2-(trifluoromethyl)benzonitrile

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: Triethylamine (0.05 g, 0.5 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 9a (0.228 g, 1 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-(4-imino)-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]undec-3-yl)-2-trifluoromethylbenzonitrile, 10b (0.036 g, 0.08 mmol, 8%). concentrated to yield a dark residue which

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

Procedure: Triethylamine (0.05 g, 0.5 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 9a (0.228 g, 1 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-(4-imino)-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]undec-3-yl)-2-trifluoromethylbenzonitrile, 10b (0.036 g, 0.08 mmol, 8%). concentrated to yield a dark residue which

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 167 μl of a 1.8 M lithium diisopropylamide THF solution (0.3 mmol) was diluted with 1.5 ml of THF. Thereafter, 1 ml of a THF solution containing 27 mg (0.10 mol) of the 4-chloro-2,N-dimethyl-5-morpholin-4-ylbenzamide prepared in Step B was added dropwise to the diluted solution at −78° C. Thereafter, 1 ml of a THF solution containing 17 mg (0.10 mmol) of 2-(trifluoromethyl)benzonitrile was further added thereto, and the obtained mixture was then stirred at −78° C. for 1 hour. The temperature of the reaction solution was increased to 0° C., and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Thereafter, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1), so as to obtain 5.4 mg (13%) of 6-chloro-7-morpholin-4-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid. was added dropwise to the diluted solution at −78° C was further added The temperature of the reaction solution was increased to 0° C. followed by extraction with ethyl acetate The extract was washed with a saturated saline solution was then dried over anhydrous sodium sulfate followed by concentration under reduced pressure Thereafter, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.3 ml of a 1.8 M lithium diisopropylamide THF solution (81.6 mmol) was diluted with 68 ml of THF. Thereafter, 28 ml of a THF solution containing 5.0 g (27.2 mmol) of the 5-chloro-2,N-dimethylbenzamide prepared in Step A was added dropwise to the diluted solution at −78° C. Thereafter, 28 ml of a THF solution containing 4.65 g (27.2 mmol) of 2-trifluoromethylbenzonitrile was further added thereto, and the obtained mixture was then stirred at −78° C. for 2.5 hours. The temperature of the reaction solution was increased to a room temperature, and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, a solid generated as a result of vacuum concentration was filtrated, so as to obtain 6.87 g (78%) of 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid. was added dropwise to the diluted solution at −78° C was further added The temperature of the reaction solution was increased to a room temperature followed by extraction with ethyl acetate The extract was washed with a saturated saline solution was then dried over anhydrous sodium sulfate a result of vacuum concentration was filtrated

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

Procedure: To a stirred and cooled (-70°~-80° C.) solution of 71.4 parts of a 1-butyllithium solution 1.6M in hexane in 105 parts of 1,1'-oxybisethane was added dropwise a solution of 40.6 parts of 3-bromopyridine in 70 parts of 1,1'-oxybisethane. Upon complete addition, stirring was continued for 15 minutes and a solution of 30 parts of 2-(trifluoromethyl)benzonitrile in 35 parts of 1,1'-oxybisethane was added dropwise at this low temperature. Upon completion, the mixture was stirred for 3 hours at this low temperature. The mixture was heated to room temperature and poured into 84 parts of a hydrochloric acid solution 10N and some crushed ice. The aqueous layer was separated and heated to the boiling point. After cooling, the mixture was made alkaline with an ammonium hydroxide solution and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The residue was purified by filtration over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was concentrated, yielding 27.8 parts (63%) of (3-pyridinyl) [2-(trifluoromethyl)phenyl]methanone as an oily residue (intermediate 3). Upon complete addition stirring Upon completion, the mixture was stirred for 3 hours at this low temperature The aqueous layer was separated heated to the boiling point After cooling the product was extracted with dichloromethane The extract was dried filtered concentrated The residue was purified by filtration over silica gel The pure fractions were collected the eluent was concentrated

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

Procedure: To a stirred and cooled (-70°~-80° C.) solution of 71.4 parts of a 1-butyllithium solution 1.6M in hexane in 105 parts of 1,1'-oxybisethane was added dropwise a solution of 40.6 parts of 3-bromopyridine in 70 parts of 1,1'-oxybisethane. Upon complete addition, stirring was continued for 15 minutes and a solution of 30 parts of 2-(trifluoromethyl)benzonitrile in 35 parts of 1,1'-oxybisethane was added dropwise at this low temperature. Upon completion, the mixture was stirred for 3 hours at this low temperature. The mixture was heated to room temperature and poured into 84 parts of a hydrochloric acid solution 10N and some crushed ice. The aqueous layer was separated and heated to the boiling point. After cooling, the mixture was made alkaline with an ammonium hydroxide solution and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The residue was purified by filtration over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was concentrated, yielding 27.8 parts (63%) of (3-pyridinyl) [2-(trifluoromethyl)phenyl]methanone as an oily residue (intermediate 3). Upon complete addition stirring Upon completion, the mixture was stirred for 3 hours at this low temperature The aqueous layer was separated heated to the boiling point After cooling the product was extracted with dichloromethane The extract was dried filtered concentrated The residue was purified by filtration over silica gel The pure fractions were collected the eluent was concentrated

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

Procedure: To a cold solution of 2-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol) in diethyl ether (20 mL) was added titanium isopropoxide (2.0 g, 0.70 mmol) at −70° C. and ethyl magnesium bromide (4.30 mL, 12.86 mmol). The reaction mass was stirred at RT for 2-3 h. Followed by addition of boron trifluoride solution (1.5 mL) and continued stirring for 2 h at RT. The reaction mass was quenched in 1N HCl and basified with NaOH solution. The obtained crude product was further purified by column chromatography on silica gel eluting with 1% EtOAC: DCM eluent to afford 0.250 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.82-0.84 (s, 2H), 0.91-0.93 (br s, 2H), 2.24 (br s, 2H), 7.41 (t, J=6.6 Hz, 1H), 7.58-7.67 (m, 3H). continued stirring for 2 h at RT The reaction mass was quenched in 1N HCl The obtained crude product was further purified by column chromatography on silica gel eluting with 1% EtOAC

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

Procedure: A mixture consisting of 9.3 g of 2-trifluoromethylbenzonitrile, 4.5 g of acetonitrile, 4.3 g of sodium amide and 100 ml of ether is stirred and refluxed under nitrogen over night. The resulting solid is collected on a Buchner-funnel, washed with ether and dissolved in approximately 100 ml of cold ethanol. Crushed ice is added to this solution until the total volume is about 700 ml. This mixture is allowed to stand for several hours. The resulting solid precipitate is collected by filtration then dissolved in methanol and decolorizing charcoal is added. The charcoal/methanol mixture is filtered and the filtrate is gradually treated with water until crystallization is judged complete. The crystalline solid is collected and dried under vacuum, to give 7.75 g of β-amino-2-trifluoromethylcinnamonitrile, mp 101°-103°. refluxed under nitrogen over night The resulting solid is collected on a Buchner-funnel washed with ether dissolved in approximately 100 ml of cold ethanol Crushed ice is added to this solution until the total volume is about 700 ml to stand for several hours The resulting solid precipitate is collected by filtration then dissolved in methanol is added The charcoal/methanol mixture is filtered the filtrate is gradually treated with water until crystallization The crystalline solid is collected dried under vacuum

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

Procedure: Triethylamine (0.05 g, 0.5 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 9a (0.228 g, 1 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-(4-imino)-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]undec-3-yl)-2-trifluoromethylbenzonitrile, 10b (0.036 g, 0.08 mmol, 8%). concentrated to yield a dark residue which