4-(morpholin-4-ylmethyl)benzonitrile

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 4-(morpholinomethyl)benzonitrile (preparation 5) (1.00 g, 5 mmol) in toluene (19 ml), 3M methyl magnesium bromide in ethyl ether (5 ml, 15 mmol) was added at room temperature under argon. The resulting suspension was refluxed for 4 h, allowed to reach room temperature and then cooled down to 0° C., acidified with 10% HCl and then heated to reflux for 1 h. The two phases were separated and the aqueous phase rinsed with ethyl acetate, then brought to pH 10 with NH4OH and extracted with DCM. The phases were separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A followed by a 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were concentrated to dryness under vacuum to obtain the desired compound as a white solid (0.79 g, 3.6 mmol, Yield: 70%). was added at room temperature under argon The resulting suspension was refluxed for 4 h to reach room temperature heated to reflux for 1 h The two phases were separated the aqueous phase rinsed with ethyl acetate extracted with DCM The phases were separated the organic phase was dried over MgSO4 concentrated under reduced pressure The crude product was purified by flash column chromatography eluting with DCM (Solvent A) and MeOH (Solvent B) 1 min 5 min The desired fractions were concentrated to dryness under vacuum

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

Procedure: To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%). washed with NaHCO3 saturated aqueous solution (50 ml) the organic phase was separated dried over magnesium sulphate and solvents evaporated under reduced pressure The product was purified by column chromatography MeOH, 1 min followed by 12 min ramp to 2.5% B 5 min concentrated to dryness under reduced pressure

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

Procedure: To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%). washed with NaHCO3 saturated aqueous solution (50 ml) the organic phase was separated dried over magnesium sulphate and solvents evaporated under reduced pressure The product was purified by column chromatography MeOH, 1 min followed by 12 min ramp to 2.5% B 5 min concentrated to dryness under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, add lithium aluminum hydride (1.13 g, 29.7 mmol) to THF (50 mL) at 0° C. followed by a solution of 4-(morpholin-4-ylmethyl)-benzonitrile (2 g, 9.89 mmol) in THF (10 mL). Stir at 0° C. for 1 h and at room temperature overnight. Cool the mixture to 0° C., and carefully add water (1.15 mL). Add diethyl ether (125 mL), 3N aqueous NaOH (1.15 mL), water (3.45 mL), and stir for 1 h at room temperature. Filter the solid residue and concentrate the filtrate in vacuo to obtain the title compound as a colorless oil (1.87 g, 94%). MS (APCI+) m/z: 207 (M+H)+. Cool the mixture to 0° C. Filter the solid residue concentrate the filtrate in vacuo

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

Procedure: Dissolve 4-cyanobenzaldehyde (5 g, 38.1 mmol), morpholine (4.15 g, 47.7 mmol) and acetic acid (2.2 mL, 38.1 mmol) in DCE (100 mL). Add sodium cyanoborohydride (3.59 g, 57.2 mmol), and stir the mixture overnight. Add water (100 mL), separate the layers and extract the aqueous layer with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (6.1 g, 79%). MS (APCI+) m/z: 203 (M+H)+. Add water (100 mL), separate the layers extract the aqueous layer with DCM (3×50 mL) Wash the combined organic extracts with brine dry over Na2SO4 filter concentrate in vacuo Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over 1.25 h, 80 mL/min)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-(morpholin-4-ylmethyl)benzonitrile (Description 122, 0.5 g, 2.5 mmol) in THF (7 mL) at 0° C. was added dropwise a solution of LiAlH4 (1.0 M in THF, 2.5 ml, 2.5 mmol). The reaction was stirred at 0° C. for 1 h. Additional LiAlH4 (1.0 M in THF, 1.0 ml, 1.0 mmol) was added and the reaction stirred for an additional 30 min. The reaction was quenched by the addition of water (0.13 mL) followed by 15% NaOH solution (0.13 ml) and stirred vigorously for 1 h. The reaction was filtered through celite, evaporated and azeotroped twice with toluene. The amine was used crude. the reaction stirred for an additional 30 min The reaction was quenched by the addition of water (0.13 mL) stirred vigorously for 1 h The reaction was filtered through celite evaporated azeotroped twice with toluene

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

Procedure: To a solution of 4-cyanobenzylbromide (1.0 g, 5.1 mmol) in MeCN (10 ml) was added morpholine (0.44 g, 0.44 ml, 5.1 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and partioned between CH2Cl2 and NaOH (2M). The organic layer was separated, dried over MgSO4 and dried to give the desired nitrile (0.70 g, 68%). The precipitate was filtered off The organic layer was separated dried over MgSO4 dried

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 4-(morpholinomethyl)benzonitrile (preparation 5) (1.00 g, 5 mmol) in toluene (19 ml), 3M methyl magnesium bromide in ethyl ether (5 ml, 15 mmol) was added at room temperature under argon. The resulting suspension was refluxed for 4 h, allowed to reach room temperature and then cooled down to 0° C., acidified with 10% HCl and then heated to reflux for 1 h. The two phases were separated and the aqueous phase rinsed with ethyl acetate, then brought to pH 10 with NH4OH and extracted with DCM. The phases were separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using an 80 g silica gel cartridge and eluting with DCM (Solvent A) and MeOH (Solvent B) and the following gradient: 1 min hold 100% A followed by a 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were concentrated to dryness under vacuum to obtain the desired compound as a white solid (0.79 g, 3.6 mmol, Yield: 70%). was added at room temperature under argon The resulting suspension was refluxed for 4 h to reach room temperature heated to reflux for 1 h The two phases were separated the aqueous phase rinsed with ethyl acetate extracted with DCM The phases were separated the organic phase was dried over MgSO4 concentrated under reduced pressure The crude product was purified by flash column chromatography eluting with DCM (Solvent A) and MeOH (Solvent B) 1 min 5 min The desired fractions were concentrated to dryness under vacuum

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

Procedure: To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%). washed with NaHCO3 saturated aqueous solution (50 ml) the organic phase was separated dried over magnesium sulphate and solvents evaporated under reduced pressure The product was purified by column chromatography MeOH, 1 min followed by 12 min ramp to 2.5% B 5 min concentrated to dryness under reduced pressure