3- Methylisoxazole-5-carboxylic

Using a two-step procedure, ethyl 4-amino-3-methylisoxazole-5-carboxylate (478) was condensed with ethyl malonyl chloride to afford the intermediate (479) which upon treatment with sodium ethoxide cyclized to the ester (480) in 82% overall yield <82JCS(P1)2391). Compound (480) was decarboxylated to give the product (481) (Scheme 56). 

Methylisoxazole-5-carboxylic acid was converted into the corresponding 5-carboxamides and 5-(l/7-pyrazol-l-ylcarbonyl) derivatives in satisfactory yields by treatment with thionyl chloride and amines or pyrazoles <2002SC425>. A three-component assembly of isoxazole-5-carboxylic acid chloride, 1,1-dimethylallene, and bis-pinacolatodiboron, catalyzed by a phosphine-free palladium complex, gave 2-acylallylboronate derivatives regiose-lectively (Equation 47) <2003JA12576>. On the other hand, a mild procedure allowed the preparation of /3,7-unsaturated ketones by simple reaction of 3-aryl-5-methylisoxazole-4-carboxylic acid chlorides with allyl bromide and indium in DMF (Equation 48) <1997TL8745>. 

Resistance to 3-methylisoxazole-5-carboxylic acid (IX) has also been demonstrated. 32 This compound is similar to the corresponding pyrazole in that it depresses plasma FFA and glucose levels in fasted glucose-primed rats33, and the effect is lost after 2 days pretreatment. 32 Resistance to the isoxazole is also dependent on an intact pituitary-adrenal system. 32... 

Although no detailed studies on the mechanism of action of these newer pyrazoles and isoxazoles have been reportedi it seems quite likely that they act by the same mechanism as do the earlier compounds (5-metb-ylpyrazole-3-carboxylic acid and 3-methylisoxazole-5-carboxylic acid) and they are probably subject to the same limitations as the previously studied compounds. 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

Acetylisoxazoles are converted to carboxylic acids by boiling with dilute nitric acid. This method allowed the development of a one-stage preparative method for 5-methylisoxazole-3-carboxylic acid (191) starting with acetonylacetone (190). ... 

CP608039 (2S,3S,4R,5R)-3-amino-5 6-[5-chloro-2-(3-methylisoxazol-5-yhnethoxy)benzylamino]purin-9-yl-l-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide... 

Fig. 2.4 Structures of agonists and antagonists of kainate receptors. 5-1 Will, 5-iodowillardiine (a) SYM 2081, (25,4R)-4-methylglutamate (b) 2S,AR isomer of 4-cinnamylglutamic acid (c) AMOA, (RS)-2-amino-3-(3-carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (d) AMNH, (RS)-2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-oxoisoxazo-lin-4-yl)]propionic acid (e) and LY 294486, (3SR,4aRS,6SR,8aRS)-6-[(lH-tetrazol-5-yl)methoxymethyl]-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (f)...

The 3-o-chlorophenyl-5-methylisoxazole-4-carboxylic acid, from which the acid chloride was prepared, was obtained by hydrolysis of the ester product of the reaction between o-chlorobenzohydroxamic chloride and ethyl acetoacetate in methanolic sodium methoxide. Reaction with thionyl chloride gave the starting material. 

Methylisoxazole-3-carboxylic acid chloride 4-(p-Aminoethyl)benzene sulfonamide hydrochloride Chloroformic acid methyl ester N-Amino-hexamethyleneimine... 

In US Patent No. 4,284,786 is described two methods of preparation of 5-methylisoxazole-4-carboxylic-(4-trifluoromethyl)-anilide. 

A solution 0.1 mole of 2-ethoxymethyleneacetoacetic acid 4-trifluoromethylanilide (30.1 g) in 60 ml of ethanol is added dropwise at 5-10°C to the mixture of 0.11 mole of hydroxylamine hydrochloride (7.65 g) in 50 ml of water and 0.11 mole of sodium hydroxide (4.4 g) in 10 ml of water. The mixture is heated under reflux for 15 min. The crystals which are precipitated after cooling are filtered off, washed with water and dried. 19.6 g (72.6% of theory) of crystalline 5-methylisoxazole-4-carboxylic acid 4-trifluoromethyl-anilide are thus obtained, melting point (after recrystallization from toluene) 166.5°C. 

Radical bromination with fV-bromosuccinimide often succeeds. Thus, 2,5-disubstituted 4-methyloxazoles on bromina-tion give the 4-bromomethyl compounds, and methyl groups at the 4- or 5-positions of isoxazoles 568 and 569 can be brominated with NBS. Controlled mono- or dibromination of 3-aryl-5-methylisoxazole-4-carboxylates allows access to aldehydes <2004T2301>. 

Phenyl-5-methylisoxazole-4-carboxylic acid p-Methoxyphenyl p-Methylbenzylsulfonyl... 

First the diarylether 158 was prepared by reacting isovanilline with methyl 4-bromobenzoate. 158 was condensed with the phosphonium salt 159 obtained in three steps from the readily available methyl 5-methylisoxazol 3-carboxylate. 

Closely related to the aldoxime fragmentation is the base-catalyzed ring cleavage of C(3)-substituted isoxazoles. Quite recently a novel base-catalyzed isoxazole-oxazole ring transformation was realized in the conversion of ethyl 5-hydroxy-3-(5-methylisoxazol-4-yl)isoxazole-4-carboxylate (61) into ethyl 4-cyano-5-methyloxazol-2-ylacetate (62 Scheme 5). ... 

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