5-[2-(benzenesulfonyl)ethyl]-3-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-1H-indole

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

Procedure: A stirred solution of (R)-5-(2-benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8. 5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

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

Procedure: A solution of succinic acid (95 mg) in ethanol (5 mL) was added to a solution of (R)-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole free base (620 mg) in ethanol (5 mL). The solution was evaporated to give the title compound as a foam (680 mg): [α]25D =+29° (methanol, c=0.10). Anal. Calcd for CC22H26N2O2S. 0.5 C4H6O4. 0.33 C2H5OH. 0.5 H2O; C,63.59; H,6.92; N,6.01. Found: C,63.52; H,6.91; N,6.12. The solution was evaporated

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

Procedure: A stirred solution of (R)-5-(2benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8. 5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

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

Procedure: A stirred solution of (R)-5-(2benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8. 5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

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

Procedure: A solution of succinic acid (95 mg) in ethanol (5 mL) was added to a solution of (R)-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole free base (620 mg) in ethanol (5 mL). The solution was evaporated to give the title compound as a foam (680 mg): [α]25D =+29° (methanol, c=0.10). Anal. Calcd for C22H26N2O2S. 0.5 C4H6O4. 0.33 C2H5OH. 0.5 H2O; C, 63.59; H, 6.92; N, 6.01. Found: C, 63.52; H, 6.91; N, 6.12. The solution was evaporated

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

Procedure: A solution of succinic acid (95 mg) in ethanol (5 mL) was added to a solution of (R)-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole free base (620 mg) in ethanol (5 mL). The solution was evaporated to give the title compound as a foam (680 mg): [α]25D =+29° (methanol, c=0.10). Anal. Calcd for C22H26N2O2S. 0.5 C4H6O4. 0.33 C2H5OH. 0.5 H2O; C, 63.59; H, 6.92; N, 6.01. Found: C, 63.52; H, 6.91; N, 6.12. The solution was evaporated

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

Procedure: 49% w/w Hydrobromic acid (432 mg, 0.3 ml, 2.6 mmol) was added to a stirred solution of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole (1.0 g, 2.6 mmol) in acetone (10 ml) at room temperature. After a further 15 minutes, the reaction mixture was evaporated under reduced pressure to give a yellow liquid; the residual water therein was then azeotropically removed using 2-propanol. The resulting cloudy, yellowish oil (1.55 g) was triturated with ether and then dissolved in hot 2-propanol (25 ml); this solution, on cooling, provided the title compound (1.13 g) as a pale yellow crystalline solid after filtration, washing with 2-propanol and drying in vacuo, m.p. 165-170° C. Found: C,56.67; H,5.78; N,5.82. C22H26N2O2S; HBr requires C,57.02; H,5.87; N,6.04%. the reaction mixture was evaporated under reduced pressure to give a yellow liquid the residual water therein was then azeotropically removed The resulting cloudy, yellowish oil (1.55 g) was triturated with ether dissolved in hot 2-propanol (25 ml) this solution, on cooling

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

Procedure: A stirred solution of (R)-5-(2-benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

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

Procedure: A solution of succinic acid (95 mg) in ethanol (5 mL) was added to a solution of (R)-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole free base (620 mg) in ethanol (5 mL). The solution was evaporated to give the title compound as a foam (680 mg): [α]25D =+29° (methanol, c=0.10). Anal. Calcd for C22H26N2O2S. 0.5 C4H6O4. 0.33 C2H5OH. 0.5 H2O; C,63.59; H,6.9.2; N,6.01. Found: C,63.52; H,6.91; N,6.12. The solution was evaporated

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

Procedure: A stirred solution of (R)-5-(2benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

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

Procedure: A stirred solution of (R)-5-(2benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8.5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32). was filtered (washing with acetone--85 mL--and mixed acetone/water--81 mL/4 mL) The combined filtrate and washings were diluted with water (800 mL) by addition of 40% aqueous sodium hydroxide After granulation of the precipitate the solids were collected by filtration

Conditions: temp:32.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-{[1-Methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole (274 kg) and acetone (3419 kg) were charged to a dry, glass-lined vessel. A solution of 48% aqueous hydrobromic acid (114.7 kg) in acetone (1383 kg) was added at a temperature of from 50 to 55° C. over 1 hour and the resulting slurry was stirred for 4 hours. The reaction mixture was cooled to from 30 to 35° C. and the product was isolated by filtration. The product was washed with acetone (861 kg) to yield the α-polymorphic form of 3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide (242.4 kg dry, 73.0%). the product was isolated by filtration The product was washed with acetone (861 kg)