Cignarella G, Curzu M M, Grella G, Loriga M, Anania V, Desole M S
Farmaco Sci. 1983 Mar;28(3):187-98. doi: 10.1002/chin.198330161.
The synthesis of the 6-fluoro (I a), 6-chloro (I b) and 6-bromo (I c) derivatives of the known antiinflammatory agent 2-(3-benzoylphenyl)propionic acid (ketoprofen) is reported. The procedure employed involves the direct phase-transfer methylation of the appropriate arylacetonitriles and the subsequent hydrolysis of the alpha-methyl arylacetonitriles (V) thus obtained. It is noteworthy that (V b) and (V c) were not accompanied by alpha, alpha-dimethylated contaminants, owing to the steric hindrance of the chloro and bromine substituent. The pharmacological evaluation of (I a-c) showed that the presence of the halogen unexpectedly abolished the antiinflammatory and antipyretic activities of the model drug. The 6-ethoxy derivative (I d), isolated as by-product of the synthesis of (I a) was also found inactive. A hypothesis has been formulated on the loss of activity of these compounds.
报道了已知抗炎药2-(3-苯甲酰基苯基)丙酸（酮洛芬）的6-氟衍生物（I a）、6-氯衍生物（I b）和6-溴衍生物（I c）的合成。所采用的方法包括相应芳基乙腈的直接相转移甲基化以及由此得到的α-甲基芳基乙腈（V）的后续水解。值得注意的是，由于氯和溴取代基的空间位阻，（V b）和（V c）没有伴随α,α-二甲基化污染物。（I a - c）的药理学评价表明，卤素的存在意外地消除了模型药物的抗炎和解热活性。作为（I a）合成副产物分离得到的6-乙氧基衍生物（I d）也被发现无活性。已针对这些化合物活性的丧失提出了一种假说。
