Naproxen, diastereoselectivity

S)-Naproxen, 18, and S-ibuprofen, 19, are important and widely used analgesics with annual sales of about US 1.4 billion and a production volume of about 8000 tons. A technical feasible use of R,R-tartaric acid as chiral auxiliary was demonstrated in the Zambon Process for S-naproxen manufacture [3]. The diastereoselective bromination is followed by bromine hydrogenolysis and hydrolysis to produce S-naproxen in 75 percent overall yield. 

Internal proton return to lithium enolates from secondary amines which are coordinated to the lithium ion has been used for diastereoselective (Sections 2.1.3.6. and 2.1.4.2.) and enantioselec-tive (Section 2.1.6.1.2.) protonations. A remarkable example of enantioselective internal proton return, with the exclusion of any additional proton source, occurs with racemic Naproxen amides 1l63a. 

The Zambon process also starts from P-naphthol, and affords S-naproxen directly avoiding resolution and recycling. It is one of the few examples of a non-enzymatic, non-fermentation industrial asymmetric synthesis. Clearly, the early stages of the process produce similar waste streams to the Syntex process, with additionally waste from the Friedel-Crafts step. In principle, however, the aluminium salts can be recycled by work-up involving conversion back to aluminium chloride. The key step in this route is the highly diastereoselective (94 6) bromination of the ketal diester, derived from chirality pool 2R, 3R tartaric acid, which is used as an auxiliary. The subsequent acid catalysed 1,2-aryl shift occurs with complete inversion of configuration at the migration terminus [17]. The tartaric acid auxiliary can be efficiently recycled, but clearly there is a... 

Photodecarboxylation of NSAIDs Inside Cyclodextrin Diastereoselective Photodecarboxylation of 2-Phenylpropionic Acid in Zeolite Medium Photolysis of Ibuprofen and the Methyl Ester of Naproxen 64.5 Conclusion.65-11... 

A number of processes involving chiral acetals have been examined in the synthesis of pharmaceutically important compounds. In one example, a synthesis of the antiinflammatory drug naproxen (80) includes a diastereoselective bromination reaction to furnish bromide 78 (dr 93 7, Scheme 6.15) [45]. Intramolecular rearrangement gives ester 79 with >99 1 diastereo-selectivity after recrystallization. Subsequent acidic cleavage of the auxiliary followed by reduction (H2 Pd-C) of the bromide that is adventitiously introduced on the naphthyl core afforded naproxen (80). 

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