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(11) EP 2 686 288 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 217/56 (2006.01) C07C 217/62 (2006.01) 25.03.2015 Bulletin 2015/13 C07C 227/36 (2006.01) C07C 57/15 (2006.01) C07C 213/08 (2006.01) C07C 219/28 (2006.01) (2006.01) (21) Application number: 11796817.2 C07B 57/00

(22) Date of filing: 11.11.2011 (86) International application number: PCT/IB2011/055039

(87) International publication number: WO 2012/137047 (11.10.2012 Gazette 2012/41)

(54) A PROCESS FOR PREPARING FESOTERODINE PROZESS ZUR HERSTELLUNG VON FESOTERODIN PROCÉDÉ DE PRÉPARATION DE FÉSOTÉRODINE

(84) Designated Contracting States: • PATIL, Chetan AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Gujarat GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Vadodara 390003 (IN) PL PT RO RS SE SI SK SM TR • PATEL, Ronak Gujarat (30) Priority: 07.04.2011 IN MM11722011 Vadodara 390003 (IN) • RAVAL, Prashant (43) Date of publication of application: Gujarat 22.01.2014 Bulletin 2014/04 Vadodara 390003 (IN) • PAREKH, Viral (73) Proprietor: Alembic Pharmaceuticals Limited Gujarat Vadodara 390003 (IN) Vadodara 390003 (IN) • SHAH, Hiral (72) Inventors: Gujarat • RAMAN, Jayaraman, Venkat Vadodara 390003 (IN) Gujarat Vadodara 390003 (IN) (74) Representative: Watson, Robert James et al • PATEL, Samir Mewburn Ellis LLP Gujarat 33 Gutter Lane Vadodara 390003 (IN) London EC2V 8AS (GB) • THAKOR, Indrajit Gujarat (56) References cited: Vadodara 390003 (IN) EP-A1- 2 281 801 WO-A2-2009/126844 • LADANI, Mahesh Gujarat Vadodara 390003 (IN)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 686 288 B1

Printed by Jouve, 75001 PARIS (FR) EP 2 686 288 B1

Description

Field of the invention

5 [0001] The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Fesoterodine or a pharmaceutically acceptable salt thereof in high yield and purity. More specifically the present invention relates to an improved and industrially advantageous optical resolution method of racemic benzyl tolterodine and also relates to novel intermediate compounds, their preparation and use in the process for preparation of Fesoterodine and its related compound. 10 Background of the invention

[0002] Fesoterodine is [2-[(1R)-3-(Di(propan-2-yl) amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpro- panoate and represented by formula (I). 15

[0003] The product is marketed in the form of fumarate salt. The current pharmaceutical product containing this drug is being sold by Pfizer using the trade name Toviaz, in the form of extended release oral tablets. Fesoterodine is cholinergic antagonist and muscarinic antagonist. Fesoterodine is rapidly de-esterified to its active metabolite, (R)-2-(3- 30 diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol, or 5-hydroxy methyl tolterodine, which is a muscarinic re- ceptor antagonist. Fesoterodine is used as Urinary Incontinence Products. It is used to treat overactive bladder. [0004] Few processes for the synthesis of 3,3-diphenylpropylamine derivatives have been described in the literature (EP 2 2 81 801). [0005] Tolterodine and other 3,3-diphenylpropylamine analogs were first described in US patent 5,382,600. Said patent 35 described several methods for preparing tolterodine and its analogs generally based a process for the preparation of Tolterodine which is shown in the Scheme-I.

2 EP 2 686 288 B1

[0006] The main problem associated with this process is that it involves use of less economical reagent and which 30 requires specific handling skill when used. Moreover, some of the reagents like Lithium aluminum hydride should be avoided while using at plant because it hazardously reacts towards water and being more hygroscopic in nature compared to other reducing reagents like sodium borohydride. Further use of pyridine is some time prone to hazardous and biologically nondegradable and therefore it is not environment friendly. Further use of boron tribromide is also non appropriate. All these drawbacks make the process less economical and unsuitable at industrial level. 35 [0007] US patent 6,713,464disclosed a variety of 3,3-diphenylpropylamine derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. A process for the preparation of Fesoterodine which is shown in the Scheme- II.

3 EP 2 686 288 B1

[0008] The above processes for preparation of Fesoterodine require many number of steps and involve unfriendly reagents. The process is less economical, relatively less safe and time-consuming. Hence such technology is not readily 35 suitable for commercial production. [0009] WO2005012227 describes process for preparation of Fesoterodine from Tolterodine. But, This process involves preparation of resolved Tolterodine and then its benzylation increase the number of steps such as debenzylation to prepare tolterodine, resolution of tolterodine and then further benzylation to convert in R (+) benzyl tolterodine. Which further convert in to Fesoterodine. 40 [0010] Based on the aforementioned drawbacks, prior art processes find to be unsuitable for preparation of Fesoter- odine at lab scale and commercial scale operations. Hence, a need still remains for an improved and commercially viable process of preparing pure Fesoterodine or a pharmaceutically acceptable salt thereof that will solve the aforesaid problems associated with process described in the prior art and will be suitable for large-scale preparation, in lesser reaction time, in terms of simplicity, purity and yield of the product. 45 Summary of the invention

