The Upjohn Co.

Francis L Shenton

Thomas A Hylton

A diester of .alpha.-acetyl-.alpha.'-methylsuccinic acid is prepared in improved yield under substantially anhydrous process conditions which minimizes decomposition of that diester by reacting an acetoacetate ester with an .alpha.-halopropionate ester in a solvent mixture containing a non-polar, aprotic liquid, e.g., toluene, and a dipolar aprotic liquid, e.g., DMF, at from about 50.degree. C. to reflux temperature in the presence of a phase transfer agent, a catalytic amount of iodide ion and solid form, substantially anhydrous alkali metal base or basic salt. Further improvement is obtained when the completed reaction mixture is diluted with water and adjusted to pH 8 to 9, and when the DMF/acetoacetate ester ratios are between about 1.7 and 3. The resulting diesters can be used under the conditions of this invention as intermediates in processes for making ibuprofen by combining and reacting the .alpha.-acetyl-.alpha.'-methylsuccinate diester with vinyl isobutyl ketone (or the corresponding Mannich base plus an alkylating agent) and an alkali metal base, e.g., potassium tert-butoxide, for a time sufficient to form a reaction mixture containing the .alpha.-methyl-.alpha.'-acetyl-.alpha.'-(5-methyl-3-oxohexyl)succinate ester, which can then be converted to ibuprofen by procedures now known.

Use of alkylformamide and acetamide in preparing

The present invention is a chemical method for obtaining an optically pure 2-aminonitrile or a 2-aminoamide from (1) an optically impure mixture, (2) a racemic mixture, or (3) the optically pure enantiomer of the opposite configuration, in an amount greater than actually present, by use of optically active acids with a ketone or an aldehyde catalyst. Yields of greater than 70 percent of one enantiomer are obtained from racemic mixtures in very short time periods.

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Portage, MI, United States of America

Francis L Shenton