January 9, 2012
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Improve the synthesis of drugs for bladder disorders. Inventors J. B. Ahman, B. R. Dillon, and A. J. Pettman describe a process for preparing compound 4, an intermediate in the synthesis of overactive bladder and urinary incontinence drugs tolterodine and fesoterodine. They summarize alternative methods for making 4 and claim that their improvement is a one-pot synthesis that starts from readily available p-cresol (1).
The first reaction shown in Figure 1 is carried out by condensing 1 with piperazine (2) in refluxing toluene to produce intermediate 3. This compound can be isolated and is the subject of one of the claims of the patent. No yield or purity data are provided; the only information given is its melting point of 241 °C and the statement that 1H and 13C NMR confirm the structure. Cleaving 3 with trans-cinnamaldehyde produces 4, which is isolated as a toluene solution.
The first step for preparing tolterodine (5) is to treat the toluene solution of 4 with MeOH and i-Pr2NH. This mixture is hydrogenated over a Pd(OH)2/C catalyst to give 5. After the volatiles are removed by distillation, the mixture is treated with L-tartaric acid (LTTA). The LTTA salt of 5 is isolated in 24% yield based on 1, with 100% achiral purity and 91.4% ee. The inventors also describe the preparation of the racemic HCl salt of 5.
The inventors also report syntheses of several compounds related to 5 that start from analogues of 1 and 2. As an example, the fumarate salt of fesoterodine (12) is prepared by the route shown in Figure 2. The first step is to prepare 8 by the reaction of 6 with 7 and subsequent cleavage of the intermediate analogous to 3 with trans-cinnamaldehyde. This reaction is carried out on a kilogram scale; product 8 in toluene solution is recovered in 53.4% yield and then used in the next step without isolation.
Intermediate 8 undergoes reductive amination to give racemic 10 in 89% yield, isolated as a solution in tert-amyl alcohol (t-AmOH). The racemic 10 solution is resolved by using chiral acetoxy acid 9, and the pure (R)-enantiomer 10 salt of 12 is obtained in 37.8% yield. Treating this salt with K2CO3 provides free 10, isolated in 66.7% yield and 99% purity after crystallization from toluene.
In the next stage, the phenol group in 10 is esterified with acid chloride 11 in the presence of Et3N to form 12. The free base is treated with fumaric acid to give fesoterodine fumarate. Details are not provided; these reactions are carried out by using a method from US Patent 6,858,650 (2005). (Pfizer [New York]. US Patent 8,067,594, Nov. 29, 2011; Keith Turner)