[0011] The present inventors have focused on the problems associated with the prior art process and has developed an improved process for the preparation of Fesoterodine, a metabolite of Tolterodine. 50 [0012] As a whole, a process such as the one provided by the present invention has the advantage of considerably reducing the number of synthetic steps with respect to the processes of the state of the art, while at the same time high yields are achieved with very simple steps. Likewise, said process is not toxic and allows starting from inexpensive and non-hazardous reactants, providing 3,3-diphenylpropylamines, and, particularly, Fesoterodine, with a good yield and pharmaceutical quality. All of this contributes to reducing the overall cost of the process, making it commercially interesting 55 and allowing it to be put into practice on an industrial level. [0013] Therefore, in one aspect the present invention provides a process for preparing Fesoterodine or its enantiomer, or a salt thereof, comprising a step of obtaining a compound of formula IV(a) or formula IV(b) or a salt there of,

4 EP 2 686 288 B1

10 Wherein Bn is benzyl group, by the resolution of the corresponding racemic compound of formula (III):

[0014] The present inventors develop a new process which involves resolution of racemic benzyl tolterodine to R (+) benzyl tolterodine that further convert in to fesoterodine. A present inventor’s process reduces steps such as debenzylation to prepare tolterodine, resolution of tolterodine and then further benzylation to convert in R (+) benzyl tolterodine. 25 [0015] In another aspect the present invention provides a novel compound of formula VII,

40 Wherein Bn is benzyl group. [0016] In another additional aspect the present invention also provides a fumarate salt of R(+)-[4-benzyloxy-3-(3- diisopropylamino-1-phenylpropyl)-phenyl]-methanol.

[0017] As a whole, a process such as the one provided by this invention relates to improved process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof which involves use and preparation of R(+) benzyl tol- 55 terodine and fumarate salt of R(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol. The present inventors have surprisingly found that employing intermediates of the present invention in the process for the preparation of Fesoterodine, overcomes the drawbacks of the prior art and may be prepared and subsequently converted to Fesot- erodine in high yield and purity.

5 EP 2 686 288 B1

Detailed description of the invention:

[0018] The present invention provides a process for preparation of fesoterodine or a pharmaceutically acceptable salt there of, which comprises: Reacting N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl- propane amide of for- 5 mula (II) with reducing agent such as sodium borohydride, potassium borohydride and sodium cyano borohydride in the presence of a lewis acid such as aluminium chloride, calcium chloride, boron trifluoride and zinc chloride to give N, N- diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III);

[0019] An embodiment of the present invention provides a process for the preparation of N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III) 20 [0020] Another embodiment of the present invention provides a process for resolving compound of formula (III) using a suitable optically active acid such as (+) tartaric acid, (-) tartaric acid, (+) 2,3-dibenzoyl-D-tartaric acid, (-) 2,3-diben zoyl- L-tartaric acid, mandelic acid, 3-chloro mandelic acid, abietic acid, S-(+)-camphorsulfonic acid , di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid to give (R) N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula IV(a); 25

35 [0021] In another embodiment of the present invention provides a novel compound of formula VII and process for preparation of this compound.

50 [0022] The process for converting compound of formula IV (a) to R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol of formula (V) involves oxidation of methyl group using oxidizing agent such as ruthenium chloride/ sodium periodate, fuming nitric acid, peracids, Dess-Martin reagent, chromium 4- oxide, nickel peroxide, sodium dichromate, manganese dioxide, potassium permanganate, activated silver oxide, pyridinium chlorochromate, ceric 55 ammonium nitrate or ceric ammonium citrate. Then reduction of aldehyde group is carried out using reducing agent such as sodium borohydride, potassium borohydride, Vitride, tetralkylammonium borohydride, calcium borohydride, zinc borohydride, sodium cyanoborohydride, lithium aluminium hydride or mixtures thereof. [0023] Debenzylating compound of formula (V) using hydrogenation catalyst such as Raney Nickel, palladium on

6 EP 2 686 288 B1

carbon, palladium acetate, platinum oxide, platinum black, platinum oxide adsorbed on carbon, rhodium on carbon, ruthenium and its salts adsorbed on solid support to obtain R-(+)-[4-hydroxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol of formula (VI); [0024] Condensing the compound of formula (VI) with isobutyryl chloride in a suitable solvent, optionally in the presence 5 of a suitable base, to produce substantially pure fesoterodine and optionally converting the fesoterodine formed in to a physiologically acceptable acid addition salt of fesoterodine. [0025] In yet another object of the present invention provides a resolution process for the preparation of (R)-N,N- diisopropyl-3-(2-(benzyloxy-5-halophenyl)-3-phenylpropyl amine compound of formula IV(a) or a salt thereof, which comprises: reacting racemic ( 6)N,N-diisopropyl-3-(2-(benzyloxy-5-halophenyl)-3-phenylpropylamine of formula III; with 10 a di-p-tolyl-D-tartaric acid in a mixture of water and isopropanol, to produce a diastereomeric excess of di-p-tolyl-D- tartaric acid salt of compound of formula VII. Separating the diastereomers of formula VII; and neutralizing the separated diastereomers with a base in a suitable solvent to provide enantiomericlly pure compound of formula IV(a). [0026] In an embodiment of the present invention provides an acid addition salt of a compound of formula V; comprising said compound of formula V and an acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic 15 acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid or malic acid. [0027] In an embodiment of the present invention provides a novel compound a compound of formula

[0028] In yet another embodiment of the present invention provides a process for preparation of fesoterodine or it’s a physiologically acceptable salt comprising the use of fumarate salt of compound of formula VIII.

