287979-80-0Relevant academic research and scientific papers
Asymmetric catalysis, 131([≠]) - Naproxen derivatives by enantioselective decarboxylation
Brunner, Henri,Schmidt, Peter
, p. 2119 - 2133 (2007/10/03)
A new catalytic method to synthesize the important anti-inflammatory agent naproxen [(S)-1] which has to be used as the (S) enantiomer, involves the enantioselective decarboxylation of the 6-methoxynaphth-2-yl derivative 2 of 2-cyanopropionic acid. Compound 2 was stirred in THF at 15 °C with catalytic amounts of chiral bases, which abstracted the carboxyl proton. After decarboxylation, reprotonation of the anion of 6 afforded the enantiomerically enriched naproxen nitrile 6, which may be hydrolyzed to naproxen. A variety of bases were screened, and cinchona alkaloids were found to give the best enantioselectivities. Thus, with quinidine 10, up to 34% ee was obtained for (S)-6. The enantiomeric excess could be increased by turning to amides of 9-amino-9-deoxyepicinchona alkaloids. The most successful 2- ethoxybenzantide 31a of 9-amino-9-deoxyepicinchonine 11 gave up to 71.9% ee (S)-6. Cyclic ethers like THF were suitable solvents, and at a temperature of 15 °C, conversion was quantitative within 24 h in most cases. For high enantioselectivities, 5-10 mol-% of chiral base was sufficient, and the catalyst could be fully recycled after decarboxylation. The model compound 2- cyano-2-phenylpropionic acid (40) was decarboxylated with base 31a to the (S) enantiomer of the corresponding nitrile 41 with 60% ee.
