1-morpholin-4-ylethanone

反応条件: temp:0.00; pressure:0.00; stir:

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: 10.2 g of diisopropylamine (0.1 mol) was placed in 100 ml dry THF under nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium in hexane (2.5 M, 0.1 mol) was slowly added dropwise. When the addition was completed the mixture was allowed to stir for 60 minutes and then acetylmorpholine 12.9 g (0.1 mol) was added dropwise. The reaction mixture was stirred for 20 min in the freezing mixture. In a second flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF was cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 150 ml ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.). 5.0 g of product were obtained in the form of white crystals with a melting point of 60° C. after crystallization from PE (petrol ether). cooled in a freezing mixture When the addition The reaction mixture was stirred for 20 min in the freezing mixture the cooled reaction mixture with stirring in small portions to it It was left overnight under stirring The THF was removed on a rotary evaporator The aqueous phase was extracted five times with 150 ml ethyl acetate the combined organic phases were dried over sodium sulfate concentrated on a rotary evaporator to dryness The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.)

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

実験手順: An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, tetrahydrofuran (5 mL) and lithium diisopropylamide (2.0M in hexanes, 6.7 mL, 13.5 mmol). The reaction mixture was magnetically stirred and cooled to 0° C. under argon gas. A solution of N-acetylmorpholine (6.75 mmol) in tetrahydrofuran (1 mL) was added, and the reaction was stirred at 0° C. for 1 hour. A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (4.22 mmol) in tetrahydrofuran (2 mL) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL). The resulting solution was transferred to a separatory funnel, diluted with water (80 mL), and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-(4-bromo-3-hydroxythiophen-2-yl)-3-morpholinopropane-1,3-dione (1.95 g, 5.83 mmol, 138% yield) as a brown solid. An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar the reaction was stirred at 0° C. for 1 hour to warm to room temperature overnight The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL) The resulting solution was transferred to a separatory funnel diluted with water (80 mL) extracted three times with dichloromethane (100 mL) dried over magnesium sulfate filtered concentrated in vacuo

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

実験手順: Condensation of the lithium enolate of N-acetyl morpholine (0.21 g, 1.6 mmol) with methyl 3-phenoxy-2-hydroxybenzoate (0.25 g, 1.0 mmol) followed by cyclodehydration with trifluoromethanesulfonic anhydride (0.60 ml, 3.6 mmol) as described above yielded TGX-134 as an off-white solid (0.090 g).

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

実験手順: Condensation of the lithium enolate of N-acetyl morpholine (0.21 g, 1.6 mmol) with methyl 3-phenoxy-2-hydroxybenzoate (0.25 g, 1.0 mmol) followed by cyclodehydration with trifluoromethanesulfonic anhydride (0.60 ml, 3.6 mmol) as described above yielded TGX-134 as an off-white solid (0.090 g).

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

実験手順: Condensation of the lithium enolate of N-acetyl morpholine (2.2 ml) with methyl 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoate (3.56 g, 11.9 mmol) yielded the salicylacatamide (3.6 g). Cyclodehydration of the product with trifluormethanesulfonic anhydride (5.5 ml) as described above yielded the product as a colourless solid (1.21 g). yielded the salicylacatamide (3.6 g)

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

実験手順: Condensation of the lithium enolate of N-acetyl morpholine (2.2 ml) with methyl 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoate (3.56 g, 11.9 mmol) yielded the salicylacatamide (3.6 g). Cyclodehydration of the product with trifluormethanesulfonic anhydride (5.5 ml) as described above yielded the product as a colourless solid (1.21 g). yielded the salicylacatamide (3.6 g)

反応条件: temp:0.00; pressure:0.00; stir:

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: 6.92 g (25 mmol) 4-chloro-3',4'-dimethoxybenzophenone, 12.9 g (100 mmol) N-acetylmorpholine and 11.2 g (170 mmol) powdered potassium hydroxide (85%) were mixed well and allowed to stand at room temperature for 30 minutes, with occasional stirring. The viscous mass so obtained was then added to a vigorously stirred mixture of 100 ml water and 50 ml toluene. The toluene phase was dried and separated over a column containing 50 g silica gel using 150 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant. The fractions with an Rf value of 0.37 (Toluene/Acetone 7:3) were evaporated in a rotary evaporator, after which 0.8 g of the title compound were obtained by trituration with a little diisopropyl ether. The viscous mass so obtained The toluene phase was dried separated over a column containing 50 g silica gel using 150 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant The fractions with an Rf value of 0.37 (Toluene/Acetone 7:3) were evaporated in a rotary evaporator

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

実験手順: 4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (60 mg, 0.107 mmol) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (34.2 mg, 0.161 mmol, Oakwood Products) using the procedure described in example 25 to give 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone (70.1 mg) as white solids. The enantiomers were separated by chiral chromatography (Diacel ChiralPak OD, eluting with 40/60 hexane/ethanol). The first peak coming off the column is the desired 2-(4-{(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone (31.6 mg, white solids). HR-MS (ES, m/z): observed 736.3029, calculated for C39H48Cl2N5O5 [(M+H)+] 736.3027.