1-morpholin-4-ylpropan-2-ol

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: An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N. At the end of this time, the solution was distilled under vacuum

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

実験手順: An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N. At the end of this time, the solution was distilled under vacuum

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.0 g (34.4 mmol) 1-(4-Morpholinyl)-2-propanol and 35 mg (0.34 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 3.76 g (44.77 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the water phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent. After cooling down to room temperature The phases are separated the water phase is extracted two times with toluene The combined organic phases are dried over sodium sulfate the solvent is removed in vacuo the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate

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

実験手順: An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N. At the end of this time, the solution was distilled under vacuum

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: An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N. At the end of this time, the solution was distilled under vacuum

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

実験手順: An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N. At the end of this time, the solution was distilled under vacuum

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

実験手順: A mixture of 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyric acid (1.13 g; 2.76 mmol), 1-(morpholino)propan-2-ol (0.57 ml; 4 mmol), EDC (0.768 g; 4 mmol), DMAP (0.488 g; 4 mmol) in dichloromethane (5 ml) was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give 1-(morpholinoprop-2-yl 2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate as a foam. Yield=55%. After evaporation of the solvent the residue was purified by flash chromatography eluting with dichloromethane/ethanol (97/3)

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

実験手順: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-morpholinopropan-2-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O5: [(M+H)+]: 743. found: 743.

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

実験手順: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-morpholinopropan-2-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-2-morpholin-4-yl-ethyl ester. MS (ES+) m/z calcd. for C38H43Cl2F2N4O5: [(M+H)+]: 743. found: 743.

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5.0 g (34.4 mmol) 1-(4-Morpholinyl)-2-propanol and 35 mg (0.34 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 3.76 g (44.77 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the water phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent. After cooling down to room temperature The phases are separated the water phase is extracted two times with toluene The combined organic phases are dried over sodium sulfate the solvent is removed in vacuo the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate