3-chlorobenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-{5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl}-3-chlorobenzonitrile (1.7 g, 4.52 mmol) is dissolved in anhydrous THF (30 mL) and stirred at −78° C. before a THF solution of LHMDS (8.1 mL, 1.0 M) is added. After 15 min, methyl cyanoformate (0.38 mL, 4.74 mmol) is added and the solution is left at −78° C. for 2 h. The excess LHMDS is quenched with aqueous saturated NH4Cl and the mixture is allowed to warm to room temperature. The mixture is then diluted with EtOAc and washed with aqueous saturated NH4Cl (2×). Organic is dried (Na2SO4) and evaporated. The crude residue is purified via flash column chromatography (EtOAc/hexanes 1:1→EtOAc) to give {5-[2-tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(2-chloro-4-cyanophenyl)acetic acid methyl ester as an oil. MS (ESI) m/z 434.3, 436.3 (M+H). is added the solution is left at −78° C. for 2 h The excess LHMDS is quenched with aqueous saturated NH4Cl The mixture is then diluted with EtOAc washed with aqueous saturated NH4Cl (2×) Organic is dried (Na2SO4) evaporated The crude residue is purified via flash column chromatography (EtOAc/hexanes 1:1→EtOAc)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (3.98 g, 8.5 mmol) and 4-bromomethyl-3-chlorobenzonitrile (2.93 g, 12.7 mmol) are dissolved in MeCN (40 mL) and heated at 80° C. for 5 h. After cooling to room temperature MeOH (40 mL) and Et2NH (7 mL) are then added and the solution is warmed 70° C. for 1 h. The solution is evaporated to dryness and the residue purified via flash column chromatography (acetone/CH2Cl2 1:3→MeOH/CH2Cl2 5:95) to give 4-{5-[2-tert-butyl-dimethylsilanyloxy)ethyl]-imidazol-1-ylmethyl}-3-chlorobenzonitrile as an oil. MS (ESI) m/z 376.3, 378.3 (M+H). are then added the solution is warmed 70° C. for 1 h The solution is evaporated to dryness the residue purified via flash column chromatography (acetone/CH2Cl2 1:3→MeOH/CH2Cl2 5:95)

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Isopropylaniline (3 mL, 21.19 mmol) was added dropwise to a solution of trichloroborane (1M in dichloromethane) (23.31 mL, 23.31 mmol) and dichloroethane (50 mL) at 0° C. and the mixture was stirred for 10 min. Next, 3-chlorobenzonitrile (5.83 g, 42.4 mmol), followed by aluminum trichloride (3.11 g, 23.31 mmol) were added and the mixture was stirred at 0° C. for 25 minutes. The ice bath was removed and the mixture was heated to 75° C. overnight. The mixture was then cooled to room temperature. Next, 6N HCl (60 mL, 10 eq) was added and the mixture was heated to 75° C. After 4 hrs, 12N HCl (10 mL) was added and heating was continued overnight at 75° C. The mixture was cooled to room temperature, transferred to an Erlenmeyer flask, diluted with ethyl acetate, cooled to 0° C., and cautiously raised to pH 10 with 50% aqueous NaOH. The resulting mixture was extracted with ethyl acetate (4×). The ethyl acetate extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a clear amber oil. The oil was suspended in a minimum of heptane and purified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min) to provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield). HPLC RT=3.876 min 10/90 to 90/10 (MeOH/H2O/0.1% TFA, Waters Sunfire C18 3.5 μm, 2.1×30 mm, 1 mL/min, 4 min gradient, wavelength=254 nm); MS(ES): m/z=274 [M+H+]; 1H NMR (400 MHz, chloroform-d) δ 7.63 (t, J=1.7 Hz, 1H), 7.55-7.48 (m, 2H), 7.44-7.29 (m, 3H), 6.65 (t, J=7.7 Hz, 1H), 6.43 (br. s., 2H), 3.11-2.87 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). were added the mixture was stirred at 0° C. for 25 minutes The ice bath was removed The mixture was then cooled to room temperature the mixture was heated to 75° C After 4 hrs heating was continued overnight at 75° C The mixture was cooled to room temperature cooled to 0° C. The resulting mixture was extracted with ethyl acetate (4×) washed with brine dried over anhydrous sodium sulfate filtered concentrated to give a clear amber oil purified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min) to provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield)

