(4-benzylmorpholin-2-yl)methanamine

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: (RS)-2-Aminomethyl-4-benzylmorpholine (326.1 g) was dissolved in ethanol (3 L) and dibenzoyl-D-tartaric monohydrate (535 g) was added. The mixture was refluxed for dissolution and then left standing at room temperature for 16 hours. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of ethanol:water=25:1. The obtained crystals were suspended in water (1.2 L) and aqueous sodium hydroxide solution was added with stirring to make the suspension basic, which was followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to give 138.4 g of (S)-2-aminomethyl-4-benzylmorpholine as a colorless oil. The mixture was refluxed for dissolution left The precipitated crystals were collected by filtration recrystallized from a mixed solvent of ethanol aqueous sodium hydroxide solution was added was followed by extraction with chloroform The chloroform layer was dried over anhydrous magnesium sulfate the solvent was distilled off

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

Procedure: A mixture of 31.8 g of 2-chloromethyl-4-benzylmorpholine and 30.5 g of potassium phthalimide in 200 ml of dimethylformamide is refluxed for 4 hours and then poured into water. The precipitated crystals are collected by filtration and dried to give 40.2 g of 2-phthalimidomethyl-4-benzylmorpholine. To 400 ml of the ethanol solution of this product is added dropwise a solution of 12.3 g of hydrazine hydrate in 100 ml of ethanol. Further, the resultant mixture is refluxed for 30 minutes. After cooling, insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to give 2-aminomethyl-4-benzylmorpholine as an oily substance. To the solution of 10.3 g of the obtained product in 400 ml of ethanol and 40 ml of water are added 11 g of concentrated hydrochloric acid and 1.1 g of 10% palladium-carbon and the mixture subjected to catalytic reduction at ordinary temperature and atmospheric pressure. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol-acetone to give 2-(aminomethyl)morpholine dihydrochloride as white crystals, melting at 215°-218° C. After cooling insoluble materials are filtered off the filtrate is concentrated under reduced pressure

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

Procedure: A mixture of 31.8 g of 2-chloromethyl-4-benzylmorpholine and 30.5 g of potassium phthalimide in 200 ml of dimethylformamide is refluxed for 4 hours and then poured into water. The precipitated crystals are collected by filtration and dried to give 40.2 g of 2-phthalimidomethyl-4-benzylmorpholine. To 400 ml of the ethanol solution of this product is added dropwise a solution of 12.3 g of hydrazine hydrate in 100 ml of ethanol. Further, the resultant mixture is refluxed for 30 minutes. After cooling, insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to give 2-aminomethyl-4-benzylmorpholine as an oily substance. To the solution of 10.3 g of the obtained product in 400 ml of ethanol and 40 ml of water are added 11 g of concentrated hydrochloric acid and 1.1 g of 10% palladium-carbon and the mixture subjected to catalytic reduction at ordinary temperature and atmospheric pressure. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol-acetone to give 2-(aminomethyl)morpholine dihydrochloride as white crystals, melting at 215°-218° C. After cooling insoluble materials are filtered off the filtrate is concentrated under reduced pressure

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

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

Procedure: (4-Benzylmorpholin-2-yl)methanamine 2d (1.35 g, 6.50 mmol) was dissolved in 30 mL of ethanol followed by the addition of L-(−)-dibenzoyltartaric acid (2.34 g, 6.50 mmol). The reaction solution was heated to reflux for 10 minutes, then cooled down to room temperature, placed for 16 hours resulting in the formation of crystal and filtered. The filter cake was dissolved in 10 mL of water, added with 1 M aqueous sodium hydroxide solution to adjust pH to 9 and extracted with dichloromethane (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound [(2R)-4-benzylmorpholin-2-yl]methanamine 15a (0.28 g, yield: 28.0%) as a light yellow oil liquid. The reaction solution was heated to reflux for 10 minutes resulting in the formation of crystal filtered The filter cake was dissolved in 10 mL of water added with 1 M aqueous sodium hydroxide solution extracted with dichloromethane (30 mL×3) The combined organic phase was dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure

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

Procedure: (4-Benzylmorpholin-2-yl)methanamine 2d (1.35 g, 6.50 mmol) was dissolved in 30 mL of ethanol followed by the addition of L-(−)-dibenzoyltartaric acid (2.34 g, 6.50 mmol). The reaction solution was heated to reflux for 10 minutes, then cooled down to room temperature, placed for 16 hours resulting in the formation of crystal and filtered. The filter cake was dissolved in 10 mL of water, added with 1 M aqueous sodium hydroxide solution to adjust pH to 9 and extracted with dichloromethane (30 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound [(2R)-4-benzylmorpholin-2-yl]methanamine 15a (0.28 g, yield: 28.0%) as a light yellow oil liquid. The reaction solution was heated to reflux for 10 minutes resulting in the formation of crystal filtered The filter cake was dissolved in 10 mL of water added with 1 M aqueous sodium hydroxide solution extracted with dichloromethane (30 mL×3) The combined organic phase was dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure

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

Procedure: The crude compound (4-benzylmorpholin-2-yl)methanamine 2d (141 mg, 0.69 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (300 mg, 0.69 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (221 mg, 0.69 mmol) and diisopropylethylamine (260 mL, 1.52 mmol) were dissolved in 40 mL of dichloromethane, stirred for 12 hours. The resulting mixture was added with 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[(4-benzylmorpholin-2-yl)methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 2e (190 mg, yield: 44.0%) as a white solid. extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL×3) dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: The crude compound (4-benzylmorpholin-2-yl)methanamine 2d (141 mg, 0.69 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (300 mg, 0.69 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (221 mg, 0.69 mmol) and diisopropylethylamine (260 mL, 1.52 mmol) were dissolved in 40 mL of dichloromethane, stirred for 12 hours. The resulting mixture was added with 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[(4-benzylmorpholin-2-yl)methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 2e (190 mg, yield: 44.0%) as a white solid. extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL×3) dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: 4-benzylmorpholine-2-carbonitrile 2c (0.80 g, 4 mmol) was dissolved in 30 mL of methanol followed by the addition of Raney nickel (0.50 g), filled with hydrogen two times and the resulting solution was stirred for 12 hours, filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4-benzylmorpholin-2-yl)methanamine 2d (0.60 g) as a colorless oil liquid, which was used in the next step without further furification. filtered The filtrate was concentrated under reduced pressure

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-azidomethyl-4-benzylmorpholine (15 g) in toluene (40 ml) is added dropwise to a stirred solution of 70% sodium bis(2-methoxyethoxy)aluminum hydride in toluene (60 ml) cooled to -5° C. The reaction mixture is stirred at 25° C. for 1.5 hours and cooled to 10° C., and the excess of the reducing agent is decomposed by the cautious addition of 10% aqueous sodium hydroxide solution. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the title compound is obtained a an oil (11 g). cooled to 10° C. The organic layer is separated washed successively with water and saturated aqueous sodium chloride solution dried over magnesium sulfate After removal of the solvent under reduced pressure