[(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-quinuclidin-3-ol (0.66 g, 5.2 mmol) and sodium hydride (0.21 g, 0.52 mmol, 60%) are dissolved in anhydrous toluene and stirred for 1 hour at 80° C. A solution of propyl (1s)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate (1.4 g, 4.75 mmol) in toluene (10 ml) is added and refluxed for 18 hours. Isopropyl alcohol is removed from the solution by azeotropic distillation during which toluene is necessarily added. The reaction is cooled to ambient temperature when propyl carboxylate is consumed completely according to TLC analysis. The toluene is washed with water and aq. HCl (1N)(10 ml), the organic phase is separated. Saturated sodium bicarbonate (20 ml) is added to the aqueous phase, then extracted with ethyl acetate (20 ml). The combined organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to afford yellow oil as crude Solifenacin base, 1.1 g, 63.9% with the following characteristics: HPLC: 95.8%; Chiral Purity: 99%; MS (ESI): m/z 363.2 (M+H+); 1-H-NMR (400 M, CDCl3): δ 7.32-7.17 (m, 9H), 6.55-6.17 (m, 1H), 4.20-2.90 (m, 1H), 3.36-2.86 (br, 10H), 2.18-1.47 (m, 5H). refluxed for 18 hours Isopropyl alcohol is removed from the solution by azeotropic distillation during which toluene is necessarily added The reaction is cooled to ambient temperature when propyl carboxylate is consumed completely The toluene is washed with water and aq. HCl (1N)(10 ml) the organic phase is separated Saturated sodium bicarbonate (20 ml) is added to the aqueous phase extracted with ethyl acetate (20 ml) The combined organic phase is dried over anhydrous sodium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude oily solifenacin (35 g) obtained in Example 1 is dissolved in isopropanol (100 mL) at room temperature (20-24° C.). In a separate flask the solution of succinic acid (11.30 g, 95.55 mmol) in isopropanol (130 mL) is prepared at reflux for 5 min. The hot succinic acid solution is slowly added to the solifenacin solution in isopropanol. The resulting mixture is left to reach room temperature. At ca. 45° C. the mixture turned to be cloudy and white crystalline solid begins to precipitate. The solution is left at room temperature for 2 h 30 min. The crystalline solid is filtered off and washed with cold isopropanol (10° C.) (3×40 mL), then it is dried under reduced pressure (0.1-0.15 mmHg, room temperature, 2 h) to dry mass. After two steps solifenacin succinate is obtained in 38.9 g, (84.8%) yield, of purity (HPLC) 99.39%. The final product (38 g) is recrystallized in isopropanol (150 mL), yielding 34.4 g (90.7%) of solifenacin succinate of purity (HPLC) 99.71%; T(onset)≈150° C. at reflux for 5 min The resulting mixture is left to reach room temperature At ca. 45° C. to precipitate The crystalline solid is filtered off washed with cold isopropanol (10° C.) (3×40 mL) it is dried under reduced pressure (0.1-0.15 mmHg, room temperature, 2 h) to dry mass

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above mentioned step (b) comprises treating the reaction mixture comprising (3R)-1-azabicyclo[2.2.2]oct-3-yl 4-nitrophenyl carbonate of formula (IV) of step (a) with (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (V) in an organic solvent and in an inert atmosphere at temperature of −20 to 50° C. to obtain (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (Solifenacin) of formula (I).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This solution was taken for condensation reaction with (RS)-3-quinuclidinol in the next stage to prepare Solifenacin and its diastereomer.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: According to the process disclosed in U.S. Pat. No. 6,017,927, Solifenacin may be prepared by condensation of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of formula (III) with ethyl chloroformate to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate of formula (IV), which is further reacted with (R)-(−)-3-quinuclidinol of formula (V) to produce Solifenacin (II). Solifenacin is converted to Solifenacin hydrochloride by treating with HCl.

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6 g of solifenacin base from example 1 was dissolved in 60 ml of isopropyl acetate; 1.92 g of maleic acid was added and the mixture was heated to 45° C. for 15 minutes. The mixture is kept at room temperature overnight. In these conditions a colorless oil is obtained. In these conditions a colorless oil is obtained

