Patent Watch

January 28, 2013

Enhance the synthesis of a bladder disorder drug intermediate. Inventors S. C. Ennis and B. D. Kennedy synthesized intermediates that are used to prepare compound 6, the active metabolite of tolterodine, a drug used to treat overactive bladder. An earlier patent (US 8,067,594) that describes a new process for synthesizing 6 was reviewed recently (Org. Process Res. Dev. 2012, 16, 376–388). In the current patent, the process for preparing 6 uses a Grignard reagent with enhanced activity.

The sequence begins with the preparation of Grignard agent 3 from bromo derivative 2 (made by a method described in U.S. Patent 6,713,464 [2004]). A toluene solution of 2 is treated with Grignard reagent 1, whose activity is enhanced by additional magnesium metal. In the patent’s example, 1.5 equiv Mg and 1.5 equiv 1 are used. Using twice these amounts does not improve the reaction.

After Grignard 3 is formed, the solution is treated with dimethyl carbonate to produce ester 4, isolated in 61% yield with 99.1%purity. The inventors do not describe the details for the subsequent conversion of 4 to 6, but they mention that 4 is reduced to alcohol 5 with LiAlH4 before the benzyl group is removed.

The inventors also state that reaction of 6 with i-PrCOCl in the presence of Et3N forms the corresponding isobutyl ester, which is known as fesoterodine. The fumarate salt of 6, commercially available as Toviaz, is also used to treat bladder problems.

Reagent 1 is described as a “turbo-Grignard” reagent; it was reported in Eur. Pat. EP1582523 (2005). The inventors suggest that using the enhanced reagent makes it possible to prepare a functionalized Grignard reagent in higher yield than via Br–Mg exchange. They believe that adding LiCl activates i-PrMgCl by increasing the nucleophilic character of the isopropyl group with the formation of a “magnesiate” species. This would lead to an intermediate that produces an arylmagnesium species that complexes with LiCl and enhances the activity of the Grignard.

The use of the more active Grignard reagent reduces the reaction time and gives a higher-purity product. (No assignee reported. US Patent 8,299,306, Oct. 30, 2012; Keith Turner)

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