(2-chloro-3-fluorophenyl)methanamine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1. The organic layer was then washed with brine dried over Na2SO4 concentrated under reduced pressure The resulting residue was re-dissolved in THF (300 mL) The reaction mixture was stirred for 2 h the reaction reaction completion The mixture was concentrated under reduced pressure purified on silica gel column a mixture of hexanes and EtOAc

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-propyl ester (2.9 g, 5.93 mmol) in DCM (200 mL) was added TFA (12 mL) at 0° C. The mixture was stirred for 2 h, concentrated under reduced pressure, and re-dissolved in THF (10 mL) and DIEA (6.6 mL, 37.8 mmol). To this THF solution was added pre-stirred solution of 4-nitrophenylchloroformate (1.33 g, 6.62 mmol), 2-chloro-3-fluorobenzylamine (1.0 g, 6.3 mmol), and DIEA (1.2 mL, 6.9 mmol) in THF (85 mL) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. The mixture was concentrated under reduced pressure, re-dissolved in MeOH, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester (1.1 g, 45% over two steps). LRMS (M+H+) m/z 535.1. concentrated under reduced pressure re-dissolved in THF (10 mL) The reaction mixture was stirred for 2 h the reaction The mixture was concentrated under reduced pressure re-dissolved in MeOH filtered purified by RP-HPLC a mixture of acetonitrile and H2O

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

実験手順: A 5 liter 3-neck RBF was charged with 4-nitrophenylchloroformate (126.3 g, 627 mmol), DCM (3000 mL), under N2 atm and chilled in a 0° C. ice bath. A solution of 2-chloro,3-fluorobenzylamine (100.0 g, 627 mmol) followed by solid Sodium Carbonate (155.0 g, 1460 mmol) was quickly added in one portion into the reaction solution. The reaction mixture was stirred at 0° C. for 1 h and an LC/MS was taken to confirm consumption of the starting material and presence of the nitrophenyl intermediate. The reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was filtered, and the filtrate was concentrated to give a white solid. The solid was redissolved with 600 ml of DCM and heated to 40° C. until all of the material went into solution. The solution was chilled in a 0° C. ice bath to form crystals. The crystals were collected and dried under vacuum to give 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate. (150 g, 75%). was quickly added in one portion into the reaction solution consumption of the starting material and presence of the nitrophenyl intermediate to warm to room temperature stirred for approximately 2 h The mixture was filtered the filtrate was concentrated to give a white solid heated to 40° C. until all of the material The solution was chilled in a 0° C. ice bath to form crystals The crystals were collected dried under vacuum

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1. The organic layer was then washed with brine dried over Na2SO4 concentrated under reduced pressure The resulting residue was re-dissolved in THF (300 mL) The reaction mixture was stirred for 2 h the reaction reaction completion The mixture was concentrated under reduced pressure purified on silica gel column a mixture of hexanes and EtOAc

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-propyl ester (2.9 g, 5.93 mmol) in DCM (200 mL) was added TFA (12 mL) at 0° C. The mixture was stirred for 2 h, concentrated under reduced pressure, and re-dissolved in THF (10 mL) and DIEA (6.6 mL, 37.8 mmol). To this THF solution was added pre-stirred solution of 4-nitrophenylchloroformate (1.33 g, 6.62 mmol), 2-chloro-3-fluorobenzylamine (1.0 g, 6.3 mmol), and DIEA (1.2 mL, 6.9 mmol) in THF (85 mL) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. The mixture was concentrated under reduced pressure, re-dissolved in MeOH, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester (1.1 g, 45% over two steps). LRMS (M+H+) m/z 535.1. concentrated under reduced pressure re-dissolved in THF (10 mL) The reaction mixture was stirred for 2 h the reaction The mixture was concentrated under reduced pressure re-dissolved in MeOH filtered purified by RP-HPLC a mixture of acetonitrile and H2O

