Methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate

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: Methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (5.8 g, 23.5 mmol), prepared from methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate according to the process of WO 10/122578, was refluxed in the solution of NaOH (1.88 g, 46.9 mmol) in MeOH (40 mL) and water (20 mL) overnight. After the completion of the reaction, the MeOH was evaporated and 80 mL of water was added. The pH of the solution was adjusted to 8 by addition of 6M HCl and the resulting white precipitate was filtered off and dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia. After the completion of the reaction the MeOH was evaporated 80 mL of water was added The pH of the solution was adjusted to 8 by addition of 6M HCl the resulting white precipitate was filtered off dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia

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 mixture of methyl 4-(2,4,5-trifluorophenyl)acetoacetate from Example 1 (25.0 g, 102 mmol) and ammonium acetate (38.5 g, 500 mmol) in methanol (250 ml) was stirred at reflux until the starting material totally disappeared (˜4 h). The whole reaction mixture was then concentrated, switched to dichloromethane and filtered. The filtration was washed with water, then brine, then dried over sodium sulfate, filtered and evaporated—ed. The residue oil solidified when hexane was added. The solid was collected by filtration and dried to give 22.4 g of the enamine product (89.6%). 1H NMR (300 MHz, CDCl3) 7.12-7.03 (m, 1H), 6.99-6.90 (m, 1H), 4.56 (s, 1H) 3.65 (s, 3H), 3.40 (s, 2H) at reflux until the starting material (˜4 h) The whole reaction mixture was then concentrated filtered The filtration was washed with water brine, then dried over sodium sulfate filtered evaporated—ed was added The solid was collected by filtration dried

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

実験手順: To a solution of 2,4,5-trifluorophenyl acetic acid (42.2 g, 222 mmol) in THF (400 mL) was added 1,1′-carbonyldiimidazole (39.5 g, 244 mmol) in portions at 0° C. The mixture was warmed to room temperature for 1 h, stirred at room temperature for another 1 h, and transferred to another flask containing 1.1 equivalent of methyl malonic acid magnesium salt. The stirring was continued for 24 h and quenched with 1N HCl. The mixture was extracted with dichloromethane and the organic phase was washed with saturated sodium bicarbonate, then brine, then dried over sodium sulfate, filtered and evaporated. The residue was crystallized from isopropanol/water to give 42.2 g (77.3%) of off-white solid. 1H NMR (300 MHz, CDCl3) 7.10-6.90 (m, 2H), 3.85 (s, 2H), 3.78 (s, 3H), 3.55 (s, 2H) transferred to another flask The stirring was continued for 24 h quenched with 1N HCl The mixture was extracted with dichloromethane the organic phase was washed with saturated sodium bicarbonate brine, then dried over sodium sulfate filtered evaporated The residue was crystallized from isopropanol/water

反応条件: temp:61.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The methyl 4-(2,4,5-trifluorophenyl)acetoacetate (350.0 gm, 1.42 mol) (21) and ammonium acetate (6.0 eq, 657.0 gm) were charged in methanol (5.0 vol, 1.75 Ltr) and the solution was refluxed for 5-6 hours at 60-63° C. After 5-6 hours refluxing, the methanol was distilled out completely to give a pale yellow coloured residue. The pale yellow coloured residue was further stirred with ethyl acetate (20.0 vol, 7.0 Ltr) at 25-30° C. The precipitated ammonium acetate was filtered and the ethyl acetate was distilled out completely to give a pale yellow product. The product was further stirred with hexane (10.0 vol, 3.5 Ltr) at 25-30° C. for 1 hour, filtered and dried under reduced pressure at 45-50° C. for 4-5 hours. After 5-6 hours refluxing the methanol was distilled out completely to give a pale yellow coloured residue The precipitated ammonium acetate was filtered the ethyl acetate was distilled out completely to give a pale yellow product filtered dried under reduced pressure at 45-50° C. for 4-5 hours

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

実験手順: Methyl 4-(2,4,5-trifluorophenyl)acetoacetate (21) was treated with anhydrous ammonium acetate in an alcoholic solvent, preferably methanol, and preferably at higher temperature, preferably at 60-65° C. The methyl(Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (28) formed was preferably isolated by complete removal of the solvent under reduced pressure, separation of excess of ammonium acetate by using a polar organic solvent such as ethyl acetate, distillation of the polar organic solvent and triturating the product with non-polar solvents like hexane. preferably at 60-65° C

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

実験手順: Methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (5.8 g, 23.5 mmol), prepared from methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate according to the process of WO 10/122578, was refluxed in the solution of NaOH (1.88 g, 46.9 mmol) in MeOH (40 mL) and water (20 mL) overnight. After the completion of the reaction, the MeOH was evaporated and 80 mL of water was added. The pH of the solution was adjusted to 8 by addition of 6M HCl and the resulting white precipitate was filtered off and dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia. After the completion of the reaction the MeOH was evaporated 80 mL of water was added The pH of the solution was adjusted to 8 by addition of 6M HCl the resulting white precipitate was filtered off dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia