4-fluoro-2-methoxybenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (4.53 g, 30 mmol;) and AlCl3 (5.0 g, 37.6 mmol; Aldrich) in anhydrous toluene (30 mL) was stirred at approximately 130° C. for 18 hrs. After cooling, ice water (˜50 mL) was added and the resulting mixture extracted with ether (20 mL×2). The combined extracts were washed sequentially with water and brine, then dried (MgSO4), and concentrated in vacuo to provide the title compound (3.90 g, 28.5 mmol, Yield 95%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 6.74–6.84 (2H, m, Ar—Hs), 7.71 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H), 11.64 (1H, s, OH); 13C NMR (DMSO-d6, 75.5 Hz) δ ppm: 95.13 102.45, 102.78, 106.53, 106.83 115.53, 134.68, 134.84, 161.41, 161.58, 163.00, 166.35. HRMS (ESI−) calcd for C7H3NOF (M−H) 136.0199, found 136.0199. After cooling the resulting mixture extracted with ether (20 mL×2) The combined extracts were washed sequentially with water and brine dried (MgSO4) concentrated in vacuo

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

Procedure: To a mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (800 mg, 5.3 mmol) and conc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20 mL) was added 10% Pd—C (100 mg; Aldrich), and the mixture hydrogenated at 1 atm hydrogen for 15 hrs at room temperature. To this mixture was added an additional amount of conc.HCl (1 mL) and 10% Pd—C (200 mg) and the reaction allowed to continue for another 40 hrs. The mixture was filtered through Celite and the filtrate concentrated in vacuo to dryness. The residue was triturated with ether to provide the title compound (895 mg, Yield 88%) as a white powder: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.84 (3H, s, OMe), 3.91 (2H, d, J=5.5 Hz, N—CH2), 6.81 (1H, dt, J=2.5 Hz, J=J=8.5 Hz, Ar—H), 6.99 (1H, dd, J=2.5 Hz, J=11.3 Hz, Ar—H), 7.47 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H); 3C NMR (CDCl3, 125.8 Hz) δ ppm: 36.76, 56.03, 99.30, 99.51 106.28, 106.45, 117.93, 117.95, 131.60, 131.69, 158.56, 158.64, 162.28, 164.22. HRMS (ESI) calcd for C8H11FNO (M+H) 156.0825, found 156.0830. To this mixture was added an additional amount of conc The mixture was filtered through Celite the filtrate concentrated in vacuo to dryness The residue was triturated with ether

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of intermediate 126, 1-bromo-4-fluoro-2-methoxybenzene (9.0 g) in N-methylpyrrolidone (100 mL, Sure Seal; Aldrich) was added CuCN (6.6 g, 73.7 mmol, 1.8 eq.; Aldrich), and the mixture stirred at 180° C. under anhydrous nitrogen for 5.5 hrs. After cooling, 14% aqueous NH4OH (330 mL) was added and stirring continued for 45 min at room temperature. The mixture was extracted with ether (100 mL×3), and the combined extracts washed sequentially with dilute aqueous NH4OH, dilute HCl and brine, then dried (MgSO4), and concentrated to provide the title compound (5.2 g, Yield 85% in 2 steps) as a white solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.91 (3H, s, OMe), 6.69 (1H, dd, J=2.3 Hz, J=10.5 Hz, Ar—H), 6.72 (1H, dt, J=2.5 Hz, J=J=8.0 Hz, Ar—H), 7.55 (1H, dd, J=6.5 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 56.49, 98.16, 100.06, 100.27, 108.31, 108.50, 115.83 135.37, 135.46, 163.25, 163.34 165.47, 167.50. An analytical sample was obtained by trituration with ether: Anal. calcd for C8H6FNO: C, 63.57; H, 4.00; N, 9.26; found: C, 63.36; H, 3.91; N, 9.16. After cooling stirring continued for 45 min at room temperature The mixture was extracted with ether (100 mL×3) the combined extracts washed sequentially with dilute aqueous NH4OH, dilute HCl and brine dried (MgSO4) concentrated

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

Procedure: By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,5-dimethylpyrrolidin-3-ol 0.5 oxalate (62 mg), 4-fluoro-2-methoxybenzonitrile (70 mg) and lithium carbonate (63 mg), the title compound was obtained as a colorless solid (yield: 7 mg, yield: 7.3%).

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

Procedure: A suspension (5 mL) of (2R,3S)-2,4,4-trimethylpyrrolidin-3-ol 0.5 oxalate (152 mg), 4-fluoro-2-methoxybenzonitrile (183 mg) and lithium carbonate (155 mg) in DMSO was stirred at 100° C. for 15 hr, added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as a colorless solid (yield: 103 mg, yield: 45%). the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3)

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

Procedure: By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-ethylpyrrolidin-3-ol 0.5 oxalate (185 mg), 4-fluoro-2-methoxybenzonitrile (290 mg) and lithium carbonate (198 mg), the title compound was obtained as a pale-yellow solid (yield: 144 mg, yield: 55%).

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

Procedure: By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-ethylpyrrolidin-3-ol 0.5 oxalate (185 mg), 4-fluoro-2-methoxybenzonitrile (290 mg) and lithium carbonate (198 mg), the title compound was obtained as a pale-yellow solid (yield: 144 mg, yield: 55%).

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

Procedure: By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (201 mg), 4-fluoro-2-methoxybenzonitrile (250 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 158 mg, yield: 54%).

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

Procedure: By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 4-fluoro-2-methoxybenzonitrile (320 mg) and lithium carbonate (210 mg), the title compound was obtained as a pale-yellow solid (yield: 195.8 mg, yield: 62%).

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

Procedure: By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 4-fluoro-2-methoxybenzonitrile (320 mg) and lithium carbonate (210 mg), the title compound was obtained as a pale-yellow solid (yield: 195.8 mg, yield: 62%).