[0029] In yet another embodiment of the present invention provides a process for preparation of fesoterodine or it’s a 40 physiologically acceptable salt comprises a step of crystalising the compound of formula II in isopropanol.

50 [0030] In another embodiment of the present invention provides a solid form of N, N-diisopropyl-3-(2-benzyloxy-5- methyl-phenyl)-3-phenyl propane amide. [0031] The embodiments of present invention are shown in below given scheme. [0032] The process for preparation of Fesoterodine fumarate is shown in the scheme III. 55

7 EP 2 686 288 B1

Examples

45 Example-1

Preparation of methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate:

[0033] Trans-cinammic acid (1.0 Kg) was added to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer, 50 thermocouple, and nitrogen inlet. Para-cresol (0.766 Kg) was preheated in a water bath at 60 °C and added to the cinammic acid (II) followed by concentrated sulfuric acid (13.0 mL, 243 mmol). The reaction was immediately heated to a set point of 127 °C and stirred at 120 °C -125 °C for 6-7hours. When the reaction was complete the mixture was cooled to 90 °C and toluene (3.0L) and water (0.5 L) are added to the crude product. The layers are separated and the organic layer was concentrated under reduced pressure. Methanol (1.0L) was added and distillation is continued to give 3,4- 55 dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one as oily mass. [0034] Benzyl bromide (1.372 Kg), potassium carbonate (1.275 Kg), acetone (5.0L) and methanol(5.0L)were loaded in to the mixture. The contents were heated to reflux temperature for about 4-5 hours and then distilled off the solvent from the reaction mass. 13L of water was added to the residue and extracted the solution twice with ethyl acetate (5.0L).

8 EP 2 686 288 B1

Combined organic layers and distilled the solvent completely under vacuum. Methanol (5.3L) was added to the residue and heated for 30 to 45 min at 5565°C to get clear solution, then stirred the solution at 0-5 °C for about 2 hours. The formed solid was filtered and washed with methanol (1.6 L) and the material was dried to give 1.8kg of methyl 3-(2- benzyloxy-5-methyl-phenyl)-3-phenyl propionate. Yield 74%. 5 Example-2

Preparation of N, N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide (II):

10 [0035] Methyl 3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propionate (1.0 kg) was dissolved in Methanol (4.0 L) to a 1 L 4-neck round bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet. The solution of Po- tassium hydroxide (0.232 Kg) in Process water (0.550 L) was added and refluxed reaction mixture for 3 to 4 hours. After completion of the reaction solvent was distilled out and stirred the reaction mass with Process water (3.6 L) and Dichlo- romethane (4.0 L). Then adjusted the pH to 1-2 using conc. HCl (0.5-0.8 L). Separated organic layer and d istilled out 15 solvent completely to give oil. [0036] Toluene (3.0 L), Dimethylformamide (0.01 L) and Thionyl chloride (0.411 Kg) were added in reaction mass and heated the reaction mass at 6263°C for 2-3 hours. After completion of reaction distilled Toluene completely and again charged Toluene (3.0 L) into the residue below 60°C and cooled the reaction mass to 23°C.6 Meanwhile prepared solution of Diisopropylamine (0.70 Kg) in Toluene (3.0 L) and added slowly into the reaction mass at 5 65°C. Stirred the 20 reaction mass for 3- 4 hrs at 3065°C. Process water (5.0 L) was added and separated out the organic layer. Distilled out Toluene completely under vacuum and charged Isopropyl alcohol (1.0 L) that also distilled under vacuum below 60°C and again Isopropyl alcohol (4.0 L) was added to the residue. Heated to 5565°C to get clear solution and then cooled the mass to 26 3°C. Filtered the solid under nitrogen atmosphere and washed with chilled Isopropyl alcohol. The material was dried under vacuum to obtain 0.98Kg solid N, N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl 25 propane amide. Yield 82%.

