(2S)-4-(苯基甲基)-2-吗啉甲胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (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

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (S)-(4-benzylmorpholin-2-yl)methanamine. The residue was dissolved in DCM and treated with 1-chloroethyl chloroformate (37.2 μL, 0.192 mmol) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo, methanol (4 mL) was added, and the resulting solution stirred for 2 hours at 65° C. The reaction was concentrated in vacuo, and the residue purified by elution through an SCX cartridge followed by silica gel column chromatography eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane. The reaction was concentrated in vacuo, methanol (4 mL) was added the resulting solution stirred for 2 hours at 65° C The reaction was concentrated in vacuo the residue purified by elution through an SCX cartridge eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g), 1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g). The mixture was stirred for 5 min, treated with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance with EP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18 h. The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) and eluted with methanol, followed by 0.880 ammonia:methanol 10:90 to give the title compound as a colourless gum (0.394 g). the solution was stirred at 22° C. for 18 h The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) The phases were separated in a hydrophobic frit the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) eluted with methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g), 1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g). The mixture was stirred for 5 min, treated with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance with EP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18 h. The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) and eluted with methanol, followed by 0.880 ammonia:methanol 10:90 to give the title compound as a colourless gum (0.394 g). the solution was stirred at 22° C. for 18 h The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) The phases were separated in a hydrophobic frit the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) eluted with methanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (S)-(4-benzylmorpholin-2-yl)methanamine. The residue was dissolved in DCM and treated with 1-chloroethyl chloroformate (37.2 μL, 0.192 mmol) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo, methanol (4 mL) was added, and the resulting solution stirred for 2 hours at 65° C. The reaction was concentrated in vacuo, and the residue purified by elution through an SCX cartridge followed by silica gel column chromatography eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane. The reaction was concentrated in vacuo, methanol (4 mL) was added the resulting solution stirred for 2 hours at 65° C The reaction was concentrated in vacuo the residue purified by elution through an SCX cartridge eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (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

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g), 1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211 ml) in N,N-dimethylformamide (3 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g). The mixture was stirred for 5 min, treated with 1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance with EP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18 h. The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) and eluted with methanol, followed by 0.880 ammonia:methanol 10:90 to give the title compound as a colourless gum (0.394 g). the solution was stirred at 22° C. for 18 h The mixture was partitioned between dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate (10 ml) The phases were separated in a hydrophobic frit the organic phase was loaded onto a solid phase extraction cartridge (10 g SCX) eluted with methanol