There are known techniques of preparing profen-type pharmaceuticals and other materials having a relatively complex aryl group attached to the alpha-carbon of a substituted or unsubstituted acetic acid. For example, U.S. Pat. Nos. 3,755,427 (Adams et al.), 3,959,364 (Armitage et al.) and 4,278,516 (Zaiko et al.) disclose processes for converting various starting materials into flurbiprofen, i.e., 2-(2-fluoro-4-biphenylyl)propionic acid, and similar compounds having anti-inflammatory, analgesic, and antipyretic properties; Carney et al., "A Potent Non-Steroidal Anti-Inflammatory Agent: 2-[3-Chloro-4-(3-pyrrolinyl)phenyl]propionic Acid," Experientia, Vol. 29, page 938 (1973) teach, inter alia, the preparation of their anti-inflammatory agent--also known as pirprofen--via an ethyl 2-(3-chloro-4-nitrobenzene)propionate intermediate; U.S. Pat. No. 4,239,901 (Rainer) shows that pyrazol-1-ylphenyl and pyrazolin-1-ylphenylacetic acids having anti-inflammatory properties can be synthesized from various intermediates, including polychloronitrobenzeneacetic acid esters; and it is known that indoprofen, i.e., 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]propionic acid, and indobufen, i.e., 2-[ 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric acid, can be prepared from the appropriate 2-(4-nitrobenzene)-alpha-alkylacetic acids.
Nitroarylacetic acids and their esters and nitriles, as well as the amino derivatives thereof, have been found to be particularly useful intermediates for the synthesis of these pharmaceuticals and other materials. however, in the past, a disadvantage of employing them as chemical intermediates has been the difficulty of preparing them by conventional techniques. Even the preferred procedures for preparing them have proven to be difficult, tedious, and time-consuming, as evidenced by Example 23 of U.S. Pat. No. 3,868,391 (Carney et al. II) and Example 16 of Rainer, both of which show the use of days of refluxing to accomplish only a portion of their syntheses.
It would obviously be a welcome contribution to the art to provide a method of synthesizing fluoronitroarylacetonitriles and derivatives thereof in a simple and straightforward manner. A method of synthesizing certain of these compounds, i.e., 2-(fluoronitrobenzene)acetonitriles and derivatives thereof, is disclosed in the above-identified parent of the present application, which teaches that the 2-(fluoronitrobenzene)acetontriles and derivatives may be prepared from fluoronitrobenzenes and alpha-substituted alkyl cyanides by a nucleophilic substitution reaction in a substantially anhydrous aprotic solvent and in the presence of a base.
USPTO Backgrounds
USPTO Backgrounds