Tolterodine

Chemical properties

Pale Yellow Gel

Originator

Detrol,Pharmacia and Upjohn

The Uses of Tolterodine

A muscarinic receptor antagonist. Used in the treatment of urinary incontinence.

Background

Tolterodine is an antimuscarinic drug that is used to treat urinary incontinence. Tolterodine acts on M2 and M3 subtypes of muscarinic receptors.

Indications

For the treatment of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence).

Definition

ChEBI: Tolterodine is a tertiary amine. It has a role as a muscarinic antagonist, a muscle relaxant and an antispasmodic drug. It is functionally related to a p-cresol.

Manufacturing Process

Trans-cinnamic acid (100 g, 675 mmol) is added to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet. Para-cresol (76.6 g, 708 mmol) is preheated in a water bath at 60°C and added to the cinnamic acid followed by concentrated sulfuric acid (13.0 ml, 243 mmol). The reaction is immediately heated to a set point of 122.5°C and stirred at 120°-125°C until judged to be complete by HPLC analysis. When the reaction is complete the mixture is cooled to 100°C and added to a prewarmed separatory funnel (500 ml). The bottom layer containing the sulfuric acid is removed and toluene (280 ml), water (50 ml) and potassium carbonate (47%, 10 ml) are added to the separatory funnel containing the crude product. The pH of the aqueous layer is adjusted to between 5-8 with additional 47% potassium carbonate. The layers are separated and the organic layer is then washed once with water (50 ml). The organic layer is concentrated to a final volume of approximately 150 ml under reduced pressure. Isopropanol (350 ml) is then added, and distillation is continued to a volume of 350 ml. Isopropanol (150 ml) is again added and again distilled to 350 ml (2 times). The mixture is then cooled to 30°-40°C with rapid stirring until the product crystallizes. The rapid stirring is continued after crystallization. The product is cooled to 0°-5°C and held at this temperature for 1 h, filtered and washed with isopropanol (200 ml) cooled to 0°-5°C. If the last portion of the wash is colored the wash is continued until no more color is removed. The solids are then dried at 60°C under reduced pressure to give the 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, melting point (uncorrected) 83°-85°C.
3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (100.0 g, 420.2 mmol) is added to toluene (500 ml). The mixture is degassed by purging alternately with vacuum and nitrogen and then cooled to -21°C. Diisobutylaluminum hydride in toluene solution (DIBAL, 1.5 M, 290 ml, 435 mmol) is then slowly added over 2 h via add funnel while maintaining the reaction temperature at - 20°-25°C. The reaction is usually done when the DIBAL add is completed. If the reaction is not done additional DIBAL can be added in increments. When the reaction is done (<1% lactone) ethyl acetate (45 ml) is added at -20°- 25°C via add funnel. Very little exotherm is observed. Next, citric acid (23%, 500 ml) is added. The mixture is stirred at 45°-50°C for 1 h (or stirred overnight at 20°-25°C), the phases are separated, the organic phase is washed with water (2 times 300 ml). The organic phase is concentrated to 250 ml under reduced pressure. Methanol (500 ml) is added, and the mixture is concentrated to 250 ml. The methanol addition and distillation is repeated to give the 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol in methanol solution.
3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol in methanol (500 ml) is slowly added to palladium on carbon (5%, 22 g, 1.5 mmol) while maintaining a slight nitrogen purge. If 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol is added too quickly without a nitrogen purge the catalyst will ignite the methanol. Diisopropylamine (147.0 ml, 1.05 mol) is added, and the mixture is hydrogenated at 45-50 psi and 48°C until the reaction is judged to be complete by HPLC (<2% lactol). The reaction is usually done after 10 h, but can be run overnight. The reaction mixture is cooled and removed from the hydrogenator using a methanol (150 ml) rinse. The combined reaction mixture and rinse is filtered through a bed of solka floc (10 g). The solka floc is washed thoroughly with methanol (100 ml) and the filtrate is concentrated to remove methanol while ethyl acetate is being added back. The volume of this solution of the (2-diisopropylamino)ethyl)benzyl)-p-cresol is adjusted to 700 ml using ethyl acetate and the mixture is heated to 55°C. To form the hydrochloride salt of the (2-diisopropylamino)ethyl)benzyl)-p_x0002_cresol (Tolterodine), concentrated hydrochloric acid (52.5 ml, 630 mmol) is added over 15 min. The resulting slurry is gradually cooled to -15°-20°C and held at this temperature for 1 h. Tolterodine hydrochloride is collected by filtration, washed 3 times with ethyl acetate, and dried overnight under reduced pressure at 600 to give the tolterodine hydrochloride, melting point 199°-201°C. Tolterodine hydrochloride (130.0 g, 359 mmol), methylene chloride (1.3 L) and water (650 ml) are mixed. The mixture is stirred rapidly while adding sodium hydroxide (50%, 13.0 ml) and sodium carbonate (13.0 g, 123 mmol). The pH as determined by pH paper is 10-11. After stirring thoroughly for approximately 15 min two clear homogeneous phases form. Stirring is continued for another 45 min, the layers are separated and the organic phase is washed with water (2 times 650 ml). The methylene chloride mixture is concentrated under reduced pressure. The concentrate is dissolved in ethanol (325 ml) and warmed to 60°-70°C. L-tartaric acid (80.84 g, 539 mmol) slurried in hot ethanol (810 ml) is added via add funnel at 60°-70°C over approximately 30 min. When the addition is done the slurry is refluxed for 1 h, gradually cooled to 0°C and held at this temperature for 1 h. The slurry is filtered, washed with ethanol (2 times 260 ml) previously cooled to 0°C, and dried overnight under reduced pressure at 60°C to give the crude title compound. The crude product (136.0 g) and ethanol (5.44 L) are mixed and heated to 80°C for 30 min. The mixture is concentrated to half the initial volume by distilling 2.72 L of ethanol. The mixture is gradually cooled to 20°- 25°C over 1 h, placed in an ice bath, and held at 0°C for 1 h. The tolterodine L-tartrate is collected by filtration, washed with ethanol (2 times 272 ml ) previously cooled to 0°C, and dried overnight under reduced pressure at 60°C to give product. This procedure was repeated a second time on 81.0 g of once recrystallized tolterodine L-tartrate to give the optically active (+)-(R)-2-(α- (2-(diisopropylamino)ethyl)benzyl)-p-cresol L-tartrate, melting point (uncorrected)=210°-211°C.

Therapeutic Function

Anticholinergic

General Description

Tolterodine (Detrol), 2-[3-[bis(1-methylethyl)amino]-1-phenyl-propyl]-4-methyl-phenol, is an antimuscarinicagent that acts on M2 and M3 muscarinic subtypereceptors. By competitively blocking of the muscarinicreceptors results in a reduction of the smooth muscle tone,allowing for greater volume of urine to be stored in the bladder.This results in less urinary incontinence, urgency, andfrequency.

Pharmacokinetics

Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract.

Metabolism