Ethyl 2-(4-aMino-2-fluorophenyl)acetate

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 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylic acid sodium salt (526 g, 1.51 mol) and ethyl (4-amino-2-fluorophenyl)acetate (539 g, 2.73 mol) in glacial acetic acid (5100 mL) was heated to reflux for 6 hours, with reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was allowed to cool to room temperature, stirred for 18 hours, diluted with water (14 L) and stirred for a further 30 minutes. The product was isolated by filtration, washed with water (5 L) and dried in a vacuum oven at 60° C. to give the desired product as an off-white solid (587 g, 84% yield). was heated to reflux for 6 hours, with reaction progress stirred for a further 30 minutes The product was isolated by filtration washed with water (5 L) dried in a vacuum oven at 60° C.

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thionyl chloride (986 mL, 8.51 mol) was added dropwise to a stirred suspension of 2-(4-amino-2-fluorophenyl)acetic acid (960 g, 5.68 mol) in ethanol (10 L) at 0° C. under a nitrogen atmosphere. The reaction mixture was then heated to 40° C. for 48 hours, with the reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was evaporated to dryness and the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L). Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase was basic. The layers were separated and the organic phase washed with saturated sodium hydrogen carbonate solution (4 L), dried over magnesium sulphate and the solvent removed under reduced pressure gave the desired product, ethyl (4-amino-2-fluorophenyl)acetate, as an orange oil (1042 g, 93% yield), that may crystallise upon standing. The reaction mixture was evaporated to dryness the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L) Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase The layers were separated the organic phase washed with saturated sodium hydrogen carbonate solution (4 L) dried over magnesium sulphate the solvent removed under reduced pressure

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Thionyl chloride (986 mL, 8.51 mol) was added dropwise to a stirred suspension of 2-(4-amino-2-fluorophenyl)acetic acid (960 g, 5.68 mol) in ethanol (10 L) at 0° C. under a nitrogen atmosphere. The reaction mixture was then heated to 40° C. for 48 hours, with the reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was evaporated to dryness and the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L). Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase was basic. The layers were separated and the organic phase washed with saturated sodium hydrogen carbonate solution (4 L), dried over magnesium sulphate and the solvent removed under reduced pressure gave the desired product, ethyl (4-amino-2-fluorophenyl)acetate, as an orange oil (1042 g, 93% yield), that may crystallise upon standing. The reaction mixture was evaporated to dryness the residue redissolved in a mixture of dichloromethane (8 L) and saturated sodium hydrogen carbonate solution (5 L) Further sodium hydrogen carbonate solution was added (˜8 L) until the aqueous phase The layers were separated the organic phase washed with saturated sodium hydrogen carbonate solution (4 L) dried over magnesium sulphate the solvent removed under reduced pressure

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl phenylmethyl (2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol (50 ml), was treated with ammonium formate (6.7 g, 10.6 mmol) under argon. Palladium on carbon 10% paste (380 mg) was added and the reaction was stirred under reflux for 3 hours (60° C.). The reaction was cooled to room temperature and the catalyst removed by filtration through celite. Solvent was removed to give a brown oil. The crude material was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane (1:1) over 45 minutes. Fractions were evaporated to give the title compound as a yellow oil (1.26 g, 6.4 mmol). The reaction was cooled to room temperature the catalyst removed by filtration through celite Solvent was removed to give a brown oil The crude material was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane (1:1) over 45 minutes Fractions were evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl phenylmethyl (2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol (50 ml), was treated with ammonium formate (6.7 g, 10.6 mmol) under argon. Palladium on carbon 10% paste (380 mg) was added and the reaction was stirred under reflux for 3 hours (60° C.). The reaction was cooled to room temperature and the catalyst removed by filtration through celite. Solvent was removed to give a brown oil. The crude material was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane (1:1) over 45 minutes. Fractions were evaporated to give the title compound as a yellow oil (1.26 g, 6.4 mmol). The reaction was cooled to room temperature the catalyst removed by filtration through celite Solvent was removed to give a brown oil The crude material was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane (1:1) over 45 minutes Fractions were evaporated

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

実験手順: Ethyl phenylmethyl(2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol, was treated with ammonium formate (6.7 g, 10.6 mmol) and palladium on carbon 10% paste (380 mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a yellow oil (1.26 g). LC/MS: Rt=2.10, [MH]+ 198. was added under argon The reaction mixture was refluxed for 3 hours cooled filtered Evaporated purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1)

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

実験手順: Ethyl phenylmethyl(2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol, was treated with ammonium formate (6.7 g, 10.6 mmol) and palladium on carbon 10% paste (380 mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a yellow oil (1.26 g). LC/MS: Rt=2.10, [MH]+ 198. was added under argon The reaction mixture was refluxed for 3 hours cooled filtered Evaporated purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1)

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 solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (207 mg, 0.7 mmol) in dichloromethane (3 ml) was treated with N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol, 1.5 eq) and stirred at room temperature for 30 minutes. A solution of ethyl (4-amino-2-fluorophenyl)acetate (207 mg, 1.05 mmol, 1.5 eq) in dichloromethane (2 ml) was added and the resulting mixture heated at 40° C. overnight. On cooling, the mixture was diluted with methanol and purified by SCX cartridge eluting with methanol to afford the title compound as a yellow oil (110 mg). MS (ES+) m/z 476 [M+H]+ (C24H2035Cl2FNO4). 1H-NMR (400 MHz, d6-DMSO) δ 1.19 (3H, t, J 7.2), 3.68 (2H, s), 4.09 (2H, q, J 7.2), 5.20 (2H, s), 7.15-7.68 (10H, m). the resulting mixture heated at 40° C. overnight On cooling purified by SCX cartridge eluting with methanol

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

実験手順: Ethyl phenylmethyl (2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol, was treated with ammonium formate (6.7 g, 10.6 mmol) and palladium on carbon 10% paste (380 mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a yellow oil (1.26 g). LC/MS: Rt=2.10, [MH]+ 198. was added under argon The reaction mixture was refluxed for 3 hours cooled filtered Evaporated purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1)

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

実験手順: Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100 g, 0.33 mmol) was reacted with ethyl 2-(4-amino-2-fluorophenyl)acetate (0.098 g, 0.50 mmol) to afford the title compound (0.094 g, 94%). MW=424.90. 1H NMR (CD3OD, 300 MHz) δ 7.79-7.75 (m, 1H), 7.66-7.60 (m, 1H), 7.45-7.36 (m, 2H), 7.30 (t, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.11-7.05 (m, 1H), 7.04-6.97 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.30-2.13 (m, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 425 [M+H]+.