Hydroxy-5-Methylisoxazole Derivatives

Ethyl acetoacetate (0.2 mol) was added to a solution of hydroxylamine hydrochloride (0.1 mol) in 100 mL of 2 N sodium hydroxide and reacted at -26 to -30 °C for 1 h, and the reaction mixmre was kept in pH 10. The mixmre was treated by adding an excess of concentrated hydrochloric acid at once at -20 °C and left overnight at room temperature. The product was extracted with dichloro-methane several times. Dichloromethane was evaporated under reduced pressure and the residual solid product was recrystallized from cyclohexane/trichlorome-thane (4/1, v/v) to give 3-hydroxy-5-methyl-isoxazole M13 in 70 % yield as colorless crystal, mp 86-87 °C. 

To a solution of M13 (4.75 g) dissolved in 80 mL of DMF, NaOH (1.92 g) was added with stirring at room temperature for 3 h. Ethyl bromoacetate (8.02 g) was added dropwise to the mixture at 0-5 °C and then the mixture was left overnight at room temperature. After 320 mL of water were added to the mixture, the product was extracted with 640 mL of diethyl ether. The ether solution was washed with water and brine separately, dried and evaporated to give pure ethyl (5-methyl-isoxazol-3-yl)oxyacetate M14. 

The intermediate M14 was converted to (5-methylisoxazol-3-yl)oxyacetic acid M15 by treating with 5 % sodium hydroxide (98 mL) at room temperature for 4 h, followed by acidification to pH 2 with 10 % HCl solution. The product was extracted with trichloromethane and the solvent was evaporated in vacuo. The residue was recrystallized from benzene to give pure M15 as yellowish crystal in 48 % overall yield, mp 122-124 °C. 

A mixture of M15 (0.1 mol) and thionyl chloride (50 mL) was refluxed at 60 °C for 4 h and then unreacted thionyl chloride was removed under reduced pressure to give (5-methylisoxazol-3-yl)oxyacetyl chloride M16 as a yellow liquid in 80 % yield. Cmde M16 was used for next reaction without purification. 

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Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

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