Methyl propionylacetate

The tiyptophol was condensed with methyl propionylacetate using boron trifluoride etherate as the catalyst to produce tetrahyropyranoindole. Basic hydrolysis of the ester gave [3-14C] etodolic acid (overall yield 26% from the labeled starting material). The compound was recrystallized in presence of an antioxidant to prevent formation of peroxides and stored at -10°C. The radiochemical purity was determined to be 99%. 

The synthesis of the first potent and selective secretory phospholipase Az (S-PLA2) inhibitor, LY311727, was carried out in the laboratory of M.J. Martinelli. The indole core of the target was prepared by the Nenitzescu indole synthesis, which proceeded in high yield. The enamine component was readily prepared from methyl propionylacetate (3-oxo-pentanoic acid methyl ester) and benzylamine in the presence of catalytic amounts of TsOH. A thorough screening of various solvents pinpointed nitromethane as the optimal solvent for the transformation, since the product crystallized from the reaction mixture and was easily removed by filtration. 

A solution of methyl propionylacetate (107) (25.0 mL, 199 mmol) and K2CO3 (82.6 g, 598 mmol) in THF (350 mL) was stirred at reflux for 2.5 h. The reaction mixture was then cooled to 0 °C, and iodomelhane (15.0 mL, 239 mmol) added dropwise. After stirring at 0 °C for 18 h, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure, affording methyl 2-methyl-3-oxopentanoate (102) (27.8 g, 97 %) as a yellow oil. 

The reactions of D-glucose with 2,4-pentanedione (acetylacetone), diethyl 3-oxoglutarate, ethyl benzoylacetate, ethyl propionylacetate, ethyl butyrylacetate, ethyl isovalerylacetate, and methyl acetoacetate have been effected, with formation of crystalline products. 

Benzoylacrylic acid and ethyl propionylacetate treated with aq. N KOH, stirred 1 hr., allowed to stand overnight, then refluxed 90 min. -> 2-methyl-3-phenyl-2-cyclohexen-l-one-5-carboxylic acid. Y 80%.—Similarly with acetylacetanilide instead of ethyl propionylacetate at room temp, overnight 3-phenyl-6-phenyl-carbamyl-2-cyclohexen-l-one-5-carboxylic acid. Y 73%. F. e. s. S. Julia and D. Varech, Bl. 1959, 1463. 

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