59-63-2

Pale Yellow Solid

Monoamine oxidase inhibitor. Antidepressant

Marplan,Roche,US,1959

ChEBI: 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide is a member of benzenes.

800 g of benzaldehyde was added to a hot solution (75°C) of 7 liters of ethanol containing 720 g of 5-methyl-2-isoxazole carboxylic acid hydrazide. The solution was stirred for ten minutes at which time the product began to crystallize. On cooling at 4°C for 14 hours, the solid was filtered off under vacuum and the solid filter cake was washed twice using 250 ml of ice cold ethanol for each washing. The lbenzylidene-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine was recrystallized from ethanol, MP 199°C to 200°C.
115 g of 1-benzylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was added portionwise over the period of an hour to 5 liters of anhydrous ether containing 18.5 g of lithium aluminum hydride. The reaction mixture was stirred for four hours and permitted to stand overnight. The excess lithium aluminum hydride was decomposed with 250 ml of ethyl acetate and 150 ml of water was added to decompose the complex. The solid was separated by filtration and the ether layer was concentrated to about 500 mi. 200 ml of benzene was added to dehydrate the solution. Concentration was continued until a solid remained. The 1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine was recrystallized from methanol, MP 105°C to 106°C.

Marplan (Oxford).

Antidepressant

Isocarboxazid, a monoamine oxidase inhibitor (MAOI), was introduced in 1959 for the treatment of depressive illness. Subsequently concern regarding potentially serious interactions between MAOIs and foods containing tyramine inspired much restrictive regulatory action. However, MAOIs still retain a place in the treatment of serious depressive illness although there is no international consensus on which compounds should be preferred. Thus isocarboxazid remains available in several countries and is cited in the British National Formulary as a relatively safe example of this class of compound.

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-carboxylic acid (7.2.2). Esterification of this product gives the ethyl ester of 5-methyl-isoxazol-3-carboxylic 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].

Store at -20°C