Example-3

Preparation of R-(+)-N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di-p-toluoyl L- 30 tartaric acid salt (VII):

[0037] N, N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide (1.0 Kg,), Tetrahydrofuran (5.0 lit) and Sodium borohydride (0.43 Kg) were taken into the round bottom flask. The contents were cooled to 2 63°C followed by drop wise addition of Borontrifluoride etherate (1.93 Kg). The reaction mixture was stirred for 10-12 hrs at 3362°C. 35 After completion of the reaction a solution of Conc. Hydrochloric acid (2.83 L) into Process water (2.83 L) was added to the reaction mass at 40610°C and stirred for 2-3 hrs at 6263°C. The product was extracted in dichloromethane (4.0 L). Dichloromethane distilled out completely under vacuum below 50°C. This was followed by addition of Isopropyl alcohol (1.0L) and distilled it completely to give ( 6) N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine. 40 [0038] Isopropyl alcohol (8.0 L), water (0.8L) and Di-p-toluoyl-L-tartaric acid (0.901 Kg) was added in reaction mixture and refluxed for 50-60 min. Gradually cooled the reaction mass at 3263°C within 5-6 hrs and Stirred it for 2.0-3.0 hrs. Filtered the solid and washed with Isopropyl alcohol (1.11 L). Obtain solid was recrystallized several times in Isopropyl alcohol and water to give 0.64 Kg R-(+)-N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di- p-toluoyl L-tartaric acid salt. Yield 34%. 45 1H NMR (CDCl3)300mHz δ (ppm): 1.10-1.21(12H,m); 2.10-2.32 (9H,d); 2.43-2.59 (2H,m); 2.59-2.76 (2H, m); 4.21-4.26 (1H, t); 4.96 (2H, s); 5.91 (2H, s); 6.77-6.80(1H, d); 6.94-6.95 (1H, dd); 7.06-7.09 (5H, d); 7.17-7.38 (10H, m); 7.85-7.88 (4H, d). IR : 2966, 1719, 1704, 1611, 1499, 1246.

Example-4 50 Preparation of R(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol fumarate salt (VIII):

[0039] R-(+)-N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine Di-p-toluoyl L-tartaric acid salt (100 g), Dichloromethane (400 ml) and process water (300 ml) were added in RB Flask. Followed by addition of a solution 55 of sodium carbonate (50 g) in Process water (500 ml) and stirred for 25-30 min. Separated out organic layer and distilled out Dichloromethane to give amine. Charged Acetonitrile (500 ml) and Process water (250 ml) into the reaction mass and cooled the reaction mass to 5 63°C. Slowly added solution of Ceric ammonium nitrate (230 g) in Process water (250 ml). The contents were stirred at 17 63°C for 3-4 hrs followed by lot wise addition of Sodium Borohydride (71 g) at 5 63°C.

9 EP 2 686 288 B1

Conc. Hydrochloric acid was added and stirred the reaction mass for 90-120 min at 35 63°C. The product was extracted in Dichloromethane (200 ml) and distilled out Dichloromethane completely to give oily mass. Dichloromethane (450 ml) and Fumaric acid (20.54 g) were added to Oily mass and heated it to reflux. Cooled the solution and filtered the solid to 65.0 g give R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol fumarate salt. 5 Yield 95%. 1H NMR (CDCl3)300mHz δ (ppm): 1.20-1.21(12H,d), 2.43-2.5 (2H,m), 2.96-3.02 (2H,m), 3.59-3.66 (2H, m), 4.42-4.44 (1H, t), 4.53 (2H, s), 5.04-5.08 (2H, s), 6.80(2H, s), 7.00-7.32 (13H, m), IR : 3419, 3027, 2994, 2874, 1703, 1611, 1500, 1246.

10 Example-5

Preparation of R (+)-2-(3-diisopropylamino-1-phenylpropyl)-hydroxymethyl phenol.

[0040] R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol fumarate salt (100 g), Dichlo- 15 romethane (400 ml), Process water (200 ml) and solution of sodium carbonate (50 g) in Process water (500 ml) were stirred in round bottom flask. Followed by addition of Sodium hydroxide (3.2 g) into the reaction mass and stirred it for 25-30 min. The organic layer was separated and distilled out Dichloromethane completely to give R-(+)-[4-benzyloxy- 3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol. The obtain oil, Raney Nickel (30 g) and Methanol (100 ml) were taken in to a hydrogenator and Maintained 4-5 Kg/Cm 2 pressure of Hydrogen for 30-60 min. The mixture was then 20 filtered and the solvent was removed by vacuum at below 50°C. This was crystallized in ethyl acetate (60 ml) to give 37.0 g R-(+)-[4-hydroxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol. Yield 59%.

Example-6

25 Preparation R-(+)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy methyl - phenylisobutyrate ester

[0041] A solution of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol (65.0 g) and triethylamine (20.4 g) in 750 ml dichloromethane has a solution of isobutyrate chloride (23.4 g) in 250 ml dichloromethane added under agitation and cooling. Following addition agitation takes place for a further 15 minutes at 0°C., then for 30 minutes 30 at room temperature and then one after another washing with water (250 ml) and 5% aqueous sodium hydrogen carbonate solution. The organic phase is separated and concentrated on the rotary evaporator until dry. The ester R-(+)-2-(3- diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester is obtained as colourless, viscous oil; yield: 77.1 g.

35 Example-7

Preparation of R-(+)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy methyl -phenylisobutyrate ester hydrogen fumarate.

