methyl 2-fluoroacetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into 15 ml of benzene were added 2.10 g (13.7 mmol) of 2-methyl-4-methoxy-5-aminophenol, 1.28 g (13.9 mmol, 1.0 eq.) of methyl fluoroacetate and 1.64 g (30.4 mmol) of sodium methoxide and the mixture was heated under reflux for 6.5 hours. After allowing to cool, the mixture was poured into 300 ml of water, and neutralized with acetic acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain dark-brown crystals. The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) and pale brown solid matters were obtained from the 600-900 ml fraction. The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume) to give 230 mg (1.9 mmol) of 2-methyl-4-methoxy-5-fluoroacetylaminophenol. The yield was 8%. the mixture was heated under reflux for 6.5 hours to cool extracted with 200 ml of ethyl acetate The organic layer was washed with a saturated aqueous solution of common salt dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure to obtain dark-brown crystals The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) pale brown solid matters were obtained from the 600-900 ml fraction The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+. the reaction mixture is evaporated the residue is dissolved in dichloromethane the solution washed with 1 ml of hydrochloric acid (1N) The organic layer is separated dried over sodium sulfate evaporated For purification the crude product is chromatographed on silica gel using a 98

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+. the reaction mixture is evaporated the residue is dissolved in dichloromethane the solution washed with 1 ml of hydrochloric acid (1N) The organic layer is separated dried over sodium sulfate evaporated For purification the crude product is chromatographed on silica gel using a 98

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into 15 ml of benzene were added 2.10 g (13.7 mmol) of 2-methyl-4-methoxy-5-aminophenol, 1.28 g (13.9 mmol, 1.0 eq.) of methyl fluoroacetate and 1.64 g (30.4 mmol) of sodium methoxide and the mixture was heated under reflux for 6.5 hours. After allowing to cool, the mixture was poured into 300 ml of water, and neutralized with acetic acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain dark-brown crystals. The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) and pale brown solid matters were obtained from the 600-900 ml fraction. The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume) to give 230 mg (1.9 mmol) of 2-methyl-4-methoxy-5-fluoroacetylaminophenol. The yield was 8%. the mixture was heated under reflux for 6.5 hours to cool extracted with 200 ml of ethyl acetate The organic layer was washed with a saturated aqueous solution of common salt dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure to obtain dark-brown crystals The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) pale brown solid matters were obtained from the 600-900 ml fraction The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-fluoroacetate (11.3 mg, 123 μmol, Eq: 1.5) and KOSiMe3 (21 mg, 164 μmol, Eq: 2) in Dioxane (1 ml) was stirred at room temperature over night. Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.8 μmol), N,N-diisopropylethylamine (42.3 mg, 57.0 μl, 327 μmol, Eq: 4) and TBTU (39.4 mg, 123 μmol, Eq: 1.5) were added. Reaction mixture was stirred 4 h at room temperature. The reaction mixture was solved with sat NaHCO3 (1×10 mL) and extracted with dichloromethane (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an off-white solid (21.3 mg, 66.7%), MS (ISP) m/z=391.2 [(M+H)+]. Reaction mixture was stirred 4 h at room temperature extracted with dichloromethane (2×20 mL) The organic layers were dried over MgSO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into 15 ml of benzene were added 2.10 g (13.7 mmol) of 2-methyl-4-methoxy-5-aminophenol, 1.28 g (13.9 mmol, 1.0 eq.) of methyl fluoroacetate and 1.64 g (30.4 mmol) of sodium methoxide and the mixture was heated under reflux for 6.5 hours. After allowing to cool, the mixture was poured into 300 ml of water, and neutralized with acetic acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain dark-brown crystals. The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) and pale brown solid matters were obtained from the 600-900 ml fraction. The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume) to give 230 mg (1.9 mmol) of 2-methyl-4-methoxy-5-fluoroacetylaminophenol. The yield was 8%. the mixture was heated under reflux for 6.5 hours to cool extracted with 200 ml of ethyl acetate The organic layer was washed with a saturated aqueous solution of common salt dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure to obtain dark-brown crystals The crystals were purified by silica gel column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 70-230 mesh, 200 g, eluent: ethyl acetate) pale brown solid matters were obtained from the 600-900 ml fraction The solid matters were recrystallized from the solvent mixture of hexane/ethyl acetate (2:1 by volume)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 100 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.3 ml of N,N-dimethylformamide is treated successively with 100 μl (0.6 mmol) of N-ethyl-diisopropylamine and 55 μl (0.6 mmol) of methyl fluoroacetate. The resulting beige suspension is heated to 50° C. for 18 hours. For the working-up, the reaction mixture is evaporated, thereafter, the residue is dissolved in dichloromethane and the solution washed with 1 ml of hydrochloric acid (1N). The organic layer is separated, dried over sodium sulfate, and evaporated. For purification, the crude product is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 30 mg (28% of theory) of (S)-2-fluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=378 (M+NH4)+. the reaction mixture is evaporated the residue is dissolved in dichloromethane the solution washed with 1 ml of hydrochloric acid (1N) The organic layer is separated dried over sodium sulfate evaporated For purification the crude product is chromatographed on silica gel using a 98