6-HYDROXY-2-METHYLINDOLE

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

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

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

Procedure: 1.07 g of sodium hydride in suspension in 50% of oil were added progressively to a solution of 3.28 g of 6-hydroxy-2-methyl indole in 50 ml of dimethylformamide and the suspension was stirred for one hour. A solution of 6.5 g of N'-(tertbutoxycarbonyl)-N-(chloroacetyl)-1,4-diamino-butane and 60 ml of dimethylformamide was slowly introduced. The reaction medium was stirred at 90° C. for 5 hours, then for 16 hours at ambient temperature. The suspension obtained was evaporated to dryness to obtain 13.08 g of a product which was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (30-70) to obtain 4.98 g of the sought product melting at 132° C. The reaction medium was stirred at 90° C. for 5 hours for 16 hours at ambient temperature The suspension obtained was evaporated to dryness

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

Procedure: Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (170 mg, 85%). (prepared

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

Procedure: Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.47 mol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline (157 mg, 73%). (prepared

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

Procedure: Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.47 mol), (prepared as described for the starting material in Example 1), was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline (157 mg, 73%). (prepared

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (360 mg, 1.1 mmol), 2-methyl-1H-indole-6-ol (320 mg, 2.2 mmol), potassium carbonate (450 mg, 3.3 mmol) and N,N-dimethylformamide (4 mL) was stirred at 120° C. for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10) to give the title compound (140 mg, 36%) as a brown solid. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4) Combined organic layer was washed with saturated brine dried over anhydrous sodium sulfate filtrated The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (360 mg, 1.1 mmol), 2-methyl-1H-indole-6-ol (320 mg, 2.2 mmol), potassium carbonate (450 mg, 3.3 mmol) and N,N-dimethylformamide (4 mL) was stirred at 120° C. for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10) to give the title compound (140 mg, 36%) as a brown solid. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4) Combined organic layer was washed with saturated brine dried over anhydrous sodium sulfate filtrated The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10)

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

Procedure: To a suspension of lithium aluminum hydride (3.7 g, 97 mmol) in 1,4-dioxane (97 mL) was slowly added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (2.0 g, 9.8 mmol) in 1,4-dioxane (30 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 24 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane to give 6-methoxy-2-methyl-1H-indole (1.0 g, 6.5 mmol) as a yellow solid. To a solution of 6-methoxy-2-methyl-1H-indole (1.0 g, 6.2 mmol) in acetic acid (15 mL) was added 48% aqueous hydrogen bromide (31 mL) at room temperature, and the reaction mixture was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (600 mg, 65%) as a white solid. the reaction mixture was heated under reflux for 3 hr The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3) Combined organic layer was washed with saturated brine dried over anhydrous sodium sulfate filtrated The filtrate was concentrated under reduced pressure the residue was washed with ethyl acetate/hexane

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

Procedure: Using an analogous procedure to that described in Example 8, 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline (204 mg, 0.5 mmol) was reacted with 6-hydroxy-2-methylindole (100 mg, 0.55 mmol) to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-6-yloxy)cinnoline. The crude product was then treated with TFA to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(piperidin-4-ylmethoxy)cinnoline (10 mg, 4%).

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

Procedure: Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (170 mg, 85%). (prepared