40 [0042] A solution of 41.87g (102 mmol) R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester in 90 ml 2-butanone has fumaric acid (11.81 g, 102 mmol) added while heating. Following dissolution of the acid, cyclohexane (20-30 ml) is slowly added under agitation until the onset of turbidity. The colourless, homogenous deposit is initially left for 18 hours at room temperature, and then for several hours at 0[deg.] C. The colourless crystals that have precipitated are sucked off, washed with a little cyclohexane/2-butanone (90:10, vol.-%)and dried in the vacuum 45 at 30[deg.] C. 44.6 g (83.1% of theoretical) hydrogen fumarate salt of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4- hydroxymethylphenyl-isobutyrate ester is obtained.

Claims 50 1. A process for preparing Fesoterodine or its enantiomer, or a salt thereof, comprising a step of obtaining a compound of formula IV(a) or formula IV(b) or a salt there of,

10 EP 2 686 288 B1

Wherein Bn is benzyl group, by the resolution of the corresponding racemic compound of formula (III):

2. A process according to claim 1, wherein resolution of racemic compound of formula (III) through formation of the 25 diastereomeric salt thereof with an optically active acid, which may be selected from an optically active acid is an optically active carboxylic acid or sulphonic acid.

3. A process according to claim 2, wherein an optically active acid is selected from (+) tartaric acid, (-) tartaric acid, (+) 2,3-dibenzoyl-D-tartaric acid, (-) 2,3-dibenzoyl-L-tartaric acid, mandelic acid, 3-chloro mandelic acid, abietic acid, 30 S-(+)-camphorsulfonic acid , di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid.

4. A process according to claim 1, wherein the resolution of racemic compound of formula (III) is carried out in a solvent selected from water, a dipolar aprotic solvent, a C3-C8 ketone, a cyclic or acyclic ether, an ester, a chlorinated solvent and a polar protic solvent, or a mixture of two or more, typically two, of said solvents, more preferably 35 isopropyl alcohol

5. An acid addition salt of a compound of formula V; comprising said compound of formula V and an acid.

Wherein Bn is benzyl group 50 6. An acid addition salt according to claim 5, wherein said addition salt is selected from hydrochloride, hydrobromide, sulfate, methanesulfonate, phosphate, nitrate, benzoate, citrate, tartarate, fumarate or maleate.

7. A compound according to claim 5 which is of formula VIII. 55

11 EP 2 686 288 B1

10 Wherein Bn is benzyl group

8. A process for preparing Fesoterodine or its enantiomer, or a salt thereof, comprises the use of fumarate salt of compound of formula VIII.

Wherein Bn is benzyl group 25 9. A process for preparation of fesoterodine of formula I:

40 or a pharmaceutically acceptable salt there of, characterized by the steps of:

a. Reacting N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl- propane amide of formula (II) with reducing agent in the presence of a lewis acid to give N, N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula (III); 45

55 Wherein Bn is benzyl group b. Resolving compound of formula (III) using a suitable optically active acid to give (R) N, N-diisopropyl-3-(2- benzyloxy-5-methylphenyl)-3-phenyl propane amine of formula IV(a);

12 EP 2 686 288 B1

10 c. Converting compound of formula IV(a) to R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol of formula (V);

d. Debenzylating compound of formula (V) using hydrogenation to obtain R-(+)-[4-hydroxy-3-(3-diisopropylami- 25 no-1-phenyl-propyl)-phenyl]-methanol of formula (VI);

35 e. Condensing the compound of formula (VI) with isobutyryl chloride in a suitable solvent, optionally in the presence of a suitable base, to produce substantially pure Fesoterodine and optionally converting the Fesoter- odine formed in to a physiologically acceptable acid addition salt of Fesoterodine.

40 10. The process of claim 9, wherein the reducing agent used in step (a) is a metal hydride, with the proviso that the metal hydride does not include lithium aluminium hydride, selected from the group comprising sodium borohydride, potassium borohydride and sodium cyano borohydride; wherein the lewis acid is selected from the group comprising aluminium chloride, calcium chloride, boron trifluoride and zinc chloride, more preferably the reducing agent is sodium borohydride and the lewis acid is boron trifluoride. 45 11. The process of claim 9, wherein the resolution agent used in step (b) is selected from (+) tartaric acid, (-) tartaric acid, (+) 2,3-dibenzoyl-D-tartaric acid, (-) 2,3-dibenzoyl-L-tartaric acid, mandelic acid, 3-chloro mandelic acid, Abietic acid, S-(+)-Camphorsulfonic acid , di-p-tolyl-D-tartaric acid and di-p-tolyl-L-tartaric acid wherein more preferably the resolution agent used in step (b) is di-p-tolyl-D-tartaric acid. 50 12. The process of claim 9, wherein the oxidizing agent used in step (c) is selected from the group consisting of ruthenium chloride/ sodium periodate, fuming nitric acid, peracids, Dess-Martin reagent, chromium 4- oxide, nickel peroxide, sodium dichromate, manganese dioxide, potassium permanganate, activated silver oxide, pyridinium chlorochromate, ceric ammonium nitrate or ceric ammonium citrate, wherein more preferably the oxidizing agent used in step 55 (c) is ceric ammonium nitrate.

