3-morpholin-4-ylpropane-1,2-diol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s). heated at the reflux temperature for 1 h The reaction mixture was then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86-7.88 (m, 1H, H-4), 7.79-7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19-7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35-4.45 (m, 3H), 3.75-3.98 (m, 4H), 3.26-3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3) filtered The solid was then washed with ethyl acetate and ether

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s). heated at the reflux temperature for 1 h The reaction mixture was then concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s). heated at the reflux temperature for 1 h The reaction mixture was then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86–7.88 (m, 1H, H-4), 7.79–7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19–7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35–4.45 (m, 3H), 3.75–3.98 (m, 4H), 3.26–3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3). filtered The solid was then washed with ethyl acetate and ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using the same procedure as for Example 54, a mixture of 3-morpholin-4-yl-propane-1,2-diol (40 mg, 0.25 mmol), sodium hydride (60%, 30 mg) and 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (174 mg, 0.6 mmol) in acetonitrile (1 mL) was heated to reflux, worked-up and purified on silica gel to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 8.59 (d, J=2.3 Hz, 2H), 8.35 (dd, J=2.3 & 9.2 Hz, 1H), 8.30 (dd, J=2.3 & 9.2 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 5.49 (m, 1H), 4.79 (m, 1H), 4.66 (m, 1H), 3.41 (m, 4H), 2.74 (d, J=6.1 Hz, 2H), 2.4-2.5 (m, 4H). MS+ve APCI 668 [M+1]. was heated to reflux purified on silica gel

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 33 g of 3-chloropropylene glycol was added dropwise to 65 g morpholine, with stirring, while maintaining the temperature at 80° C. The 3-chloropropylene glycol reacted quickly with the morpholine exothermically. The reaction mixture was stirred for 3 hours, with the temperature maintained at 80° C. The salt of morpholine, which separated from the reaction mixture, was filtered out. The filtrate was distilled under reduced pressure. This distillation gave 35 g of the desired product, 3-morpholino propylene glycol (bp. 135°-138° C./11 mmHg), in a 75.5% yield. The reaction mixture was stirred for 3 hours, with the temperature maintained at 80° C The salt of morpholine, which separated from the reaction mixture was filtered out The filtrate was distilled under reduced pressure This distillation

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s). heated at the reflux temperature for 1 h The reaction mixture was then concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86-7.88 (m, 1H, H-4), 7.79-7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19-7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35-4.45 (m, 3H), 3.75-3.98 (m, 4H), 3.26-3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3) filtered The solid was then washed with ethyl acetate and ether

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s). heated at the reflux temperature for 1 h The reaction mixture was then concentrated under reduced pressure