3-propoxypropan-1-amine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%). were reacted

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

Procedure: A mixture (3-formyl-phenyl)-acetic acid ethyl ester (530 mg), (3-propoxypropyl)amine (1.5 g) and acetic acid (0.17 mL) in methanol (15 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (950 mg) was added. After 5 hours, the reaction mixture was neutralised with aqueous ammonia (0.880) and the solution evaporated to dryness. The residue was diluted with toluene and the mixture evaporated. The resulting gum was dissolved in methanol and applied to a SCX cartridge (70 g, varian). The cartridge was eluted with methanol (250 mL) and then 20% ammonia in methanol to collect the reductive amination product. Toluene was added and the solution was evaporated. The crude product was dissolved in dichloromethane (20 mL) and di-tert-butyl dicarbonate (1.8 g) added. After 16 hours, the solution was evaporated, the residue dissolved in ethanol (30 mL), anhydrous calcium chloride (11.0 g) added, followed by portionwise addition of sodium borohydride (700 mg). After 16 hours, the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL), filtered and evaporated. The residue was partitioned between ethyl acetate and brine. The organic solution was dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate:dichloromethane 1:4 to give the subtitle compound (300 mg). the solution evaporated to dryness The residue was diluted with toluene the mixture evaporated The resulting gum was dissolved in methanol The cartridge was eluted with methanol (250 mL) 20% ammonia in methanol to collect the reductive amination product Toluene was added the solution was evaporated The crude product was dissolved in dichloromethane (20 mL) di-tert-butyl dicarbonate (1.8 g) added After 16 hours the solution was evaporated the residue dissolved in ethanol (30 mL) anhydrous calcium chloride (11.0 g) added followed by portionwise addition of sodium borohydride (700 mg) After 16 hours the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL) filtered evaporated The residue was partitioned between ethyl acetate and brine The organic solution was dried over sodium sulphate filtered evaporated Purification eluting with ethyl acetate:dichloromethane 1:4

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

Procedure: A mixture (3-formyl-phenyl)-acetic acid ethyl ester (530 mg), (3-propoxypropyl)amine (1.5 g) and acetic acid (0.17 mL) in methanol (15 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (950 mg) was added. After 5 hours, the reaction mixture was neutralised with aqueous ammonia (0.880) and the solution evaporated to dryness. The residue was diluted with toluene and the mixture evaporated. The resulting gum was dissolved in methanol and applied to a SCX cartridge (70 g, varian). The cartridge was eluted with methanol (250 mL) and then 20% ammonia in methanol to collect the reductive amination product. Toluene was added and the solution was evaporated. The crude product was dissolved in dichloromethane (20 mL) and di-tert-butyl dicarbonate (1.8 g) added. After 16 hours, the solution was evaporated, the residue dissolved in ethanol (30 mL), anhydrous calcium chloride (11.0 g) added, followed by portionwise addition of sodium borohydride (700 mg). After 16 hours, the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL), filtered and evaporated. The residue was partitioned between ethyl acetate and brine. The organic solution was dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate:dichloromethane 1:4 to give the subtitle compound (300 mg). the solution evaporated to dryness The residue was diluted with toluene the mixture evaporated The resulting gum was dissolved in methanol The cartridge was eluted with methanol (250 mL) 20% ammonia in methanol to collect the reductive amination product Toluene was added the solution was evaporated The crude product was dissolved in dichloromethane (20 mL) di-tert-butyl dicarbonate (1.8 g) added After 16 hours the solution was evaporated the residue dissolved in ethanol (30 mL) anhydrous calcium chloride (11.0 g) added followed by portionwise addition of sodium borohydride (700 mg) After 16 hours the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL) filtered evaporated The residue was partitioned between ethyl acetate and brine The organic solution was dried over sodium sulphate filtered evaporated Purification eluting with ethyl acetate:dichloromethane 1:4

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexaness/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%). were reacted

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

Procedure: Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2CO3 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%). were reacted

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

Procedure: This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-propoxypropylamine employing methods similar to those described in Example 2 and was obtained a white solid: 1H NMR (d6-DMSO) δ 11.83 (1H, br s), 10.26 (1H, br s), 8.48 (1H, br s), 7.43 (1H, s), 7.30-7.26 (2H, m), 7.16-7.11 (2H, m), 4.09 (2H, s), 3.42-3.38 (4H, m), 3.30-3.28 (2H, m), 1.76-1.71 (2H, m), 1.49 (2H, q, J=7 Hz), 0.83 (3H, t, J=7.3 Hz); HRMS calcd for C22H24FN3O4+H+: 414.1829. Found 414.1844. was obtained a white solid

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

Procedure: A mixture (3-formyl-phenyl)-acetic acid ethyl ester (530 mg), (3-propoxypropyl)amine (1.5 g) and acetic acid (0.17 mL) in methanol (15 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (950 mg) was added. After 5 hours, the reaction mixture was neutralised with aqueous ammonia (0.880) and the solution evaporated to dryness. The residue was diluted with toluene and the mixture evaporated. The resulting gum was dissolved in methanol and applied to a SCX cartridge (70 g, varian). The cartridge was eluted with methanol (250 mL) and then 20% ammonia in methanol to collect the reductive amination product. Toluene was added and the solution was evaporated. The crude product was dissolved in dichloromethane (20 mL) and di-tert-butyl dicarbonate (1.8 g) added. After 16 hours, the solution was evaporated, the residue dissolved in ethanol (30 mL), anhydrous calcium chloride (11.0 g) added, followed by portionwise addition of sodium borohydride (700 mg). After 16 hours, the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL), filtered and evaporated. The residue was partitioned between ethyl acetate and brine. The organic solution was dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate:dichloromethane 1:4 to give the subtitle compound (300 mg). the solution evaporated to dryness The residue was diluted with toluene the mixture evaporated The resulting gum was dissolved in methanol The cartridge was eluted with methanol (250 mL) 20% ammonia in methanol to collect the reductive amination product Toluene was added the solution was evaporated The crude product was dissolved in dichloromethane (20 mL) di-tert-butyl dicarbonate (1.8 g) added After 16 hours the solution was evaporated the residue dissolved in ethanol (30 mL) anhydrous calcium chloride (11.0 g) added followed by portionwise addition of sodium borohydride (700 mg) After 16 hours the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL) filtered evaporated The residue was partitioned between ethyl acetate and brine The organic solution was dried over sodium sulphate filtered evaporated Purification eluting with ethyl acetate:dichloromethane 1:4