tert-butyl N-[4-(aminomethyl)phenyl]carbamate

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 173 (470 mg, 1.3 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 128 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (289 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 174 as white solid (540 mg, 68%). 1H NMR (DMSO): δ 1.61 (s, 9H), 3.02 (m, 2H), 4.24 (s, 2H), 4.60 (m, 1H), 5.22 (s, 4H), 6.38 (d, 1H, J=7.6 Hz), 6.62 (m, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.75 (m, 2H), 7.21 (m, 4H), 7.47 (m, 11H), 9.35 (s, 1H). to warm to room temperature refluxed for 1 h the resulting solution was stirring at room temperature overnight The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (AcOEt/Hexane 5/5)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 160 (530 mg, 1.76 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 173 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (391 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 161 as white solid (960 mg, 99%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 1.61 (s, 9H), 3.01 (dd, 1H, J=13.8, 8.3 Hz), 3.09 (dd, 1H, J=13.8, 5.0 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.24 (d, 2H, J=5.1 Hz), 4.57 (s, 1H), 5.20 (s, 2H), 6.38 (d, 1H, J=7.8 Hz), 6.61 (t, 1H, J=5.1 Hz), 6.90 (d, 1H, J=7.1 Hz), 7.02 (d, 1H, J=8.7 Hz), 7.21 (d, 2H, J=8.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.50 (m, 5H), 7.57 (d, 2H, J=8.1 Hz), 9.35 (s, 1H). to warm to room temperature refluxed for 1 h the resulting solution was stirring at room temperature overnight The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (AcOEt/Hexane 5/5)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-ethyl 2-amino-5-(benzyloxycarbonylamino)pentanoate (1 equivalent, 146 mg, 0.50 mmol) was dissolved in anhydrous THF (4 mL) and trisphosgene (0.33 equivalent, 49 mg, 0.17 mmol) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, and then refluxed for 2 h. Tert-butyl-N-[4-(aminomethyl)phenyl]carbamate (1 equivalent, 110 mg, 0.50 mmol) and triethylamine (2 equivalent, 138 μl, 1 mmol) were added successively and the resulting solution was stirring at room temperature overnight. The reaction mixture was concentrated, washed by 30 ml of NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (EDP/EtOAc) to afford the urea protected (146 mg, 54%) as a colourless oil Rf=0.59 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (s, 5H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.84-6.66 (m, 1H), 5.62-5.42 (m, 2H), 5.28-5.10 (m, 1H), 5.00 (s, 2H), 4.46-4.29 (m, 1H), 4.18 (d, J=5.5 Hz, 2H), 4.05 (q, J=7.1 Hz, 3H), 3.16-3.00 (m, 2H), 1.82-1.28 (m, 4H), 1.43 (s, 9H), 1.16 (t, J=7.2 Hz, 3H). to warm to room temperature refluxed for 2 h the resulting solution was stirring at room temperature overnight The reaction mixture was concentrated washed by 30 ml of NaHCO3 extracted by 3×30 ml EtOAc The organic phase was dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (EDP/EtOAc)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-ethyl 6-acetamido-2-aminohexanoate 186 (1 equivalent, 120 mg, 0.55 mmol) was dissolved in anhydrous THF (4 mL) and trisphosgene (0.33 equivalent, 55 mg, 0.18 mmol) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 2 h. tert-butyl-N-[4-(aminomethyl)phenyl]carbamate (1 equivalent, 123 mg, 0.55 mmol) and triethylamine (2 equivalent, 154 μl, 1.1 mmol) were added successively and the resulting solution was stirring at room temperature overnight. The reaction mixture was concentrated, washed by 30 ml of NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH) to afford the urea protected (21 mg, 8%) Rf=0.18 (CH2Cl2/MeOH 95/5). 1H NMR (200 MHz, CDCl3) δ 7.30 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 6.68 (s, 1H), 6.10-5.90 (m, 1H), 5.43 (d, J=7.7 Hz, 1H), 5.30 (t, J=5.7 Hz, 1H), 4.51-4.35 (m, 1H), 4.35-4.25 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.26-3.08 (m, 2H), 1.91 (s, 3H), 1.85-1.15 (m, 6H), 1.50 (s, 9H), 1.25 (t, J=7.1 Hz, 3H). Finally, the urea was dissolved in 2 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture was concentrated and purified on reverse phase (H2O/MeCN) to afford the urea deprotected (7 mg, 44%) as a colorless oil Rf=0.42 (CH2Cl2/MeOH 90110). 1H NMR (200 MHz, CDCl3): δ 7.06 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.4 Hz, 2H), 6.15-5.92 (m, 1H), 5.36 (d, J=8.1 Hz, 1H), 5.16 (t, J=5.8, 1H), 4.55-4.35 (m, 1H), 4.22 (d, J=5.6 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.28-3.10 (m, 2H), 1.92 (s, 3H), 1.90-1.27 (m, 6H), 1.25 (t, J=7.1 Hz, 3H). HPLC method A tr=6.75 nm (91.30%). ESI-MS m/z: 365.2 [M+H]+. to warm to room temperature were added successively the resulting solution was stirring at room temperature overnight The reaction mixture was concentrated washed by 30 ml of NaHCO3 extracted by 3×30 ml EtOAc The organic phase was dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (CH2Cl2/MeOH)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 173 (470 mg, 1.3 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 128 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (289 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 174 as white solid (540 mg, 68%). 1H NMR (DMSO): δ 1.61 (s, 9H), 3.02 (m, 2H), 4.24 (s, 2H), 4.60 (m, 1H), 5.22 (s, 4H), 6.38 (d, 1H, J=7.6 Hz), 6.62 (m, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.75 (m, 2H), 7.21 (m, 4H), 7.47 (m, 11H), 9.35 (s, 1H). to warm to room temperature refluxed for 1 h the resulting solution was stirring at room temperature overnight The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (AcOEt/Hexane 5/5)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 160 (530 mg, 1.76 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 173 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (391 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 161 as white solid (960 mg, 99%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 1.61 (s, 9H), 3.01 (dd, 1H, J=13.8, 8.3 Hz), 3.09 (dd, 1H, J=13.8, 5.0 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.24 (d, 2H, J=5.1 Hz), 4.57 (s, 1H), 5.20 (s, 2H), 6.38 (d, 1H, J=7.8 Hz), 6.61 (t, 1H, J=5.1 Hz), 6.90 (d, 1H, J=7.1 Hz), 7.02 (d, 1H, J=8.7 Hz), 7.21 (d, 2H, J=8.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.50 (m, 5H), 7.57 (d, 2H, J=8.1 Hz), 9.35 (s, 1H). to warm to room temperature refluxed for 1 h the resulting solution was stirring at room temperature overnight The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (AcOEt/Hexane 5/5)

