We have developed a new and straightforward synthesis of racemic tolterodine [N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine]. The synthesis involves selective nosylation on the primary alcohol of 1-phenylpropane-1,3-diol using 4-nitrobenzenesulfonyl chloride, subsequent diisopropylamine substitution, and Friedel-Crafts alkylation using aqueous perchloric acid.Tolterodine is the drug of choice for most patients for the treatment of urinary urge incontinence resulting from an overactive bladder as it has fewer side effects. 1 Through the years there have been myriad ways published for its racemic 2 and asymmetric synthesis. 3 Mostly these methods made used of coumarin or hydrocoumarin derivatives as starting material or intermediates. Most of these methods employed protection and deprotection techniques. This makes the routes lengthy, hence requiring more reagents and solvents. In addition, some of these routes entail longer reaction times and an inert environment while others utilize harsh conditions and hazardous chemicals such as diisobutylaluminum hydride, lithium aluminum hydride, methyl iodide, among others. There are also shorter routes, however, they gave lower yields or enantioselectivities whereas others require tedious workup. For asymmetric synthesis, the use of chiral auxiliaries 3a,c or expensive metal catalysts such as rhodium 2b,3b,d is impractical due to the cost incurred. Recently, we published a new route for the synthesis of tolterodine that also employed a protection-deprotection technique via a twophase reaction. 4 This route is simple and short, however, we have found a new route that is even simpler and eliminates the use of protecting groups. It is straightforward and has very short reaction times making it advantageous over other known procedures. We believed that this new method is economical and strategically feasible for industrial application. Thus, we wish to report here our new approach towards the synthesis of rac-tolterodine.Our aim was to develop a method of synthesizing tolterodine without using the protection-deprotection strategy impelled us to study thoroughly the structure of tolterodine. We considered the retrosynthetic analysis shown in Scheme 1. We reported recently that 1-phenylpropane-1,3-diol could be produced easily from the reduction of ethyl benzoylacetate (3) in excellent yield. 4 Thus, we thought that converting the hydroxy functionality into a better leaving group would easily facilitate diisopropylamine substitution and subsequent Friedel-Crafts alkylation to form tolterodine in a straightforward manner.
Scheme 1 Retrosynthetic analysis of rac-tolterodineWe first considered chlorination of 1-phenylpropane-1,3-diol using 2,4,6-trichloro-1,3,5-triazine and N,Ndimethylformamide 5 followed by Friedel-Crafts alkylation using graphite 6 in chlorobenzene. The reactions proceeded quite well. Chloride is a better leaving group than the hydroxy group thus we expected diisopropylamine substitution to be smooth, however, we failed to obtain our desired pro...