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetone (260 ml), Succinic acid (12.7 g, 0.107 mol) and water (5 ml) are combined in a flask. The mixture is heated under reflux until total dissolution and then kept at 42° C. Then, the “Solution of solifenacin base” is charged and the mixture is heated to reflux and kept under reflux for 15 minutes. The content is distilled until a final volume of 260 ml. The mixture is cooled slowly until a final temperature of 3° C. and then filtered. The residue is washed with Ethyl acetate (50 ml) at 0/5° C. and is drained for 1 hour. The wet cake is dried in the vacuum oven at 60° C. to give a white solid. The mixture is heated under reflux until total dissolution kept at 42° C the mixture is heated to reflux under reflux for 15 minutes The content is distilled until a final volume of 260 ml filtered The residue is washed with Ethyl acetate (50 ml) at 0/5° C. The wet cake is dried in the vacuum oven at 60° C. to give a white solid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a mixture of 0.38 g of sodium tert-butoxide, 60 ml of toluene and 3 ml of DMF, 2.96 g of (R)-quinuclidin-3-ol was allowed to react with 6.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester for 8 hours while evaporating the solvent, thereby obtaining 0.274 g of a solifenacin-containing composition. while evaporating the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a mixture of sodium isopropoxide prepared from 0.20 g of 2-propanol and 0.08 g of metallic sodium with 20 ml of toluene and 2.5 ml of DMF, 2.58 g of (R)-quinuclidin-3-ol was allowed to react with 5.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid propan-2-yl ester for 8 hours while evaporating the solvent, thereby obtaining 3.97 g of a solifenacin-containing composition. while evaporating the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a mixture of 10 ml of toluene and 0.5 ml of DMF and in the presence of 0.21 g of sodium ethoxide, 1.00 g of ethyl (R)-quinuclidin-3-yl carbonate and 1.05 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline were stirred for 7 hours while evaporating the solvent, 20 ml of toluene and 20 ml of water were added thereto, and the thus obtained organic layer was washed with 20 ml of water and then mixed with 15 ml of 1 M hydrochloric acid aqueous solution. A 30 ml portion of EtOAc and 1 M sodium hydroxide aqueous solution were added to the obtained water layer. The thus obtained organic layer was dried with sodium sulfate, concentrated under a reduced pressure and then dried, and the thus obtained solid was purified by a silica gel column chromatography to obtain 0.22 g of solifenacin. while evaporating the solvent, 20 ml of toluene and 20 ml of water were added the thus obtained organic layer was washed with 20 ml of water mixed with 15 ml of 1 M hydrochloric acid aqueous solution A 30 ml portion of EtOAc and 1 M sodium hydroxide aqueous solution were added to the obtained water layer The thus obtained organic layer was dried with sodium sulfate concentrated under a reduced pressure dried the thus obtained solid was purified by a silica gel column chromatography

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The thus obtained solifenacin was mixed with 12 ml of EtOH, 28 ml of EtOAc and 2.74 g of succinic acid, heated, cooled to 30° C. and then again heated to 50° C. This was kept at 50° C. for 2 hours and then cooled to 0° C. spending 5 hours, and the precipitated crystals were collected by filtration, washed twice with 8 ml of EtOAc and then dried under a reduced pressure to obtain 9.013 g of solifenacin succinate. heated again heated to 50° C cooled to 0° C. spending 5 hours the precipitated crystals were collected by filtration washed twice with 8 ml of EtOAc dried under a reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 4.26 g portion of 1,1′-carbonyldiimidazole was added to 5.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 25 ml of toluene and stirred at room temperature for 30 minutes. By adding 25 ml of water thereto, the water layer was separated, the organic layer was washed with 25 ml of water, and the solvent was evaporated under a reduced pressure. A 10 ml portion of toluene was added to the residue. This solution was added dropwise at room temperature to a solution prepared by adding 1.00 g of sodium hydride to a mixture of 3.65 g of (R)-quinuclidin-3-ol, 25 ml of toluene and 5 ml of DMF and heating to 100° C., and 5 ml of toluene was further added thereto. This was heated at 110° C. for 3 hours, cooled and mixed with 25 ml of water, and the water layer was separated. This was again washed with 25 ml of water, and the organic layer was extracted with a mixture of 3.25 g of concentrated hydrochloric acid and 18 ml of water. 34 ml of EtOAc, and a mixture of 5.28 g of potassium carbonate and 14 ml of water were added to the thus obtained water layer, the thus obtained organic layer was washed with 7 ml of water, and then the solvent was evaporated under a reduced pressure to obtain solifenacin. the water layer was separated the organic layer was washed with 25 ml of water the solvent was evaporated under a reduced pressure A 10 ml portion of toluene was added to the residue This solution was added dropwise at room temperature to a solution prepared heating to 100° C. This was heated at 110° C. for 3 hours cooled the water layer was separated This was again washed with 25 ml of water the organic layer was extracted with a mixture of 3.25 g of concentrated hydrochloric acid and 18 ml of water 34 ml of EtOAc, and a mixture of 5.28 g of potassium carbonate and 14 ml of water were added to the thus obtained water layer the thus obtained organic layer was washed with 7 ml of water the solvent was evaporated under a reduced pressure