5-Bromo-3-[[(2R)-1-methyl-2-pyrrolidinyl]methyl]-1H-indole

Light Brown Solid

Preparation of BIP from BIP OxalateBIP oxalate salt (170 g, 0.4435 mol) and DM water (1500 mL) was stirred at 15° C. The pH was adjusted to 7.8 using aqueous sodium carbonate (70.5 g, 0.6650 mol) in 200 mL DM water. Toluene (1000 mL) was added and stirred at 30-35° C. for 30 minutes. The layers were separated and the aqueous layer was washed with toluene (500 mL). The layers were again separated. The two toluene layer were combined and washed with 10percent w/v aqueous sodium carbonate. The layers were separated and the toluene layer was distilled under reduce pressure at 50-55° C. to 70percent (1050 mL). The distilled mass was gradually cooled to 5-10° C. with stirring. A solid product precipitated and was collected by filtration and washed, first with cold toluene (100 mL) and then with n-heptane (100 mL). Dry. Wt: 117.0 g; Yield: 90.5percent; Purity: 99.12percent (as a Bip).A solution of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (60.0 g, 1.0 eq.) in dry tetrahydrofuran (600 ml) was added dropwise over the period of 60 min to the stirred 70percent solution of SDMA in toluene (210 ml, 2.1 eq.) diluted by dry tetrahydrofuran (270 ml) under atmosphere of dry nitrogen while maintaining the temperature between 30 and 40° C. SDMA in toluene (70percent solution, 72 ml, 252 mmol), diluted with dry 2-methyltetrahydrofurane (12 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (24 g, 56.2 mmol) in dry 2-methyltetrahydrofurane (140 ml) at 30-40° C. during 10 min. The reaction temperature was raised to 48° C. and the resulting yellow solution was stirred for 3 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (120 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 30 min at 20° C. Organic layer was separated and extracted with 1M HCl (70-80 ml) to pH 3. The aqueous layer was extracted with toluene (2.x.50 ml). The aqueous layer was combined with toluene (120 ml) in a separatory funnel and 2M NaOH was added in portions to pH 12 (40-45 ml) and the product was extracted to the organic phase. The organic phase was separated, the aqueous phase was re-extracted with a fresh portion of toluene (50 ml) and combined toluene extracts were evaporated under reduced pressure. The residue was dissolved in toluene (30 ml) and the product was crystallized upon cooling. The product was filtered off, washed with cold toluene and cold heptane and dried (11.5 g; 70percent).Example 9Preparation of 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indoleA solution of 3-[(R)-N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)]-5-bromo-1H-indole (1.0 g) in dry tetrahydrofuran (19.2 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.26 g) in dry tetrahydrofuran (14.4 ml) at 25-30° C. under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled to 25-30° C. Additional lithium aluminium hydride (48.1 mg) was added and refluxing was continued for an additional 3 hours. The mixture was further cooled and lithium aluminium hydride (38.5 mg) was added. Refluxing was continued for further 18 hours. The mixture was cooled and then successively water (0.42 ml), 20percent aqueous sodium hydroxide (0.42 ml) and water (1.28 ml) were added to the mixture. The mixture was diluted with ethyl acetate and filtered through a celite bed. The filtrate was washed with water, followed by brine and then dried over sodium sulphate. Evaporation of the solvent under reduced pressure gave an oil which was chromatographed on silica gel. Elution with dichloromethane:ethanol:concentrated aqueous ammonia (90:10:0.5) gave the title compound as a solid.Yield: 0.4 g, 56percent.Example 33; Preparation of 5-Bromo-3-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indole (BIP) According to U.S. Pat. No. 5, 545, 644, Example 27 BIPCAM 3.64 g (8.52 mmol) LAH 1.26 g (33.2 mmol 3.9 eq) THF 122.5 A solution of (R)-2-(5-bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (BIPCAM) (3.64 g, 8.55 mmol) in dry THF (70 mL) was added drop-wise to a stirred suspension of lithium aluminum hydride (LAH)(0.945 g, 24.9 mmol) in dry THF (52.5 mL) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 h and then cooled. Additional LAH (175 mg, 4.61 mmol) was added and refluxing was continued for an additional 3 h. The mixture was again cooled, and LAH (140 mg, 3.69 mmol) was added, and refluxing was continued for a further 18 h. The mixture was cooled and HSDMA in toluene (70percent solution, 72 ml, 252 mmol), diluted with dry MTBE (12 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (24 g, 56.2 mmol) in dry MTBE (140 ml) at 30-40° C. during 10 min. The reaction temperature was raised to 48° C. and the resulting yellow solution was stirred for 3 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (120 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 30 min at 20° C. Organic