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

Procedure: Use a method similar to the General Procedure 1-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.32 g, 0.76 mmol) with a solution of 4-(tert-butoxycarbonylamino)-benzylamine (0.338 g, 1.524 mmol) in anhydrous toluene/dioxane (4:1, 10 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1 gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over 30 min and 1:1 over 3 min; 35 mL/min) to obtain the desired intermediate as a yellow oil (0.338 g, 89%). MS (ES+) m/z: 498.2 (M+H)+. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:1 gradient over 30 min; 3:1 over 3 min; 3:1 to 1:1 gradient over 30 min and 1:1 over 3 min; 35 mL/min)

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

Procedure: Add a solution of 4-(tert-butoxycarbonylamino)-benzonitrile (1 g, 4.58 mmol) in THF/iso-propanol (1:1, 142 mL) to 10% Pd/C (Degussa type E101, 0.56 g, 0.26 mmol) via syringe under N2. Purge the reaction mixture with nitrogen and submit the mixture to hydrogenation at 50 psi overnight. Filter the catalyst through Celite® and wash thoroughly with iso-propanol (100 mL) and THF (100 mL). Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0 to 95:5 gradient over 30 min; 95:5 over 3 min; 95:5 to 9:1 gradient over 30 min and 9:1 over 30 min) to obtain the desired intermediate (0.364 g, 36%). MS (ES−) m/z: 220.1 (M−2H)−. Purge the reaction mixture with nitrogen at 50 psi overnight Filter the catalyst through Celite® wash thoroughly with iso-propanol (100 mL) and THF (100 mL) Concentrate in vacuo purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0 to 95:5 gradient over 30 min; 95:5 over 3 min; 95:5 to 9:1 gradient over 30 min and 9:1 over 30 min)