Naproxen Zambon process

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. 

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... 

Clearly, both the Syntex and Zambon processes for production of 5-naproxen afford considerable quantities of waste for disposal. Some of these waste streams are in principle recyclable. This situation is in common with most pharmaceutical/fine chemical operations, where the use of batch production methods and stoichiometric quantities of reagents is the norm. Had naproxen been produced and marketed as a racemic drug, in common with most other NSAI agents, the amount of waste produced would presumably be even greater. Thus production of drugs in homochiral form is itself a positive environmental factor. This is even more true for agrochemicals which are applied directly to the environment, as stated earlier. 

The preparation of optically pure naproxen by the Zambon procedure (Figure 16.2) [22] is another example of a molecule from the chiral pool. Rearrangement of the tartaric acid-derived ketal 3 establishes the chiral center in naproxen, and the overall yield is excellent. However, this process does bear the burdens of recovering and regenerating the chiral tartrate auxiliary and of neutralizing the HBr generated by hydrogenolysis. 

An interesting solution was provided by a process developed by the Zambon company. [197] Friedel-Crafts acylation of 2-methoxynaphthalene is followed by a ketaUsation with diethyl (RJl)-tartrate and a double bromination, at C-1 and in the side-chain, yielding a 92 8 mixture of diastereomers. After hydrolysis of the tartrate, the reaction mixture is heated to 90 °C in water. Thereby, under kinetic resolution and by a [l,2]-aryl migration with complete inversion at the stereogenic centre, bromonaproxen is formed, which is finally converted by reductive dehalogenation into enantiomericaUy pure (S)-naproxen. 

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