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 Zambon process is an example of a chirality pool material used as a covalently bound auxiliary, i.e. a diastereoselective reaction. Chirality pool materials may also be used as catalysts, modifiers, ligands and metal-based reagents. These have been adequately reviewed by Blaser [18]. A good example of an industrial scale synthesis has been reported by workers at Roche [19] and related examples have been reviewed by Kagan [20] (equation 7.1). 

Schering-Plough undertook abroad-based effort with third parties, both university and industrial, to search for a more practical process than that outlined in Scheme 8. The most important collaboration was that with Zambon S.p.A in Italy. 

Zambon devised the fluorination process outlined in Scheme 9, and used the new intermediate XIV to produce useful quantities of Florfenicol for Schering-Plough s ongoing development programs. 

The process steps up to compound XV were the subject of disclosure in a Zambon patent.18 The Zambon patent was part of a family of patents that Zambon was to build up over time, in both the United States and Europe, covering its process R D work. Claim 1 in Zambon s patent, covering the process to compound XIV is provided to illustrate the breadth and complexity of their coverage. It can be adduced that compound XVI in Claim 1 embraces the key intermediate XIV. Claim 1 reads as follows ... 

The Schering-Plough chemical process development group was drawn into the Florfenicol clinical supply program in 1984 with a view to determining whether a lower-cost process might be found which would overcome the need to routinely recrystallize the Florfenicol produced by Zambon. Recrystallization had proved necessary to... 

Schering-Plough s Improved Process in Relation to Zambon s Patent Rights... 

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. 

Such process is based on the comparison of two chromatograms, one of which corresponds to the established standard and the other one to the component being studied. In such comparisons, we have to dilute the standard (purity > 95.0 % from Aldrich) of the component to be determined. For example, (+)- CitroneUa GC (Zambon et al, 2011). A known volume of what has been diluted is injected and the reference area (Aref) and the correspxmding peak in the chromatogram is measured. Then, without changing any of the analysis conditions, an identical volume of the sample is injected and the area corresponding to the sample (Asample) is measured. Since the volume in both cases is equal, there is proportionality between the areas, which depends on the injected masses and the concentrations. Thus, we can determine the sample concentration with the equation (2) (Rouessac et aL, 2003)... 

Carvalho A.J.E, Zambon M.D., Curvelo A.A.S., Gandini A., Thermoplastic starch modification during melting processing Hydrolysis catalyzed by carboxylic acids, Carbohydr. Polym., 62, 2005, 387-390. 

A.J.F. Carvalho, M.D. Zambon, A.A. da Silva Curvelo, and A. Gandini, Thermoplastic starch modification during melt processing hydrolysis catalyzed by carboxyhc acids. Carbohydr. Polym. 62, 387-390 (2005). 

An additional example of ATH of ketones in industrial processes is the total synthesis of the drug, Dorzolamide HCl, indicated for the treatment of high intraocular pressure. A Ru(II)-catalysed ATH process has been developed by ZaCh System-Zambon Chemicals [230]. The complex (5,5)-26 (Fig. 66) efficiently controls the stereoselectivity affording the (5,5)-hydroxy sulfone with high selectivity (98 % de and 99.9 % ee after isolation) (Fig. 69),... 

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