The present invention relates to a cost effective and industrially advantageous process for the preparation of tolterodine, and pharmaceutically acceptable salts thereof.
Tolterodine is a muscarinic receptor antagonist which has recently been launched for the treatment of urinary urge incontinence and other symptoms of bladder overactivity. Chemically, tolterodine is (+)-(R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenyl propylamine having structural formula I and was first disclosed in U.S. Pat. No. 5,382,600. 
A process for preparing tolterodine is described in U.S. Pat. No. 5,382,600. The process involves the reaction of 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of structural Formula II 
with methyl iodide and potassium carbonate in refluxing acetone/methanol to give methyl-3-(2-methoxy-5-methylphenyl) 3-phenyl propionate of Formula III. 
The ester of Formula III is reduced with lithium aluminium hydride in ether to the corresponding propanol of Formula IV 
which is reacted with tosyl chloride and pyridine to yield the tosylate of Formula V 
which on condensation with diisopropylamine in hot acetonitrile is converted into the tertiary amine of Formula VI. 
The compound of Formula VI is treated with boron tribromide in dichloromethane to give the amine of Formula I as a racemic mixture, which is resolved with L-(+) tartaric acid. Long reaction time and low overall yields makes this process very expensive and less productive. Furthermore, the use of expensive and hazardous reagents like methyl iodide, lithium aluminum hydride, and boron tribromide also renders this process unsuitable and hazardous on a commercial scale.
U.S. Pat. No. 5,922,914 provides an alternate method for the preparation of tolterodine. The process involves the cyclization of trans-cinnamic acid of Formula VIII 
with p-cresol of Formula IX 
in hot sulfuric acid to give 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of Formula II which is reduced with diisobutyl aluminium hydride (DIBAL) in toluene to yield 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol of Formula X 
The reductocondensation of compound of Formula X with diisopropylamine by means of hydrogen over palladium on charcoal in methanol affords racemic tolterodine of Formula I which is resolved with L-tartaric acid. This process is also not commercially feasible since it makes use of an expensive and hazardous reagent DIBAL. Although the number of steps are reduced but the cost incurred to produce tolterodine is high.
It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of tolterodine which process improves the economics by employing less expensive and less hazardous raw materials and is more productive. The process is convenient to operate on a commercial scale and gives the desired product in good yield and quality.
The present invention provides a process for the preparation of tolterodine of structural Formula I, and pharmaceutically acceptable salts thereof, 
comprising:
(a) reacting 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of structural Formula II 
xe2x80x83with dimethyl sulphate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl-3-(2-methoxy-5-methylphenyl)-3-phenyl propionate of Formula III, 
(b) reducing the ester of Formula III with a reducing agent in the presence of a Lewis acid to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of Formula IV, 
(c) protecting the hydroxy group of the alochol of Formula IV to give a compound of Formula V, 
(d) aminating with diisopropylamine to give N,N-diisopropylamine-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine of Formula VI, 
(e) removing the hydroxy protecting group to obtain N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine of formula I and
(f) if desired, converting the compound of formula I into its pharmaceutically acceptable salts.
The starting material, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of Formula II is prepared by methods known in the literature (Example 1 of U.S. Pat. No. 5,922,914).
The reaction at step a) is performed in the presence of a phase transfer catalyst to yield the compound of Formula III. The phase transfer catalyst used is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium hydrogen sulphate.
The reducing agent used at step b) is a metal hydride such as sodium borohydride in the presence of a Lewis acid. The Lewis acid used is selected from the group consisting of boron trifluoride, aluminium chloride, ferric chloride and zinc bromide. The solution of the ester of Formula III in an organic solvent is treated with sodium borohydride in combination with aluminium chloride at about 25-30xc2x0 C. for about 2-3 hours. After a suitable work up 3,3-diphenylpropanol of Formula IV is obtained. The organic solvent is selected from inert solvents such as acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, monoglyme, diglymne, and mixtures thereof.
The protecting group used in step c) is an arylsulfonyloxy group such as p-toluene sulphonyl chloride. The reaction of step c) is performed in methylene chloride at about 10-25xc2x0 C. for 4-5 hours in the presence of triethylamine. After a suitable work up, the protected intermediate compound of Formula V is obtained.
The amination of compound of Formula V at step d) is carried out with diisopropylamine in an autoclave to give a compound of Formula VI. The removal of hydroxy protective groups can be achieved by treatment with hydrobromic acid, boron tribromide or by catalytic hydrogenation. It is preferably carried out with aqueous hydrobromic acid in acetic acid. The reaction of step e) is performed at about 70-115xc2x0 C. to afford tolterodine hydrobromide.
Tolterodine is an amine and forms acid addition salts both with organic and inorganic acids. Examples of such salts include hydrochloride, hydrobromide, sulfate, methane sulfonate, phosphate, nitrate, benzoate, citrate, tartarate, fumarate and meleate.