2-(4-吗啉基)乙酸乙酯

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

实验步骤: To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 2.75 g (53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+). and was concentrated to dryness The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3 The mixture was washed with saturated NaHCO3 washed with brine dried over Na2SO4 filtered concentrated to dryness

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

实验步骤: Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%) washed with saturated NaCl solution The separated organic layer was dried over anhydrous sodium sulfate concentrated under a reduced pressure

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

实验步骤: Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%) washed with saturated NaCl solution The separated organic layer was dried over anhydrous sodium sulfate concentrated under a reduced pressure

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

实验步骤: To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67 mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringe and stirring was continued for 3 h. Concentration in vacuo afforded 122 mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture of morpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol), 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added DIEA (51 μL, 0.29 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by silica gel preparative TLC afforded 8.1 mg (12%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (br s, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s, 1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1 Hz), 9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C28H34N6O3, 503.27 (M+H). found 503.1. Concentration in vacuo

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

实验步骤: To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 2.75 g (53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+). and was concentrated to dryness The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3 The mixture was washed with saturated NaHCO3 washed with brine dried over Na2SO4 filtered concentrated to dryness

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

实验步骤: To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonate and 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 2.75 g (53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+). and was concentrated to dryness The residue was partitioned between 20% isopropanol/chloroformn and saturated aqueous NaHCO3 The mixture was washed with saturated NaHCO3 washed with brine dried over Na2SO4 filtered concentrated to dryness

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

实验步骤: Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%) washed with saturated NaCl solution The separated organic layer was dried over anhydrous sodium sulfate concentrated under a reduced pressure

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

实验步骤: The solution of ethyl 2-morpholinoacetate (0.73 g, 4.24 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated on vacuum pump and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 60% yield (0.37 g). LC-MS (ESI): Calculated mass: 145.1; Observed mass 146.3 [M+H]+ (rt: 0.28 min). The mixture was concentrated on vacuum pump quenched extracted as in Intermediate Example 15(b) The solvent was distilled off to afford the product in 60% yield (0.37 g) Observed mass 146.3 [M+H]+ (rt: 0.28 min)

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

实验步骤: To a solution of morpholine (0.5 g, 5.739 mmol, 1.0 eq) in DMF were added K2CO3 (1.98 g, 14.34 mmol, 2.5 eq.) and ethyl 2-chloroacetate (1.05 g, 8.60 mmol, 1.5 eq.). The mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 73.9% yield (0.735 g). LC-MS (ESI): Calculated mass: 173.21; Observed mass 174.0 [M+H]+ (rt: 0.1-0.4 min). The mixture was quenched extracted as in Intermediate Example 5(a) The solvent was distilled off to afford the product in 73.9% yield (0.735 g) Observed mass 174.0 [M+H]+ (rt: 0.1-0.4 min)

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

实验步骤: The solution of ethyl 2-morpholinoacetate (1 g, 57.8 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 96.3% yield (0.8 g). LC-MS (ESI): Calculated mass: 145.16; Observed mass: 146.3 [M+H]+ (rt: 0.21 min). The mixture was concentrated quenched extracted as in Intermediate Example 15(b) The solvent was distilled off to afford the product in 96.3% yield (0.8 g) 146.3 [M+H]+ (rt: 0.21 min)

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

实验步骤: To a solution of morpholine (1.4 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (4.07 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 71.4% yield (2 g). LC-MS (ESI): Calculated mass: 173.2; Observed mass: 174.0 [M+H]+ (rt: 0.20 min). quenched extracted as in Intermediate Example 5(a) The solvent was distilled off to afford the product in 71.4% yield (2 g) 174.0 [M+H]+ (rt: 0.20 min)

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

实验步骤: A solution of ethyl 2-morpholinoacetate (1.8 g, 11.44 mmol) in 8 N HCl (5 ml) was heated at 90° C. for 12 h. The mixture was concentrated to give the product in 64% yield (0.9 g). LC-MS (ESI): Calculated mass: 145.16; Observed mass: 146.3 [M+H]+ (rt: 0.21 min). The mixture was concentrated to give the product in 64% yield (0.9 g) 146.3 [M+H]+ (rt: 0.21 min)