carboxylic acid and the resulting cloxacillin base is adequately purified by reerystallization. The base thus obtained is converted to the corresponding sodium salt by treating with an equimolar concentration of NaOH. 

The reaction of methyl acetylpyruvate (312) with hydroxylamine hydrochloride gave the 3-carboxylate (313) in 76% yield together with traces of the isomeric 5-carboxylate (314) (78MIP41600). However, the sodium salt (315) of acetylpyruvic acid resulted in 3-methyl-isoxazole-5-carboxylic acid (316) as the major product. 

The addition of benzonitrile oxide to acrylic acid gave only the 4-carboxylic acid (441) (59MI41601), while addition to cis- and trans-cinnamic esters gave cis and trans diastereomeric pairs of 4-carboxylic acids (442) (Scheme 100) (59MI41600). Arbisono repeated the experiment and, when methyl c/s-cinnamate was used, in addition to the 4-carboxylic acid some 5-carboxylic acid (442) was isolated (66MI41600). The reaction of vinyl bromides with benzonitrile oxide yielded only an isoxazole and not a bromoisoxazoline (Scheme 101) (78JCR(S)192). 

Isoxazole-4-carbaldehyde, 6, 84 Isoxazole-4-carbaldehyde, 5-methyl-3-phenyl-oxidation, 6, 27, 53 Isoxazole-5-carbaldehyde synthesis, 6, 84 Isoxazole-3-carboxylic acid esters... 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

Decarboxylation of isoxazole-3-carboxylic acids is related to the nucleophilic cleavage of the isoxazole ring as far as the nature of the reaction products is concerned. It occurs at temperatures above 200°C and is accompanied by the cleavage of the nitrogen-oxygen bond of the heterocyclic ring to yield a j8-ketonitrile. It was first reported by Claisen with 5-methyl- and 5-phenyl-isoxazole-3-carboxylic acids (153- 154).Under the reaction conditions, j8-ketonitriles condense... 

Methyl-isoxazole-(3)-carboxylic acid chloride 4-(/3-Aminoethyl)benzene sulfonamide hydrochloride Chloroformic acid methyl ester N-Amlno-hexamethylene imine... 

There is obtained from 4-[)3-[5-methyl-isoxazolyl-(3)-carboxamido]-ethyl]-benzene-sulfonamide (prepared from 5-methyl-isoxazole-(3)-carboxylic acid chloride and 4-()3-aminoethyl)-benzene-sulfonamide hydrochloride, MP 213° to 214°C in pyridine) and chloroformic acid methyl ester, in a yield of 69%, the compound N-[ [-4-[)3-[5-methyl-isoxazolyl-(3)-carbox-amido] -ethyl] ] -benzene-sulfonyl] ] -methyl-urethane in the form of colorless crystals of MP 173°C. 

Isocarboxazid Isocarboxazid, 2-benzylhydrazid-5-methyl-3-isoxazolecarboxylate (7.2.6), can be synthesized from acetylacetone, which on nitrosation with nitrous acid gives 5-methyl-isoxazol-3-carboxyhc acid (7.2.2). Esterification of this product gives the ethyl ester of 5-methyl-isoxazol-3-carboxyhc acid (7.2.3). The synthesized ester (7.2.3) is further reacted with benzylhydrazine, to give isocarboxazide (7.2.6), or with hydrazine, which forms 5-methyl-isoxazol-3-carboxylic acid hydrazide (7.2.4). Reacting the latter with benzaldehyde gives hydrazone (7.2.5), which is further reduced to the isocarboxazide (7.2.6) [46,47]. 

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