2-(2-morpholin-4-ylethoxy)benzaldehyde

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

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 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.51 g) and xylenes (15 ml) was heated to 120° C. for 1 hour, then to 160° C. until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate (100%), followed by ethanol/ethyl acetate (1/1) to afford 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 11 (b)), as an oil. The free base was then converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110° C. under high vacuum to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one monohydrochloride, as an off-white powder, m.p. 235-237° C., labelled as Example 11 (c). to 160° C. The reaction mixture was then cooled to room temperature the solvent was removed in vacuo the residue was purified by silica gel chromatography eluting with ethyl acetate (100%)

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

Procedure: A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.51 g) and xylenes (15 ml) was heated to 120° C. for 1 hour, then to 160° C. until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate (100%), followed by ethanol/ethyl acetate (1/1) to afford 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 11 (b)), as an oil. The free base was then converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110° C. under high vacuum to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one monohydrochloride, as an off-white powder, m.p. 235-237° C., labelled as Example 11 (c). to 160° C. The reaction mixture was then cooled to room temperature the solvent was removed in vacuo the residue was purified by silica gel chromatography eluting with ethyl acetate (100%)

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

Procedure: To a solution of salicylaldehyde (2 ml) in acetonitrile (20 ml) was added K2CO3 (5.71 g), followed by N-(2-chloroethyl)morpholine hydrochloride (3.5 g) and then the mixture was stirred at room temperature for 2 hours, then at reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to afford 2-[2-(4-morpholinyl)ethoxy]benzaldehyde, as a yellow oil. at reflux overnight The reaction mixture was cooled to room temperature filtered the filtrate was concentrated in vacuo

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

Procedure: To dried dimethylformamide (20 ml) solution in which 4-(2-hydroxyethyl)morpholine (1 g, 7.62 mmol) was dissolved, sodium hydride (201.2 mg, 8.38 mmol) was slowly added under nitrogen at room temperature. The mixture was stirred for 30 minutes at room temperature, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, 20 ml of ice water was added to the resulting mixture, and the mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried over anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the intermediate compound 4-(2-(morpholinoethoxy)benzaldehyde (1.42 g, 79%). The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product the mixture was extracted with ethyl acetate and water The organic layer was washed with water several times dried over anhydrous magnesium sulfate filtered solvent-evaporated The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1)

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

Procedure: To dried dimethylformamide (20 ml) solution in which 4-(2-hydroxyethyl)morpholine (1 g, 7.62 mmol) was dissolved, sodium hydride (201.2 mg, 8.38 mmol) was slowly added under nitrogen at room temperature. The mixture was stirred for 30 minutes at room temperature, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, 20 ml of ice water was added to the resulting mixture, and the mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried over anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the intermediate compound 4-(2-(morpholinoethoxy)benzaldehyde (1.42 g, 79%). The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product the mixture was extracted with ethyl acetate and water The organic layer was washed with water several times dried over anhydrous magnesium sulfate filtered solvent-evaporated The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1)

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

Procedure: 2-[2-(4-Morpholinyl)ethoxy]benzaldehyde (55.9 g) is reacted with 29 g of phenethylamine in 240 ml of toluene following the procedure described in Example 1A to yield 68.8 g of product as an oil, boiling point 204°-210° C. at 0.1-0.2 mm of Hg.

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

Procedure: Salicylaldehyde (34 g) is treated first with 13.4 g of 50% sodium hydride in 220 ml of dimethylformamide and then with 185 ml of a 2 N toluene solution of N-(2-chloroethyl)morpholine. The mixture is heated at 105°-110° C. for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 56.6 g of product as an oil, boiling point 145°-150° C. at 0.05-0.1 mm of Hg. The mixture is heated at 105°-110° C. for 4 hours cooled The product is extracted three times with ether dried concentrated on a rotary evaporator the residue distilled

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

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

Procedure: 2-[2-(4-Morpholinyl)ethoxy]benzaldehyde (55.9 g) is reacted with 29 g of phenethylamine in 240 ml of toluene following the procedure described in Example 1A to yield 68.8 g of product as an oil, boiling point 204°-210° C. at 0.1-0.2 mm of Hg.

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

Procedure: Salicylaldehyde (34 g) is treated first with 13.4 g of 50% sodium hydride in 220 ml of dimethylformamide and then with 185 ml of a 2 N toluene solution of N-(2-chloroethyl)morpholine. The mixture is heated at 105°-110° C. for 4 hours, cooled and poured into 300 ml of water. The product is extracted three times with ether. The extracts are combined, dried, concentrated on a rotary evaporator and the residue distilled to give 56.6 g of product as an oil, boiling point 145°-150° C. at 0.05-0.1 mm of Hg. The mixture is heated at 105°-110° C. for 4 hours cooled The product is extracted three times with ether dried concentrated on a rotary evaporator the residue distilled