13. The process of claim 9, wherein the reducing agent used in step (c) is selected from the group consisting of sodium borohydride, potassium borohydride, Vitride, tetralkylammonium borohydride, calcium borohydride, zinc borohy-

13 EP 2 686 288 B1

dride,sodium cyanoborohydride,lithium aluminium hydride or mixtures thereof, whereinmore preferably thereducing agent used in step (c) is sodium borohydride.

14. The process of claim 9, wherein the debenzylation is carried out by hydrogenation of compound of formula (V) by 5 using a hydrogen gas and hydrogenation catalyst selected from Raney Ni, palladium on carbon, palladium acetate, platinum oxide, platinum black, platinum oxide adsorbed on carbon, rhodium on carbon, ruthenium and its salts adsorbed on solid support, wherein more preferably the hydrogenation catalyst used in step (d) is Raney Nickel.

10 Patentansprüche

1. Verfahren zur Herstellung von Fesoterodin oder dessen Enantiomer oder einem Salz davon, das einen Schritt des Gewinnens einer Verbindung der Formel IV(a) oder der Formel IV(b) oder eines Salzes davon,

worin Bn eine Benzylgruppe ist, durch Auftrennung der entsprechenden racemischen Verbindung der Formel (III) umfasst: 30

2. Verfahren nach Anspruch 1, worin die Auftrennung der racemischen Verbindung der Formel (III) durch die Bildung von deren diastereomerem Salz mit einer optisch aktiven Säure erfolgt, wobei die optisch aktive Säure gegebenen- 45 falls aus einer optisch aktiven Carbonsäure oder Sulfonsäure ausgewählt ist.

3. Verfahren nach Anspruch 2, worin die optisch aktive Säure aus (+)-Weinsäure, (-)-Weinsäure, (+)-2,3-Dibenzoyl- D-weinsäure, (-)-2,3-Dibenzoyl-L-weinsäure, Mandelsäure, 3-Chlormandelsäure, Abietinsäure, S-(+)-Camphersul- fonsäure, Di-p-tolyl-D-weinsäure und Di-p-tolyl-L-weinsäure ausgewählt ist. 50 4. Verfahren nach Anspruch 1, worin die Auftrennung der racemischen Verbindung der Formel (III) in einem aus Wasser, einem dipolaren aprotischen Lösungsmittel, einem C3-C8-Keton, einem zyklischen oder azyklischen Ether, einem Ester, einem chlorierten Lösungsmittel und einem polaren protischen Lösungsmittel ausgewählten Lösungs- mittel oder in einem Gemisch aus zwei oder mehreren, typischerweise zwei, der Lösungsmittel, noch bevorzugter 55 in Isopropylalkohol, durchgeführt wird.

5. Säureadditionssalz einer Verbindung der Formel V, das eine Verbindung der Formel V und eine Säure umfasst:

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worin Bn eine Benzylgruppe ist. 15 6. Säureadditionssalz nach Anspruch 5, worin das Additionssalz aus Hydrochlorid, Hydrobromid, Sulfat, Methansul- fonat, Phosphat, Nitrat, Benzoat, Citrat, Tartarat, Fumarat und Maleat ausgewählt ist.

7. Verbindung nach Anspruch 5, die der Formel VIII entspricht: 20

worin Bn eine Benzylgruppe ist.

35 8. Verfahren zur Herstellung von Fesoterodin oder dessen Enantiomer oder einem Salz davon, das die Verwendung des Fumaratsalzes der Verbindung der Formel VIII umfasst:

worin Bn eine Benzylgruppe ist. 50 9. Verfahren zur Herstellung von Fesoterodin der Formel I:

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15 oder einem pharmazeutisch annehmbaren Salz davon, gekennzeichnet durch die folgenden Schritte:

a. Umsetzen von N,N-Diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpropanamid der Formel (II) mit Re- duktionsmittel in Gegenwart einer Lewis-Säure, um N,N-Diisopropyl-3-(2-benzyloxy-4-methylphenyl)-3-phenylpropanamin der Formel (III) zu erhalten: 20

worin Bn eine Benzylgruppe ist; b. Auftrennen der Verbindung der Formel (III) unter Verwendung einer geeigneten optisch aktiven Säure, um (R)-N,N-Diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpropanamin der Formel IV(a) zu erhalten: 35

45 c. Überführen der Verbindung der Formel IV(a) in R-(+)-[4-Benzyloxy-3-(3-di-isopropylamino-1-phenylpropyl)phenyl]methanol der Formel (V):

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d. Debenzylieren der Verbindung der Formel (V) mittels Hydrierung, um R-(+)-[4-Hydroxy-3-(3-diisopropylamino-1-phenylpropyl)phenyl]methanol der Formel (VI) zu erhalten:

15 e. Kondensieren der Verbindung der Formel (VI) mit Isobutyrylchlorid in einem geeigneten Lösungsmittel, gegebenenfalls in Gegenwart einer geeigneten Base, um im Wesentlichen reines Fesoterodin zu produzieren, und gegebenenfalls Überführen des gebildeten Fesoterodins in ein physiologisch annehmbares Säureadditi- onssalz von Fesoterodin.

