2-chloro-3-fluorobenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: BH3.THF in THF (1.0 M, 50.0 ml) was carefully added into the THF (40.0 ml) solution of 2-chloro-3-fluorobenzonitrile (662 mg, 4.17 mmol) at rt. The resulting mixture was heated at 70° C. under an atmosphere of nitrogen for 16 h. After cooling to ambient temperature, conc. HCl (5.18 ml, 62.5 mmol) was added slowly. The combined mixture was heated at 70° C. for 30 min. After that time, the mixture was concentrated in vacuo to remove most of solvent, water (20 ml) was added, and the mixture was extracted with Et2O (3×30 ml). The extracts were washed with water (20 ml). The combined aqueous layers were basified by saturated Na2CO3 until pH=9 and extracted with EtOAc (3×50 ml). These EtOAc extracts were washed with brine (50 ml) dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.67 (brs, 2H), 3.97 (s, 2H), 7.03-7.09 (m, 1H), 7.17-7.26 (m, 2H). MS(ES+): m/z=160.14/162.09 (64/32) [MH+]. HPLC: tR=0.40 & 0.70 min (polar—5 min, ZQ3; peak splitting). After cooling to ambient temperature The combined mixture was heated at 70° C. for 30 min After that time, the mixture was concentrated in vacuo to remove most of solvent, water (20 ml) was added the mixture was extracted with Et2O (3×30 ml) The extracts were washed with water (20 ml) extracted with EtOAc (3×50 ml) These EtOAc extracts were washed with brine (50 ml) dried over MgSO4 filtered concentrated in vacuo

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

実験手順: 320 ml (0.32 mmol) of a 1 molar solution of lithium hexamethyl disilazide (LiHMDS) in hexane are placed in 800 ml diethyl ether and combined at ambient temperature with 25.0 g (0.161) 2-chloro-3-fluoro-benzonitrile. The mixture is stirred for 2 h at ambient temperature and after cooling to 0° C. it is combined with 280 ml 3 normal hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried. after cooling to 0° C. it The precipitate formed filtered washed with water dried

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of NaBH4 (24.3 g, 0.643 mol) in THF (400 mL) was added TFA (48 mL, 0.643 mol) slowly at 0° C. After the addition was completed, the mixture was stirred at 0° C. for about 20 min. 2-Chloro-3-fluorobenzonitrile (20 g, 0.128 mol) in THF (100 mL) was then added slowly into the mixture at 0° C. The mixture was stirred from 0° C. to RT until no starting material was observed by LCMS. Half of the solvent was removed, then 10% HCl (250 mL) was added slowly into the residue at 0° C. The mixture was warmed up and heated to reflux until no boron complex was observed by LCMS. The mixture was extracted by diethyl ether. The aqueous solution was basified to pH 8-10 using NaOH (3 N), extracted with EtOAc. The organic layers were combined and concentrated to about 300 mL. HCl (4 N, 50 mL) was added slowly into the resulting solution. The white solid was precipitated and collected by filtration to give (2-chloro-3-fluorophenyl)methanamine hydrochloride (21 g, 84%). LRMS (M+H+) m/z 160.1. After the addition The mixture was stirred from 0° C. to RT until no starting material Half of the solvent was removed 10% HCl (250 mL) was added slowly into the residue at 0° C The mixture was warmed up heated to reflux until no boron complex The mixture was extracted by diethyl ether extracted with EtOAc concentrated to about 300 mL HCl (4 N, 50 mL) was added slowly into the resulting solution The white solid was precipitated collected by filtration