methyl 2-cyano-4-fluorobenzoate

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

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

Procedure: To a stirred solution of 4.03 g (22.5 mmol) 2-Cyano-4-fluoro-benzoic acid methyl ester (J. Med. Chem., 35; 24; (1992); 4613-4627) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 9 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 9a was obtained in 85% yield (3.90 g, 19.1 mmol). was concentrated with high vacuum rotation evaporator at 65° C The residue was diluted with dichloromethane washed twice with water The combined water phases were extracted with dichloromethane The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The oily crude was purified by column chromatography

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

Procedure: A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 106a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 106b (1.29 g) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, 1H, J=8.5, 5.5 Hz), 7.21-7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H). A 250-mL Parr reactor bottle was purged with nitrogen charged with Raney nickel (4.00 g) evacuated charged with hydrogen gas to a pressure of 50 psi After this time, the hydrogen was evacuated nitrogen was charged into the bottle Celite 521 (5.00 g) was added the mixture was filtered through a pad of Celite 521 The filter cake was washed with ethanol (2×75 mL) the combined filtrates were concentrated to dryness under reduced pressure

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography

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

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

Procedure: A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 123a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 123b (1.29 g) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, 1H, J=8.5, 5.5 Hz), 7.21-7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H). A 250-mL Parr reactor bottle was purged with nitrogen charged with Raney nickel (4.00 g) evacuated charged with hydrogen gas to a pressure of 50 psi After this time, the hydrogen was evacuated nitrogen was charged into the bottle Celite 521 (5.00 g) was added the mixture was filtered through a pad of Celite 521 The filter cake was washed with ethanol (2×75 mL) the combined filtrates were concentrated to dryness under reduced pressure

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography

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

Procedure: To a stirred solution of 4.03 g (22.5 mmol) 2-Cyano-4-fluoro-benzoic acid methyl ester (J. Med. Chem., 35; 24; (1992); 4613-4627) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 9 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 9a was obtained in 85% yield (3.90 g, 19.1 mmol). was concentrated with high vacuum rotation evaporator at 65° C The residue was diluted with dichloromethane washed twice with water The combined water phases were extracted with dichloromethane The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The oily crude was purified by column chromatography

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

Procedure: A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 106a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 106b (1.29 g) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, 1H, J=8.5, 5.5 Hz), 7.21-7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H). A 250-mL Parr reactor bottle was purged with nitrogen charged with Raney nickel (4.00 g) evacuated charged with hydrogen gas to a pressure of 50 psi After this time, the hydrogen was evacuated nitrogen was charged into the bottle Celite 521 (5.00 g) was added the mixture was filtered through a pad of Celite 521 The filter cake was washed with ethanol (2×75 mL) the combined filtrates were concentrated to dryness under reduced pressure

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H). A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen the reaction mixture was cooled to room temperature The resulting suspension was filtered the filter cake was washed with water (100 mL) To the solid obtained the layers were separated The aqueous phase was extracted with ethyl acetate (2×10 mL) dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by flash chromatography