20 10. Verfahren nach Anspruch 9, worin das in Schritt (a) verwendete Reduktionsmittel ein Metallhydrid ist, mit der Maßgabe, dass das Metallhydrid nicht Lithiumaluminiumhydrid umfasst, ausgewählt aus der Natriumborhydrid, Kaliumborhydrid und Natriumcyanoborhydrid bestehenden Gruppe; worin die Lewis-Säure aus der aus Aluminium- chlorid, Calciumchlorid, Bortrifluorid und Zinkchlorid bestehenden Gruppe ausgewählt ist, wobei das Reduktions- mittel noch bevorzugter Natriumborhydrid ist und die Lewis-Säure noch bevorzugter Bortrifluorid ist. 25 11. Verfahren nach Anspruch 9, worin das in Schritt (b) verwendete Trennmittel aus (+)-Weinsäure, (-)-Weinsäure, (+)- 2,3-Dibenzoyl-D-weinsäure, (-)-2,3-DibenzoylL-weinsäure, Mandelsäure, 3-Chlormandelsäure, Abietinsäure, S-(+)-Camphersulfonsäure, Di-p-tolyl-D-weinsäure und Di-p-tolyl-L-weinsäure ausgewählt ist, worin das in Schritt (b) verwendete Trennmittel noch bevorzugter Di-p-tolyl-D-weinsäure ist. 30 12. Verfahren nach Anspruch 9, worin das in Schritt (c) verwendete Oxidationsmittel aus der aus Rutheniumchlorid/Na- triumperiodat, rauchender Salpetersäure, Persäuren, Dess-Martin-Reagens, Chrom(IV)-oxid, Nickelperoxid, Natri- umdichromat, Mangandioxid, Kaliumpermanganat, aktiviertem Silberoxid, Pyridiniumchlorochromat, Cerammoni- umnitrat und Cerammoniumcitrat bestehenden Gruppe ausgewählt ist, worin das in Schritt (c) verwendete Oxida- 35 tionsmittel noch bevorzugter Cerammoniumnitrat ist.

13. Verfahren nach Anspruch 9, worin das in Schritt (c) verwendete Reduktionsmittel aus der aus Natriumborhydrid, Kaliumborhydrid, Vitrid, Tetralkylammoniumborhydrid, Calciumborhydrid, Zinkborhydrid, Natriumcyanoborhydrid, Lithiumaluminiumhydrid oder Gemischen davon bestehenden Gruppe ausgewählt ist, worin das in Schritt (c) ver- 40 wendete Reduktionsmittel noch bevorzugter Natriumborhydrid ist.

14. Verfahren nach Anspruch 9, worin die Debenzylierung durch Hydrierung der Verbindung der Formel (V) unter Verwendung von Wasserstoffgas und eines aus Raney-Ni, Palladium auf Kohlenstoff, Palladiumacetat, Platinoxid, Platinschwarz, an Kohlenstoff adsorbiertem Platinoxid, Rhodium auf Kohlenstoff, an einen festen Träger adsorbier- 45 tem Ruthenium und dessen Salzen ausgewählten Hydrierungskatalysators durchgeführt wird, worin der in Schritt (d) verwendete Hydrierungskatalysator noch bevorzugter Raney-Nickel ist.

Revendications 50 1. Procédé pour préparer de la fésotérodine ou son énantiomère, ou un sel de celle-ci, comprenant une étape d’ob- tention d’un composé de formule IV(a) ou de formule IV(b) ou d’un sel de celui-ci :

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où Bn est un groupe benzyle, par dédoublement du composé racémique correspondant de formule (III) :

2. Procédé selon la revendication 1, dans lequel le dédoublement du composé racémique de formule (III) est réalisé par formation de son sel diastéréomère avec un acide optiquement actif, qui peut être choisi parmi un acide optiquement actif, est un acide sulfonique ou un acide carboxylique optiquement actif. 30 3. Procédé selon la revendication 2, dans lequel l’acide optiquement actif est choisi parmi l’acide (+)-tartrique, l’acide (-)-tartrique, l’acide (+)-2,3-dibenzoyl-D-tartrique, l’acide (-)-2,3-dibenzoyl-L-tartrique, l’acide mandélique, l’acide 3- chloromandélique, l’acide abiétique, l’acide S-(+)-camphosulfonique, l’acide di-p-tolyl-D-tartrique et l’acide di-p-tolyl- L-tartrique. 35 4. Procédé selon la revendication 1, dans lequel le dédoublement du composé racémique de formule (III) est réalisé dans un solvant choisi parmi l’eau, un solvant aprotique dipolaire, une cétone en 3C à C8, un éther cyclique ou acyclique, un ester, un solvant chloré et un solvant protique polaire, ou un mélange de deux ou plus, typiquement deux, desdits solvants, mieux encore l’alcool isopropylique. 40 5. Sel d’addition d’un composé de formule V, comprenant ledit composé de formule V et un acide,

55 où Bn est un groupe benzyle.

6. Sel d’addition d’acide selon la revendication 5, lequel sel d’addition d’acide est choisi parmi le chlorhydrate, le bromhydrate, le sulfate, le méthanesulfonate, le phosphate, le nitrate, le benzoate, le citrate, le tartrate, le fumarate

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et le maléate.

