3-(bromomethyl)-5-fluorobenzonitrile

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 14, step 1, 10 g, 0.47 mol) in THF (50 mL) was added ammonium hydroxide solution 25% (2.0 L). The resulting mixture was stirred for 2 h at 85° C. It was then cooled down to RT and extracted with dichloromethane. The organic layer was washed with water, brine, dried and concentrated, affording the title compound as a slight yellow liquid (5 g, 71%). 1H NMR (DMSO-d6, 400 MHz): δ 7.6 (d, J=6.6 Hz, 1H), 7.57 (t, J=0.6 Hz, 1H), 7.55 (s, 1H), 3.74 (d, 2H), 1.97 (s, 2H). LC/MS (Method A) 151.0 (M+H)+. HPLC (Method A) Rt: 0.88 min (Purity 98%). It was then cooled down to RT extracted with dichloromethane The organic layer was washed with water, brine dried concentrated

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

Procedure: To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H). extracted with ethyl acetate The organic phase was washed with water, brine dried concentrated The crude product was purified by chromatography

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-5-methylbenzonitrile (Hognda Trading; 100 g, 0.74 mol) was taken in acetonitrile (1 L) at 25° C. under nitrogen atmosphere. N-Bromosuccinimide (105 g, 0.59 mol) and AIBN (2.4 g, 0.014 mol) were added and the reaction mixture was heated at 70° C. for 1 h 20 minutes. The reaction mixture was cooled to 25° C. and concentrated. The residue was diluted, cooled to 0-5° C. and stirred for 15 minutes at the same temperature. The precipitated succinimide was filtered and the filtrate was concentrated to get crude product as yellow oil (90 g). It was taken in petroleum ether (200 mL) and cooled to −20° C. stirred for 30 minutes. The precipitated solids were filtered and dried to get the title product as white solid. 1H NMR (DMSO-d6; 400 MHz): δ 7.83 (m, 2H), 7.73 (m, 1H), 4.72 (s, 2H). HPLC (Method A) Rt: 4.17 min (Purity: 99.4%). The reaction mixture was cooled to 25° C. concentrated The residue was diluted cooled to 0-5° C. The precipitated succinimide was filtered the filtrate was concentrated to get crude product as yellow oil (90 g) cooled to −20° C. stirred for 30 minutes The precipitated solids were filtered dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Fluoro-5-methylbenzonitrile (Hognda Trading; 100 g, 0.74 mol) was taken in acetonitrile (1 L) at 25° C. under nitrogen atmosphere. N-Bromosuccinimide (105 g, 0.59 mol) and AIBN (2.4 g, 0.014 mol) were added and the reaction mixture was heated at 70° C. for 1 h 20 minutes. The reaction mixture was cooled to 25° C. and concentrated. The residue was diluted, cooled to 0-5° C. and stirred for 15 minutes at the same temperature. The precipitated succinimide was filtered and the filtrate was concentrated to get crude product as yellow oil (90 g). It was taken in petroleum ether (200 mL) and cooled to −20° C. stirred for 30 minutes. The precipitated solids were filtered and dried to get the title product as white solid. 1H NMR (DMSO-d6; 400 MHz): δ 7.83 (m, 2H), 7.73 (m, 1H), 4.72 (s, 2H). HPLC (Method A) Rt: 4.17 min (Purity: 99.4%). The reaction mixture was cooled to 25° C. concentrated The residue was diluted cooled to 0-5° C. The precipitated succinimide was filtered the filtrate was concentrated to get crude product as yellow oil (90 g) cooled to −20° C. stirred for 30 minutes The precipitated solids were filtered dried

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

Procedure: The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%). It was isolated as a pale yellow oil

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

Procedure: The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%). It was isolated as a pale yellow oil

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

Procedure: The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%). It was isolated as a pale yellow oil

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

Procedure: The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%). It was isolated as a pale yellow oil

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Step 4) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-5-fluorobenzonitrile (0.29 g) obtained in Step 3, and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (69 mg). The precipitate was collected by filtration washed with ethyl acetate The obtained precipitate was recrystallized from methanol-ethyl acetate

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

Procedure: (Step 3) Triphenylphosphine (1.91 g) was suspended in acetonitrile (50 ml), bromine (0.38 ml) was added, and the suspension was stirred for 30 min. 3-Fluoro-5-(hydroxymethyl)benzonitrile (1.1 g) synthesized by the method of Steps 1 and 2 was added to the reaction mixture, and the mixture was stirred at 85° C. for 2 hr. The reaction solution was quenched with water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:5) to give 3-(bromomethyl)-5-fluorobenzonitrile (0.69 g). was added to the reaction mixture the mixture was stirred at 85° C. for 2 hr The reaction solution was quenched with water extracted with ethyl acetate The extract was washed with aqueous sodium hydrogen carbonate solution with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:5)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 14, step 1, 10 g, 0.47 mol) in THF (50 mL) was added ammonium hydroxide solution 25% (2.0 L). The resulting mixture was stirred for 2 h at 85° C. It was then cooled down to RT and extracted with dichloromethane. The organic layer was washed with water, brine, dried and concentrated, affording the title compound as a slight yellow liquid (5 g, 71%). 1H NMR (DMSO-d6, 400 MHz): δ 7.6 (d, J=6.6 Hz, 1H), 7.57 (t, J=0.6 Hz, 1H), 7.55 (s, 1H), 3.74 (d, 2H), 1.97 (s, 2H). LC/MS (Method A) 151.0 (M+H)+. HPLC (Method A) Rt: 0.88 min (Purity 98%). It was then cooled down to RT extracted with dichloromethane The organic layer was washed with water, brine dried concentrated

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

Procedure: To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H). extracted with ethyl acetate The organic phase was washed with water, brine dried concentrated The crude product was purified by chromatography