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Naproxen Derivatives by Enantioselective Decarboxylation
Author(s) -
Brunner Henri,
Schmidt Peter
Publication year - 2000
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200006)2000:11<2119::aid-ejoc2119>3.0.co;2-5
Subject(s) - chemistry , decarboxylation , enantioselective synthesis , naproxen , nitrile , enantiomer , enantiomeric excess , organic chemistry , catalysis , ketone , medicine , alternative medicine , pathology
Abstract 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‐ethoxybenzamide 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 .