Yield:-

Reaction Conditions:

with N-ethyl-N,N-diisopropylamine in dichloromethane at -10 - -5; for 2.5 h;Product distribution / selectivity;

Steps:

1; 2

20.0 g of active metabolite is solved in 140 ml dichloromethane (DCM) . The temperature of this solution is adjusted to -10⁰C. Subsequently, a solution of 7.90 g N, iV-diisopropylethylamine (Huenig's base) in 40 ml DCM is added, while the temperature rises to -8°C. The reaction solution is again cooled to -10⁰C, and 6.50 g of isobutyric acid chloride in 120 ml of DCM are added dropwise to the reaction mixture within 30 min, while the temperature is maintained between -8°C and -10⁰C. After stirring for 2 h at a temperature of -10⁰C to -5°C, the reaction mixture was sampled and analysed by HPLC . Subsequently, the organic phase is successively washed twice with 100 ml water, 100 ml of a solution of Na2CC>3 (5wt.-%), and 100 ml of water. After these washing steps, it is separated, filtered and evaporated under reduced pressure using a rotation evaporator and a bath temperature of 50⁰C until the weight of the residue remains constant, thereby obtaining 24.83 g of product (yield: 103 %) . A sample of the reaction product is analysed using HPLC.HPLC analysis:The sample is taken up in a 1:1 mixture of acetonitrile and 0,01 N HCl (e.g. 5 ml acetonitrile and 5 ml 0,01N HCl) and shaken, so as to adjust the amount of fesoterodine to approximately 250 μg per ml acetonitrile. This solution is subjected to HPLC analysis.Further, a solution of 250 μg of fesoterodine fumarate and of 0.375 μg of each impurity per ml acetonitrile is employed as a reference.HPLC parameters :? Column: Polaris C18-Ether, 3 μm, 250 mm x 4.6 mm? Eluent A: Water/methanesulfonic acid 1000 : 0.5 (v/v)? Eluent B: Acetonitrile/methanesulfonic acid 1000 : 0.5 (v/v)? Typical gradient profile:Time (mm) % A % B0.0 67 3316.0 38 6218.0 0 100? Column temperature: 35°C? Flow rate: : 1.2 mL/min? Detection wavelength: 220 nm? Injection volume: 20 μL ? Run time: 22 minThe amount of fesoterodine, active metabolite and diester are calculated from the HPLC chromatogram using the area-% method known to the skilled person.The following response factors have been determined: active metabolite: 1.4 diester: 1.1 benzylic ester: 1.1Reactions were performed in an analogous manner but substituting triethylamine for Huenig ' s base (Example 3) or without the addition of a base (Example 4) . The results are shown in Table 1 below.* comparative example according to US 6,713,464** reference example according to copending applicationIt is clearly derivable from Table 1 above that the present process results in a higher yield and purity of fesoterodine as compared to the process of the prior art.

References:

WO2007/140986,2007,A1 Location in patent:Page/Page column 12-14