3-氨基-1-吗啉基-4-苯硫基-1-丁酮

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of EXAMPLE 21E (6.00 g, 21.4 mmol) in THF (80 mL) was heated to 55° C. and treated dropwise with a solution of 1M borane in THF (85 mL, 85.0 mmol) over a 1 hour period. The resulting reaction mixture was stirred at 55° C. for 18 hours, cooled to 0° C., treated dropwise with methanol (10 mL), treated with 150 mL additional methanol, and concentrated. The crude residue was dissolved in methanol (70 mL), treated with methanolic HCl (100 mL), and heated to reflux for 24 hours. The mixture was allowed to cool to room temperature, concentrated, diluted with 2M NaOH (200 mL), and extracted with ethyl acetate (3×250 mL). The combined extracts were washed with 1M NaOH and brine, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate to provide the desired product (3.45 g, 73%). The resulting reaction mixture cooled to 0° C. concentrated The crude residue was dissolved in methanol (70 mL) treated with methanolic HCl (100 mL) heated to reflux for 24 hours to cool to room temperature concentrated diluted with 2M NaOH (200 mL) extracted with ethyl acetate (3×250 mL) The combined extracts were washed with 1M NaOH and brine dried (Na2SO4) filtered concentrated purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-3-amino-1-morpholino-4-(phenylthio)butan-1-one (INTERMEDIATE 72, 375.5 mg, 1.34 mmol) in DMF (2.5 ml) and DIPEA (1.20 Ml, 6.87 mmol) was added 4-fluoro-3-nitrobenzenesulfonamide (INTERMEDIATE 18, 325.8 mg, 1.48 mmol), and the resulting dark solution was stirred at 50° C. overnight, under a nitrogen atmosphere. The mixture was diluted with EtOAc (50 ml) and washed with water and brine (30 ml each), dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM) to give the title product (532.5 mg, yield: 83%). washed with water and brine (30 ml each) dried (Na2SO4) filtered evaporated under reduced pressure The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM)

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

实验步骤: A suspension of (R)-benzyl 4-morpholino-4-oxo-1-(phenylthio)butan-2-ylcarbamate (INTERMEDIATE 71, 25 g, 60 mmol) in 40% HBr in acetic acid (500 ml) was stirred at room temperature for 50 hrs. The reaction mixture became homogeneous during this time. The reaction mixture was concentrated to dryness, diluted with water (400 ml) and 5% aq. HCl (200 ml) and washed with diethyl ether (3×100 ml). The aqueous phase was brought to pH ˜8-9 with solid Na2CO3 and extracted vigorously with CH2Cl2 (5×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the title product (16.9 g, yield: almost quantitative), which was used in the preparation of Intermediate 73 without further purification. The reaction mixture was concentrated to dryness diluted with water (400 ml) and 5% aq. HCl (200 ml) washed with diethyl ether (3×100 ml) extracted vigorously with CH2Cl2 (5×) The combined organic layers were dried (MgSO4) concentrated under reduced pressure

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-3-amino-1-morpholino-4-(phenylthio)butan-1-one (INTERMEDIATE 72, 375.5 mg, 1.34 mmol) in DMF (2.5 ml) and DIPEA (1.20 Ml, 6.87 mmol) was added 4-fluoro-3-nitrobenzenesulfonamide (INTERMEDIATE 18, 325.8 mg, 1.48 mmol), and the resulting dark solution was stirred at 50° C. overnight, under a nitrogen atmosphere. The mixture was diluted with EtOAc (50 ml) and washed with water and brine (30 ml each), dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM) to give the title product (532.5 mg, yield: 83%). washed with water and brine (30 ml each) dried (Na2SO4) filtered evaporated under reduced pressure The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM)

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

实验步骤: A suspension of (R)-benzyl 4-morpholino-4-oxo-1-(phenylthio)butan-2-ylcarbamate (INTERMEDIATE 71, 25 g, 60 mmol) in 40% HBr in acetic acid (500 ml) was stirred at room temperature for 50 hrs. The reaction mixture became homogeneous during this time. The reaction mixture was concentrated to dryness, diluted with water (400 ml) and 5% aq. HCl (200 ml) and washed with diethyl ether (3×100 ml). The aqueous phase was brought to pH ˜8-9 with solid Na2CO3 and extracted vigorously with CH2Cl2 (5×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the title product (16.9 g, yield: almost quantitative), which was used in the preparation of Intermediate 73 without further purification. The reaction mixture was concentrated to dryness diluted with water (400 ml) and 5% aq. HCl (200 ml) washed with diethyl ether (3×100 ml) extracted vigorously with CH2Cl2 (5×) The combined organic layers were dried (MgSO4) concentrated under reduced pressure

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of EXAMPLE 21E (6.00 g, 21.4 mmol) in THF (80 mL) was heated to 55° C. and treated dropwise with a solution of 1M borane in THF (85 mL, 85.0 mmol) over a 1 hour period. The resulting reaction mixture was stirred at 55° C. for 18 hours, cooled to 0° C., treated dropwise with methanol (10 mL), treated with 150 mL additional methanol, and concentrated. The crude residue was dissolved in methanol (70 mL), treated with methanolic HCl (100 mL), and heated to reflux for 24 hours. The mixture was allowed to cool to room temperature, concentrated, diluted with 2M NaOH (200 mL), and extracted with ethyl acetate (3×250 mL). The combined extracts were washed with 1M NaOH and brine, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate to provide the desired product (3.45 g, 73%). The resulting reaction mixture cooled to 0° C. concentrated The crude residue was dissolved in methanol (70 mL) treated with methanolic HCl (100 mL) heated to reflux for 24 hours to cool to room temperature concentrated diluted with 2M NaOH (200 mL) extracted with ethyl acetate (3×250 mL) The combined extracts were washed with 1M NaOH and brine dried (Na2SO4) filtered concentrated purified by silica gel chromatography eluting with 5% triethylamine/10% methanol/0% acetonitrile/ethyl acetate