methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate

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:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The methyl(3RS)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (260 gm, 1.05 mol) (29) was charged in isopropanol (6.0 vol, 1.56 Ltr) at 25-30° C. and the reaction mixture was stirred for 15 minutes to give a clear solution. After 15 minutes stirring, controlled addition of a solution of (R)-(−)-mandelic acid [2.0 eq, 320 gm in 6.0 vol, 1.56 Ltr of isopropanol] was carried out. After completion of the addition, the reaction mixture was stirred at 25-30° C. for 3 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate as a white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 260 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (135 gm, molar yield: 64%). The dried enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate product (135 gm) was charged in isopropanol (20.0 vol, 2.7 Ltr) at 25-30° C. and the white suspension was further heated at 75-80° C. for 0.5 hour to give a partially clear solution. The partially clear solution was made clear by the addition of water (2.0 vol, 270.0 ml) at 75-80° C. The clear solution was further stirred for 0.5 hour. After stirring for 0.5 hour, the clear solution was gradually cooled to 0-5° C. within 3 hours to give enantiomerically enriched pure methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (30) as white coloured product. The product was filtered, washed with isopropanol (1.0 vol, 135.0 ml), and dried in a vacuum oven at 40-45° C. for 4-5 hours. to give a clear solution After 15 minutes stirring After completion of the addition the reaction mixture was stirred at 25-30° C. for 3 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate as a white coloured product The product was filtered washed with isopropanol (1.0 vol, 260 ml) dried in a vacuum oven at 40-45° C. for 4-5 hours to give enantiomerically enriched crude methyl(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (R)-(−)-mandelate (135 gm, molar yield: 64%) The dried enantiomerically was charged in isopropanol (20.0 vol, 2.7 Ltr) at 25-30° C. to give a partially clear solution The clear solution was further stirred for 0.5 hour After stirring for 0.5 hour the clear solution was gradually cooled to 0-5° C. within 3 hours

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

実験手順: The methyl(Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate (350.0 gm, 1.42 mol) (28) was charged in methanol (10.0 vol, 3.5 Ltr) at 25-30° C. and the reaction was stirred for 10-15 minutes to give a clear solution. To the clear pale yellow solution, controlled addition of sulphuric acid (70.0 ml, 0.2 vol) was done at 0 to −10° C. and the clear solution was stirred for 10-15 minutes at 0 to −10° C. After 10-15 minutes stirring at 0 to −10° C., sodium cyanoborohydride (2.0 eq, 170.0 gm) was charged in 10 lots. The clear white suspension was stirred at 0 to −10° C. for 2 hours. The methanol was distilled completely at 45-50° C. under reduced pressure to give a pale yellow residue. The pale yellow residue was further treated with a 1:1 mixture of 35% hydrochloric acid:water at 0-5° C. to give pH 2. The suspension was stirred at 0-5° C. for 10-15 minutes and the suspension was further basified by using 20% sodium carbonate to give pH 8-9. The product was extracted in ethyl acetate (2×10.0 vol, 2×3.5 Ltr). The combined ethyl acetate layers were washed with water (3×10.0 vol, 3×3.5 Ltr). The product was isolated by distillation of the ethyl acetate to give a pale yellow coloured oil. to give a clear solution was done at 0 to −10° C. the clear solution was stirred for 10-15 minutes at 0 to −10° C After 10-15 minutes stirring at 0 to −10° C. The clear white suspension was stirred at 0 to −10° C. for 2 hours The methanol was distilled completely at 45-50° C. under reduced pressure to give a pale yellow residue The suspension was stirred at 0-5° C. for 10-15 minutes to give pH 8-9 The product was extracted in ethyl acetate (2×10.0 vol, 2×3.5 Ltr) The combined ethyl acetate layers were washed with water (3×10.0 vol, 3×3.5 Ltr) The product was isolated by distillation of the ethyl acetate to give a pale yellow coloured oil

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