N-[[4-(aminomethyl)phenyl]methyl]cyclopropanecarboxamide

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

Procedure: Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (458 mg, 1.076 mmol) with 4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (275 mg, 1.346 mmol) using tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.108 mmol), BINAP (134 mg, 0.215 mmol) and cesium carbonate (710 mg, 2.17 mmol) in toluene (17 mL). Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 3:1 over 30 min, 1:1; 50 mL/min) to obtain 7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg, 65%) as a white solid. MS (ES+) m/z: 480 (M+H)+. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 3:1 over 30 min, 1:1; 50 mL/min)

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

Procedure: Dissolve N-(tert-butoxycarbonyl)-4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (529 mg, 1.74 mmol) in EtOAc (20 mL) and MeOH (15 mL). Bubble hydrogen chloride through the solution for 15 min, and stir the mixture overnight at room temperature. Concentrate the mixture in vacuo and dissolve the resulting solid in water. Adjust the pH to 9-11 with 20% aqueous K2CO3 (w/w %) and extract three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 4:1 over 5 min, 1:1 over 10 min, 1:3; 50 mL/min) to obtain the desired intermediate (275 mg, 77%). MS (APCI+) m/z: 188 (M-NH3+H)+. Concentrate the mixture in vacuo dissolve the resulting solid in water extract three times with chloroform/iso-propanol (3:1) Dry the combined organic extracts over MgSO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel (40 g, pre-packed cartridge) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 4:1 over 5 min, 1:1 over 10 min, 1:3; 50 mL/min)