One of the most frequently employed synthetic methods for the preparation of arylalkanoic acids has been the coupling of an aryl organometallic reagent with a haloalkanoic acid derivative such as a haloalkanoic acid ester. This method has proven to be of particular importance for the preparation of the valuable anti-inflammatory agent 2-(6-methoxy-2-naphthyl)propionic acid. In particular, for the preparation of this compound, couplings involving an alpha-halopropionic acid ester and 2-(6-methoxynaphthyl)copper (U.S. Pat. No. 3,658,863), zinc (U.S. Pat. No. 3,663,584) and cadmium (U.S. Pat. Nos. 3,658,858 and 3,694,476) reagents have been utilized. One disadvantage of these procedures is that the organometallic reagent used for the coupling must be prepared from the corresponding Grignard reagent, thus necessitating an additional chemical reaction, additional reagents, and so forth.
In German OLS No. 2145650 the direct coupling of aryl magnesium halides with potassium 2-iodopropionate was described. More recently, in U.S. Pat. No. 3,959,364, it was shown that an improved direct coupling could be effected by reaction of an aryl Grignard reagent with the lithium, sodium, magnesium or calcium salts of 2-bromopropionic acid of the structure CH.sub.3 CH(X)COM wherein X is bromo and M stands for OLi, ONa, O(Mg).sub.1/2 or O(Ca).sub.1/2 (cf. Table II of U.S. Pat. No. 3,959,364). However, it has been found that the preparation of 2-aryl-propionic acids, especially the valuable compound 2-(6-methoxy-2-naphthyl)propionic acid, by this method suffers from a number of inherent disadvantages including preparation of halopropionate salt in the aprotic solvent media that must be employed for the coupling reaction, leading to poor results for large scale preparations.
It would, therefore, be of extreme value to have a coupling process utilizing an aryl Grignard reagent and a suitable halopropionic acid derivative which afforded the desired 2-aryl-propionic acids easily and in reproducible high yield and purity and was readily adaptable to large scale commercial production.
USPTO Backgrounds
USPTO Backgrounds