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Isopropylaniline (3 mL, 21.19 mmol) was added dropwise to a solution of trichloroborane (1M in dichloromethane) (23.31 mL, 23.31 mmol) and dichloroethane (50 mL) at 0° C. and the mixture was stirred for 10 min. Next, 3-chlorobenzonitrile (5.83 g, 42.4 mmol), followed by aluminum trichloride (3.11 g, 23.31 mmol) were added and the mixture was stirred at 0° C. for 25 minutes. The ice bath was removed and the mixture was heated to 75° C. overnight. The mixture was then cooled to room temperature. Next, 6N HCl (60 mL, 10 eq) was added and the mixture was heated to 75° C. After 4 hrs, 12N HCl (10 mL) was added and heating was continued overnight at 75° C. The mixture was cooled to room temperature, transferred to an Erlenmeyer flask, diluted with ethyl acetate, cooled to 0° C., and cautiously raised to pH 10 with 50% aqueous NaOH. The resulting mixture was extracted with ethyl acetate (4×). The ethyl acetate extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a clear amber oil. The oil was suspended in a minimum of heptane and purified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min) to provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield). HPLC RT=3.876 min 10/90 to 90/10 (MeOH/H2O/0.1% TFA, Waters Sunfire C18 3.5 μm, 2.1×30 mm, 1 mL/min, 4 min gradient, wavelength=254 nm); MS(ES): m/z=274 [M+H+]; 1H NMR (400 MHz, chloroform-d) δ 7.63 (t, J=1.7 Hz, 1H), 7.55-7.48 (m, 2H), 7.44-7.29 (m, 3H), 6.65 (t, J=7.7 Hz, 1H), 6.43 (br. s., 2H), 3.11-2.87 (m, 1H), 1.34 (d, J=6.8 Hz, 6H). were added the mixture was stirred at 0° C. for 25 minutes The ice bath was removed The mixture was then cooled to room temperature the mixture was heated to 75° C After 4 hrs heating was continued overnight at 75° C The mixture was cooled to room temperature cooled to 0° C. The resulting mixture was extracted with ethyl acetate (4×) washed with brine dried over anhydrous sodium sulfate filtered concentrated to give a clear amber oil purified on an ISCO companion chromatography system (220 g silica cartridge, eluting with 0-20% ethyl acetate/heptane, 150 mL/min) to provide Intermediate A-10 (2.85 g, 10.41 mmol, 49.1% yield)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure in COMPOUND 3 for the synthesis of intermediate 5-(3-bromophenyl)-2H-tetrazole, 3-chlorobenzonitrile (1.88 g, 13.67 mmol) was employed to obtain 5-(3-chlorophenyl)-2H-tetrazole.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure in COMPOUND 3 for the synthesis of intermediate 5-(3-bromophenyl)-2H-tetrazole, 3-chlorobenzonitrile (1.88 g, 13.67 mmol) was employed to obtain 5-(3-chlorophenyl)-2H-tetrazole.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H) washed with water The organic phase was dried concentrated A mixture of 3-chlorobenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H) washed with water The organic phase was dried concentrated A mixture of 3-chlorobenzonitrile

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in ethanol (40 mL) was added to a solution of 2.47 g (35.5 mmol) hydroxylamine hydrochloride and 1.42 g (35.5 mmol) NaOH in water (20 mL) at r.t. and then heated at 90° C. for 24 h. After cooling, the reaction mixture was concentrated, the residue diluted with water, followed by filtration and drying to afford 1.13 g (93%) of the title compound. 1H NMR: 8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H). After cooling the reaction mixture was concentrated the residue diluted with water followed by filtration drying

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in ethanol (40 mL) was added to a solution of 2.47 g (35.5 mmol) hydroxylamine hydrochloride and 1.42 g (35.5 mmol) NaOH in water (20 mL) at r.t. and then heated at 90° C. for 24 h. After cooling, the reaction mixture was concentrated, the residue diluted with water, followed by filtration and drying to afford 1.13 g (93%) of the title compound. 1H NMR: 8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H). After cooling the reaction mixture was concentrated the residue diluted with water followed by filtration drying

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under a nitrogen atmosphere, 36.7 mL (0.11 mole) of methylmagnesium bromide (3.0M in diethyl ether) is stirred, and a solution of 13.8 grams (0.10 mole) of 3-chlorobenzonitrile in 50 mL of dry tetrahydrofuran is added slowly dropwise. Upon completion of addition, the reaction mixture is warmed to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature, and about 40 mL of methanol is added dropwise. Upon completion of addition, the reaction mixture is stirred for two hours and then filtered. The filtrate is then stirred for about 18 hours with 35 grams of silica gel and 100 mL of water. The mixture is filtered, and the filtrate is diluted with ethyl acetate. The mixture is then washed with water, and the organic layer is dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure, yielding methyl 3-chlorophenyl ketone. Upon completion of addition the reaction mixture is warmed to reflux where it Upon completion of addition the reaction mixture is stirred for two hours filtered The filtrate is then stirred for about 18 hours with 35 grams of silica gel and 100 mL of water The mixture is filtered the filtrate is diluted with ethyl acetate The mixture is then washed with water the organic layer is dried with magnesium sulfate The mixture is filtered the filtrate is concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4.86 g (0.2 mol) of magnesium turnings, 30 ml of dry diethyl ether and a grain of iodine are placed in a one liter three-necked round-bottomed flask equipped with a condenser, a calcium chloride drying tube, a pressure equalizing funnel and a magnetic stirrer; the flask is purged with nitrogen, and 21.8 g (0.2 mol) of ethyl bromide in 30 ml of dry diethyl ether are then added. The mixture is then heated under reflux for one hour and left to cool. At ambient temperature, 16.51 g (0.12 mol) of 3-chlorobenzonitrile in 70 ml of dry diethyl ether are then added. A copious precipitate forms. The mixture is stirred overnight at ambient temperture and then cooled in an ice bath and hydrolysed by slowly adding 50 ml of water and then about 100 ml of 6N hydrochloric acid until the pH is acid. The mixture is stirred for one and a half hours and then extracted with ethyl acetate. The organic extract is then washed twice with water, dried and concentrated on a rotary evaporator. This gives 26 g of an orange oil, which is concentrated in vacuo to give about 18.2 g of ochre crystals of 3'-chloropropiophenone melting at about 40° C. equipped with a condenser, a calcium chloride drying tube are then added The mixture is then heated under reflux for one hour left to cool cooled in an ice bath The mixture is stirred for one and a half hours extracted with ethyl acetate The organic extract is then washed twice with water dried concentrated on a rotary evaporator This gives 26 g of an orange oil, which is concentrated in vacuo