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

実験手順: A 5 liter 3-neck RBF was charged with 4-nitrophenylchloroformate (126.3 g, 627 mmol), DCM (3000 mL), under N2 atm and chilled in a 0° C. ice bath. A solution of 2-chloro,3-fluorobenzylamine (100.0 g, 627 mmol) followed by solid Sodium Carbonate (155.0 g, 1460 mmol) was quickly added in one portion into the reaction solution. The reaction mixture was stirred at 0° C. for 1 h and an LC/MS was taken to confirm consumption of the starting material and presence of the nitrophenyl intermediate. The reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was filtered, and the filtrate was concentrated to give a white solid. The solid was redissolved with 600 ml of DCM and heated to 40° C. until all of the material went into solution. The solution was chilled in a 0° C. ice bath to form crystals. The crystals were collected and dried under vacuum to give 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate. (150 g, 75%). was quickly added in one portion into the reaction solution consumption of the starting material and presence of the nitrophenyl intermediate to warm to room temperature stirred for approximately 2 h The mixture was filtered the filtrate was concentrated to give a white solid heated to 40° C. until all of the material The solution was chilled in a 0° C. ice bath to form crystals The crystals were collected dried under vacuum

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1. The organic layer was then washed with brine dried over Na2SO4 concentrated under reduced pressure The resulting residue was re-dissolved in THF (300 mL) The reaction mixture was stirred for 2 h the reaction reaction completion The mixture was concentrated under reduced pressure purified on silica gel column a mixture of hexanes and EtOAc

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of Isoquinolin-3-yl-carbamic acid 2-(tert-butoxycarbonyl-methyl-amino)-3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-propyl ester (2.9 g, 5.93 mmol) in DCM (200 mL) was added TFA (12 mL) at 0° C. The mixture was stirred for 2 h, concentrated under reduced pressure, and re-dissolved in THF (10 mL) and DIEA (6.6 mL, 37.8 mmol). To this THF solution was added pre-stirred solution of 4-nitrophenylchloroformate (1.33 g, 6.62 mmol), 2-chloro-3-fluorobenzylamine (1.0 g, 6.3 mmol), and DIEA (1.2 mL, 6.9 mmol) in THF (85 mL) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. The mixture was concentrated under reduced pressure, re-dissolved in MeOH, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H2O to give isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-3-(2,3-dihydroxy-propoxy)-propyl ester (1.1 g, 45% over two steps). LRMS (M+H+) m/z 535.1. concentrated under reduced pressure re-dissolved in THF (10 mL) The reaction mixture was stirred for 2 h the reaction The mixture was concentrated under reduced pressure re-dissolved in MeOH filtered purified by RP-HPLC a mixture of acetonitrile and H2O

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

実験手順: A 5 liter 3-neck RBF was charged with 4-nitrophenylchloroformate (126.3 g, 627 mmol), DCM (3000 mL), under N2 atm and chilled in a 0° C. ice bath. A solution of 2-chloro,3-fluorobenzylamine (100.0 g, 627 mmol) followed by solid Sodium Carbonate (155.0 g, 1460 mmol) was quickly added in one portion into the reaction solution. The reaction mixture was stirred at 0° C. for 1 h and an LC/MS was taken to confirm consumption of the starting material and presence of the nitrophenyl intermediate. The reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The mixture was filtered, and the filtrate was concentrated to give a white solid. The solid was redissolved with 600 ml of DCM and heated to 40° C. until all of the material went into solution. The solution was chilled in a 0° C. ice bath to form crystals. The crystals were collected and dried under vacuum to give 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate. (150 g, 75%). was quickly added in one portion into the reaction solution consumption of the starting material and presence of the nitrophenyl intermediate to warm to room temperature stirred for approximately 2 h The mixture was filtered the filtrate was concentrated to give a white solid heated to 40° C. until all of the material The solution was chilled in a 0° C. ice bath to form crystals The crystals were collected dried under vacuum

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1. The organic layer was then washed with brine dried over Na2SO4 concentrated under reduced pressure The resulting residue was re-dissolved in THF (300 mL) The reaction mixture was stirred for 2 h the reaction reaction completion The mixture was concentrated under reduced pressure purified on silica gel column a mixture of hexanes and EtOAc