Process for preparing 3,3-diarylpropylamines

Abstract

Described is a process of preparing a pure solid or crystalline racemic 3,3-diarylpropylamine compound and the compounds formed thereof. The solid and crystalline forms of racemic 3,3-diarylpropylamine compound are especially suitable for producing highly pure 3,3-diarylpropylamine salts such as tolterodine tartrate. Also described are the highly pure solid or crystalline forms of racemic tolterodine, racemic tolterodine salt and tolterodine tartrate.

1 - 17 . (canceled) 
     
     
         18 . A process for making tolterodine tartrate with a chemical purity in the range selected from the group consisting of about 99.85% to about 99.99% and about 99.90% to about 99.95% and an optical purity selected from the group consisting of about 99.50% to about 99.99% and about 99.60% to about 99.70% which comprises:
 (a) reacting crystalline racemic tolterodine, obtained by a process comprising:
 (i) forming a mixture of racemic tolterodine salt and an inert solvent; 
 (ii) adjusting the pH of the mixture with a sufficient amount of base to a range selected from the group consisting of about 10 to about 12 and about 11 to form racemic tolterodine; 
 (iii) isolating the racemic tolterodine formed in step (ii); and 
 (iv) optionally, a purification step which comprises mixing the racemic tolterodine of step (iii) with an inert organic solvent to form an inert organic solution, heating the inert organic solution to reflux, optionally followed by filtering the inert organic solution to form a filtrate containing racemic tolterodine and then cooling to allow the racemic tolterodine to precipitate out of the filtrate, with L-(+)-tartaric acid; 
   (b) recrystallizing the crude tolterodine tartrate formed in step (b) which comprises:
 (i) mixing the crude tolterodine tartrate with a first solvent or mixture of first solvents, heating to reflux, cooling to allow for crystallization and separating the tolterodine tartrate crystals; and optionally 
 (ii) mixing the tolterodine tartrate crystals with a second solvent or mixture of second solvents, heating to reflux, cooling to allow for crystallization and separating the tolterodine tartrate. 
   
     
     
         19 . The process of  claim 18 , wherein the first solvent in step (i) is a mixture of methanol and ethanol. 
     
     
         20 . A tolterodine tartrate produced by the process of  claim 18 . 
     
     
         21 . (canceled) 
     
     
         22 . The tolterodine tartrate of  claim 18  which has a chemical purity selected from the group consisting of about 99.85% to about 99.99% and about 99.90% to about 99.95% and an optical purity selected from the group consisting of about 99.50% to about 99.99% and about 99.60% to about 99.70%. 
     
     
         23 . The tolterodine tartrate of  claim 18  which has a particle size distribution wherein 10% of the total volume is made of particles having a diameter below 10 μm, 50% of the total volume is made of particles having a diameter below 35 μm and 90% of the total volume is made of particles having a diameter below 80 μm. 
     
     
         24 . The process of  claim 18 , wherein the racemic tolterodine salt of step (a)(i) is racemic tolterodine hydrobromide. 
     
     
         25 . The process of  claim 24 , wherein the base is sodium hydroxide and the inert solvent is a mixture of water and acetone. 
     
     
         26 . The process of  claim 25 , wherein the inert organic solvent in the recrystallization step is acetonitrile. 
     
     
         27 . The process of  claim 26 , wherein the chemical purity of the racemic tolterodine is selected from the ranges consisting of at least about 90%, at least about 95%, at least about 98% and at least about 99%. 
     
     
         28 . The process of  claim 27 , wherein the crystalline racemic tolterodine of step (a) is characterized by a powder X-ray diffraction pattern generated using CuK α  radiation with peaks at 5.67, 8.37, 9.66, 11.33, 14.68, 17.04, 17.89, 18.21 and 19.67±0.2 degrees two-theta.