3-(bromomethyl)-4-fluorobenzonitrile

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

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

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

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

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

Procedure: To a solution of 9-Fluoro-10-methyl-7H-5-oxa-4,7-diaza-benzo[c]fluoren-6-one 1G (167 mg, 0.622 mmol) in DMF (3.0 mL) was added 3-Bromomethyl-4-fluoro-benzonitrile (160.0 mg, 0.747 mmol) and CsCO3 (243 mg, 0.747 mmol) at room temperature and the reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The concentrated crude was purified using chromatography over SiO2 using 0 to 30% ethyl acetate in hexane to provide 4-Fluoro-3-(9-fluoro-10-methyl-6-oxo-6H-5-oxa-4,7-diaza-benzo[c]fluoren-7-ylmethyl)-benzonitrile 1H (200 mg, 80%). M.S. found for C23H13F2N3O2: 402.9 (M+H)+. washed with water and brine dried over MgSO4 filtered concentrated in vacuo The concentrated crude was purified

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), tert-butyl N-methyl-beta-alaninate (1.34 g; 8.41 mmol; 1.20 eq.) (prepared as described by Howard N., I. et al. in Bioorg. Med. Chem. 11 (2003), 3083-3099) and potassium carbonate (1.94 g; 14.02 mmol; 2 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for 16 hours. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over sodium sulfate and concentration in vacuo gave title compound as a slightly yellow oil (1.9 g; 92%). 1H NMR (CDCl3) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%). at RT for 16 hours The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over sodium sulfate and concentration in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), sarcosine tert-butyl ester hydrochloride (BACHEM; F-1135; 1 527.73 mg; 8.41 mmol; 1.20 eq.) and potassium carbonate (2.91 g; 21.02 mmol; 3 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for one night. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over magnesium sulfate and concentration in vacuo gave the title compound as a slightly yellow oil (1.9 g; 97%). 1H NMR (CDCl3) δ 7.86 (dd, J=6.5, 2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.13 (t, J=9.0 Hz, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.38 (s, 3H), 1.49 (s, 9H). 19F NMR (CDCl3) δ-108.3. GC/MS: 278. LC/MS (Method B): 279.1 (M+H)+. HPLC (Method A) Rt 2.25 min (Purity: 91.4%). at RT for one night The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over magnesium sulfate and concentration in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), tert-butyl N-methyl-beta-alaninate (1.34 g; 8.41 mmol; 1.20 eq.) (prepared as described by Howard N., I. et al. in Bioorg. Med. Chem. 11 (2003), 3083-3099) and potassium carbonate (1.94 g; 14.02 mmol; 2 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for 16 hours. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over sodium sulfate and concentration in vacuo gave title compound as a slightly yellow oil (1.9 g; 92%). 1H NMR (CDCl3) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%). at RT for 16 hours The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over sodium sulfate and concentration in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-cyano-2-fluorobenzylbromide (CARBOCORE; CO-0137; 1.50 g; 7.01 mmol; 1 eq.), sarcosine tert-butyl ester hydrochloride (BACHEM; F-1135; 1 527.73 mg; 8.41 mmol; 1.20 eq.) and potassium carbonate (2.91 g; 21.02 mmol; 3 eq.) in CH3CN (25 mL) was stirred at 60° C. for 6 hours then at RT for one night. The acetonitrile was evaporated in vacuo and the resulting mixture diluted with water. Extraction with EtOAc, washing with NaCl sat. solution, drying over magnesium sulfate and concentration in vacuo gave the title compound as a slightly yellow oil (1.9 g; 97%). 1H NMR (CDCl3) δ 7.86 (dd, J=6.5, 2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.13 (t, J=9.0 Hz, 1H), 3.78 (s, 2H), 3.23 (s, 2H), 2.38 (s, 3H), 1.49 (s, 9H). 19F NMR (CDCl3) δ-108.3. GC/MS: 278. LC/MS (Method B): 279.1 (M+H)+. HPLC (Method A) Rt 2.25 min (Purity: 91.4%). at RT for one night The acetonitrile was evaporated in vacuo the resulting mixture diluted with water Extraction with EtOAc washing with NaCl sat. solution drying over magnesium sulfate and concentration in vacuo

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

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

Procedure: The title compound was prepared following the general procedure 10 starting from 5-cyano-2-fluorobenzylbromide (1.5 g, 7.0 mmol) and tert-butyl N-methyl-beta-alaninate (1.3 g, 8.4 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil (1.9 g, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (m, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%).

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

Procedure: The title compound was prepared following the general procedure 10 starting from 5-cyano-2-fluorobenzylbromide (1.5 g, 7.0 mmol) and tert-butyl N-methyl-beta-alaninate (1.3 g, 8.4 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil (1.9 g, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (m, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%).