7. Composé selon la revendication 5, qui est de formule VIII,

15 où Bn est un groupe benzyle.

8. Procédé pour préparer de la fésotérodine ou son énantiomère, ou un sel de celle-ci, comprenant l’utilisation du sel fumarate du composé de formule VIII, 20

où Bn est un groupe benzyle.

9. Procédé pour la préparation de fésotérodine de formule I : 35

ou d’un sel pharmaceutiquement acceptable de celle-ci, caractérisé par les étapes suivantes :

50 a. réaction de N,N-diisopropyl-3-(2-benzyloxy-5-méthyl-phényl)-3-phénylpropanamide de formule (II) avec un agent réducteur en présence d’un acide de Lewis pour former la N,N-diisopropyl-3-(2-benzyloxy-5-méthylphé- nyl)-3-phényl-propanamide de formule (III) :

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10 où Bn est un groupe benzyle, b. le dédoublement du composé de formule (III) par utilisation d’un acide convenable optiquement actif pour former la (R)-N,N-diisopropyl-3-(2-benzyloxy-5-méthyl-phényl)-3-phénylpropanamine de formule IV(a) :

c. la conversion du composé de formule IV(a) en R-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phénylpropyl)phé- 25 nyl]-méthanol de formule (V) :

d. débenzylation du composé de formule (V) par utilisation d’une hydrogénation pour former le R-(+)-[4-hydroxy- 3-(3-diisopropylamino-1-phénylpropyl)phényl]-méthanol de formule (IV) :

e. condensation du composé de formule (VI) avec du chlorure d’isobutyryle dans un solvant convenable, éven- 50 tuellement en présence d’une base convenable, pour produire de la fésotérodine pratiquement pure, et éven- tuellement la conversion de la fésotérodine formée en un sel d’addition d’acide physiologiquement acceptable de fésotérodine.

10. Procédé selon la revendication 9, dans lequel l’agent réducteur utilisé dans l’étape (a) est un hydrure métallique, à 55 la condition que l’hydrure métallique n’englobe pas l’hydrure de lithium et d’aluminium, choisi dans l’ensemble constitué par le borohydrure de sodium, le borohydrure de potassium et le cyanoborohydrure de sodium ; dans lequel l’acide de Lewis est choisi dans l’ensemble comprenant le chlorure d’aluminium, le chlorure de calcium, le trifluorure de bore et le chlorure de zinc, mieux encore l’agent réducteur est le borohydrure de sodium et l’acide de

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Lewis est le trifluorure de bore.

11. Procédé selon la revendication 9, dans lequel l’agent de dédoublement utilisé dans l’étape (b) est choisi parmi l’acide (+)-tartrique, l’acide (-)-tartrique, l’acide (+)-2,3-dibenzoyl-D-tartrique, l’acide (-)-2,3-dibenzoyl-L-tartrique, 5 l’acide mandélique, l’acide 3-chloromandélique, l’acide abiétique, l’acide S-(+)-camphosulfonique, l’acide di-p-tolyl- D-tartrique et l’acide di-p-tolyl-L-tartrique, et dans lequel mieux encore l’agent de dédoublement utilisé dans l’étape (b) est l’acide di-p-tolyl-D-tartrique.

12. Procédé selon la revendication 9, dans lequel l’agent d’oxydation utilisé dans l’étape (c) est choisi dans l’ensemble 10 constitué par le chlorure de ruthénium/ periodate de sodium, l’acide nitrique fumant, les peracides, le réactif de Dess-Martin, le 4-oxyde de chrome, le peroxyde de nickel, le dichromate de sodium, le dioxyde de manganèse, le permanganate de potassium, l’oxyde d’argent activé, le chlorochromate de pyridinium, le nitrate d’ammonium cérique et le citrate d’ammonium cérique, et dans lequel mieux encore l’agent oxydant utilisé dans l’étape (c) est le nitrate d’ammonium cérique. 15 13. Procédé selon la revendication 9, dans lequel l’agent d’oxydation utilisé dans l’étape (c) est choisi dans l’ensemble constitué par le borohydrure de sodium, le borohydrure de potassium, le Vitride, un borohydrure de tétraalkylam- monium, le borohydrure de calcium, le borohydrure de zinc, le cyanoborohydrure de sodium, l’hydrure de lithium et d’aluminium, et leurs mélanges, et dans lequel mieux encore l’agent réducteur utilisé dans l’étape (c) est le boro- 20 hydrure de sodium.

14. Procédé selon la revendication 9, dans lequel la débenzylation est mise en oeuvre par hydrogénation du composé de formule (V) par utilisation d’hydrogène gazeux et d’un catalyseur d’hydrogénation choisi parmi le Ni Raney, le charbon palladié, l’acétate de palladium, l’oxyde de platine, le noir de platine, l’oxyde de platine adsorbé sur du 25 charbon, le charbon rhodié, le ruthénium et ses sels adsorbés sur un support solide, et dans lequel mieux encore le catalyseur d’hydrogénation utilisé dans l’étape (d) est le nickel Raney.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• EP 2281801 A [0004] • US 6713464 B [0007] • US 5382600 A [0005] • WO 2005012227 A [0009]