layer was separated and extracted with 1M HCl (80 ml) to pH 3. The aqueous layer was extracted with MTBE (2.x.50 ml). The aqueous layer was combined with MTBE (120 ml) in a separatory funnel and 2M NaOH was added in portions to pH 12 (40-45 ml) and the product was extracted to the organic phase. The organic phase was separated, the aqueous phase was re-extracted with a fresh portion of MTBE (50 ml) and combined MTBE extracts were evaporated under reduced pressure. The residue was dissolved in toluene (30 ml) and the product was crystallized upon cooling. The product was filtered off, washed with cold toluene and cold heptane and dried (12.6 g; 77percent). BIP purity: 93.7 Norm percent. Level of impurities found (Norm percent): Des-Bromo-BIP: 0.41percent; OH-BIP: 0.55percent; Keto-BIP: 4.75percent.SDMA in toluene (70percent solution, 143.9 ml, 504 mmol), diluted with dry THF (25 ml), was added to a stirred solution of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (48 g, 112.3 mmol) in dry THF (200 ml) at 30-40° C. during 15 min. The reaction temperature was raised to 48° C. and the resulting yellow solution was stirred for 2.5 h. The reaction was diluted with toluene (200 ml) and cooled to 15° C. 5percent Aqueous NaOH (240 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 30 min at 20° C. The organic layer was separated, the aqueous phase was extracted with toluene (1.x.100 ml), both organic phases were combined and extracted with 1M HCl (160-180 ml) to pH 3. The aqueous layer was extracted with toluene (2.x.100 ml). The aqueous layer was combined with toluene (200 ml) in a separatory funnel and 2M NaOH was added in portions to pH 12 (80-90 ml) and the product was extracted to the organic phase. Organic phase was separated, the aqueous phase was re-extracted with a fresh portion of toluene (2.x.100 ml) and combined toluene extracts were evaporated under reduced pressure. The residue was dissolved in toluene (60 ml) and the product was crystallized upon cooling. The product was filtered off, washed with cold toluene (40 ml) and cold heptane (40 ml) and dried (23 g, 70percent). BIP purity (Norm percent): 93.0percent. Level of impurities found (Norm percent): Des-Bromo-BIP: 0.70percent; OH-BIP: 0.07percent; Keto-BIP: 5.46percent.Example 3 SDMA in toluene (70percent solution, 172 ml, 0.6 mol), diluted with dry toluene (30 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester (60 g, 0.14 mol) in dry toluene (350 ml) at 30-40° C. during 10 min. The reaction temperature was raised to 48° C. and the resulting yellow solution was stirred for 2.5 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (300 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 60 min at 20° C. The organic layer was separated and analyzed by HPLC. Crude BIP purity: 66.49 Norm percent. Levels of impurities found (Norm percent): Benzyl-alcohol: 24.11percent; Des-Bromo-BIP: 1.91percent; OH-BIP: 1.38percent; Keto-BIP: 1.90percent.The organic layer was extracted with 2M acetic acid (1.x.250 ml) and (1.x.50 ml). The aqueous layer was combined with toluene (250 ml) in a separatory funnel and 10percent NaOH was added in portions to pH 12 (250 ml) and the product was extracted to the organic phase. The organic phase was separated, the aqueous phase was re-extracted with a fresh portion of toluene (50 ml) and combined toluene extracts were evaporated under reduced pressure. The residue was dissolved in toluene (75 ml) and the product was crystallized upon cooling. The product was filtered off, washed with cold toluene and cold heptane and dried (23.5 g; 57percent). BIP purity: 96.5 Norm percent. Levels of impurities found (Norm percent): Des-Bromo-BIP: 0.85percent; OH-BIP: 0.56percent; Keto-BIP: 1.90percent.; Example 5Preparation of 5-Bromo-3-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indole (BIP)SDMA in toluene (70percent solution, 40 ml, 131.2 mmol), diluted with dry toluene (5 ml), was added to a stirred suspension of (R)-2-(5-Bromo-1H-indole-3-carbonyl)pyrrolidine-1-carboxylic acid benzyl ester (12 g, 28.1 mmol) in dry toluene (70 ml) at 30-40° C. during 10 min. The temperature was raised to 48° C. and the resulting yellow solution was stirred for 2.5 h. The reaction was cooled to 15° C. and 5percent aqueous NaOH (60 ml) was added dropwise while the temperature was maintained between 15-20° C. The reaction mixture was stirred vigorously for additional 60 min at 20° C. Crude BIP purity: 72.36 Norm percent. Levels of impurities found (Norm percent): Benzyl alcohol: 21.50percent; Des-Bromo-BIP: 2.16percent; OH-BIP: 0.47percent; Keto-BIP: 2.14percent.

Molecular Weight:293.20
XLogP3:3.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:2
Exact Mass:292.05751
Monoisotopic Mass:292.05751
Topological Polar Surface Area:19
Heavy Atom Count:17
Complexity:271
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes