(2-chloro-3-fluorophenyl)methanamine;hydrochloride

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

Procedure: To a solution of 4-nitrophenylchloroformate (7.69 g, 38.3 mmol) in THF (20 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (6.09 g, 38.3 mmol) and DIEA (7.9 mL, 47.9 mmol) in THF (20 mL). The resulting solution was stirred at RT for 20 min. The reaction mixture was added into a solution of (S)-1-(tert-butyldimethylsilyloxy)-N-methylpent-4-en-2-amine (31.9 mmol) in THF (100 mL). The resulting solution was stirred at RT overnight. The solvent was removed and the resulting residue was re-dissolved in EtOAc (500 mL). The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (10.08 g, 76%) as a white solid. LRMS (M+H+) m/z 415.2. The resulting solution was stirred at RT overnight The solvent was removed the resulting residue was re-dissolved in EtOAc (500 mL) The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of DCM and MeOH

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

Procedure: To a solution of 4-nitrophenylchloroformate (460 mg, 2.29 mmol) in THF (20 mL) was added 2-chloro-3-fluorobenzylamine hydrochloride (626 mg, 2.29 mmol) and DIEA (0.76 mL, 4.58 mmol) and the mixture was stirred at RT until TLC showed complete consumption of 2-chloro-3-fluorobenzylamine. The mixture was then added into a solution of (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (500 mg, 1.91 mmol) in THF (10 mL). The mixture was stirred overnight, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (401 mg, 47%). LRMS (M+H+) m/z 448.3. consumption of 2-chloro-3-fluorobenzylamine The mixture was stirred overnight concentrated purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 4-nitrophenylchloroformate 8 (2.28 g, 11.3 mmol) in THF (10 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (2.22 g, 11.3 mmol) and DIEA (5.38 mL, 30.9 mmol) in THF (10 mL). The resulting solution was stirred at RT for 20 min. The reaction solution was added into a solution of (S)-2-(methylamino)pent-4-en-1-ol hydrochloride (10.3 mmol), DIEA (5.38 mL, 30.9 mmol) in THF (100 mL). The resulting solution was stirred at RT for 1 h. The solvent was removed, and the resulting residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(1-hydroxypent-4-en-2-yl)-1-methylurea (2.56 g, 82%) as a white solid. LRMS (M+H+) m/z 301.2. The resulting solution was stirred at RT for 1 h The solvent was removed the resulting residue was purified on silica gel column a mixture of DCM and MeOH

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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

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

Procedure: To a solution of 4-nitrophenylchloroformate (7.69 g, 38.3 mmol) in THF (20 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (6.09 g, 38.3 mmol) and DIEA (7.9 mL, 47.9 mmol) in THF (20 mL). The resulting solution was stirred at RT for 20 min. The reaction mixture was added into a solution of (S)-1-(tert-butyldimethylsilyloxy)-N-methylpent-4-en-2-amine (31.9 mmol) in THF (100 mL). The resulting solution was stirred at RT overnight. The solvent was removed and the resulting residue was re-dissolved in EtOAc (500 mL). The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (10.08 g, 76%) as a white solid. LRMS (M+H+) m/z 415.2. The resulting solution was stirred at RT overnight The solvent was removed the resulting residue was re-dissolved in EtOAc (500 mL) The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of DCM and MeOH

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

Procedure: To a solution of 4-nitrophenylchloroformate (460 mg, 2.29 mmol) in THF (20 mL) was added 2-chloro-3-fluorobenzylamine hydrochloride (626 mg, 2.29 mmol) and DIEA (0.76 mL, 4.58 mmol) and the mixture was stirred at RT until TLC showed complete consumption of 2-chloro-3-fluorobenzylamine. The mixture was then added into a solution of (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (500 mg, 1.91 mmol) in THF (10 mL). The mixture was stirred overnight, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (401 mg, 47%). LRMS (M+H+) m/z 448.3. consumption of 2-chloro-3-fluorobenzylamine The mixture was stirred overnight concentrated purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 4-nitrophenylchloroformate 8 (2.28 g, 11.3 mmol) in THF (10 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (2.22 g, 11.3 mmol) and DIEA (5.38 mL, 30.9 mmol) in THF (10 mL). The resulting solution was stirred at RT for 20 min. The reaction solution was added into a solution of (S)-2-(methylamino)pent-4-en-1-ol hydrochloride (10.3 mmol), DIEA (5.38 mL, 30.9 mmol) in THF (100 mL). The resulting solution was stirred at RT for 1 h. The solvent was removed, and the resulting residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(1-hydroxypent-4-en-2-yl)-1-methylurea (2.56 g, 82%) as a white solid. LRMS (M+H+) m/z 301.2. The resulting solution was stirred at RT for 1 h The solvent was removed the resulting residue was purified on silica gel column a mixture of DCM and MeOH

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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

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

Procedure: To a solution of 4-nitrophenylchloroformate (7.69 g, 38.3 mmol) in THF (20 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (6.09 g, 38.3 mmol) and DIEA (7.9 mL, 47.9 mmol) in THF (20 mL). The resulting solution was stirred at RT for 20 min. The reaction mixture was added into a solution of (S)-1-(tert-butyldimethylsilyloxy)-N-methylpent-4-en-2-amine (31.9 mmol) in THF (100 mL). The resulting solution was stirred at RT overnight. The solvent was removed and the resulting residue was re-dissolved in EtOAc (500 mL). The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-1-(1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea (10.08 g, 76%) as a white solid. LRMS (M+H+) m/z 415.2. The resulting solution was stirred at RT overnight The solvent was removed the resulting residue was re-dissolved in EtOAc (500 mL) The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), saturated NaHCO3, and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of DCM and MeOH

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

Procedure: To a solution of 4-nitrophenylchloroformate (460 mg, 2.29 mmol) in THF (20 mL) was added 2-chloro-3-fluorobenzylamine hydrochloride (626 mg, 2.29 mmol) and DIEA (0.76 mL, 4.58 mmol) and the mixture was stirred at RT until TLC showed complete consumption of 2-chloro-3-fluorobenzylamine. The mixture was then added into a solution of (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (500 mg, 1.91 mmol) in THF (10 mL). The mixture was stirred overnight, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl)-1-methylurea (401 mg, 47%). LRMS (M+H+) m/z 448.3. consumption of 2-chloro-3-fluorobenzylamine The mixture was stirred overnight concentrated purified on RP-HPLC a mixture of acetonitrile and H2O

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

Procedure: To a solution of 4-nitrophenylchloroformate 8 (2.28 g, 11.3 mmol) in THF (10 mL) was added a solution of 2-chloro-3-fluorobenzylamine hydrochloride (2.22 g, 11.3 mmol) and DIEA (5.38 mL, 30.9 mmol) in THF (10 mL). The resulting solution was stirred at RT for 20 min. The reaction solution was added into a solution of (S)-2-(methylamino)pent-4-en-1-ol hydrochloride (10.3 mmol), DIEA (5.38 mL, 30.9 mmol) in THF (100 mL). The resulting solution was stirred at RT for 1 h. The solvent was removed, and the resulting residue was purified on silica gel column using a mixture of DCM and MeOH to give (S)-3-(2-chloro-3-fluorobenzyl)-1-(1-hydroxypent-4-en-2-yl)-1-methylurea (2.56 g, 82%) as a white solid. LRMS (M+H+) m/z 301.2. The resulting solution was stirred at RT for 1 h The solvent was removed the resulting residue was purified on silica gel column a mixture of DCM and MeOH

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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