N-[(3,5-dichlorophenyl)methyl]-1-(4-fluorophenyl)methanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (48 mg, 0.10 mol) in DMF, were added. N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (28 mg, 0.1 mmol), HATU (48 mg, 0.15 mmol), and DIPEA (0.052 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 h and purified by preparative HPLC (Column YMC S5 ODS C18 20×100 mm; Solvent A=10% MeOH-90% H2O with 0.1% TFA; Solvent B=10% H2O-90% MeOH with 0.1% TFA). The desired fractions were combined, concentrated and lyophilized to give the title compound (40 mg, 51%) as a white solid. 1H NMR (CD3OD) δ 7.71 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.5 Hz), 7.37-7.05 (m, 13H), 6.85 (t, 2H, J=8.8 Hz), 4.70 (br, 1H), 4.64 (br, 1H), 4.54 (s, 2H), 4.50 (s, 2H), 4.46 (br, 1H), 4.42 (br, 1H). MS (ESI): 750.8 (M+H)+. purified by preparative HPLC (Column YMC S5 ODS C18 20×100 mm; Solvent A=10% MeOH-90% H2O with 0.1% TFA; Solvent B=10% H2O-90% MeOH with 0.1% TFA) concentrated

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

Procedure: A solution of N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (0.5 g, 1.76 mmol), EDCI.HCl (0.47 g, 2.46 mmol), 3-(Boc-aminomethyl)benzoic acid (0.53 g, 2.11 mmol) and HOBT.H2O (0.16 g, 1.06 mmol) in DMF (8 mL) was stirred at rt for 20 h. The residue was diluted with ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with 1N NaOH solution, brine, dried over MgSO4, concentrated and the residue was purified by flash chromatography on silica gel (Eluent: A: CH2Cl2, B: ethyl acetate; condition: 100% A to 15% B. (35 min gradient) to obtain the desired product as a white solid (0.81 g, 89%). 1H NMR (CDCl3): δ 7.42-7.32 (m, 5H), 7.17-6.99 (m, 6H), 4.88-4.63 (m, 2H), 4.42-4.35 (m, 4H), 1.47 (s, 9H). The organic layer was separated washed with 1N NaOH solution, brine dried over MgSO4 concentrated the residue was purified by flash chromatography on silica gel (Eluent

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

Procedure: To a solution of N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (1.40 g, 4.91 mmol) in THF (15 mL) was added 3-cyanobenzene-1-sulfonyl chloride (0.9 g, 4.46 mmol) and Et3N (1.22 mL, 8.93 mmol) at rt for 2 h. Additional sulfonyl chloride (0.35 g) and Et3N (0.5 mL) were added. The reaction mixture was stirred at rt for 15 h. The mixture was concentrated and the residue was diluted with ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with brine, saturated aq NaHCO3 solution, dried over MgSO4, and concentrated to give a glassy material which was purified by flash silica gel column chromatography on silica gel (ISCO. Column: 24 g. Eluent: A: hexane. B: ethyl acetate. Condition: A to 25% of B (50 min gradient) to obtain the desired product as a white solid (1.8 g, 81%). 1H NMR (CDCl3): δ 8.08-8.02 (m, 2H), 7.93-7.90 (m, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.25-7.24 (m, 1H), 7.13-7.09 (m, 2H), 6.98 (t, J=8.0 Hz, 2H), 6.90 (d, J=4.0 Hz, 2H), 4.38 (s, 2H), 4.30 (s, 2H); MS (ESI): [M−H]−=506.9. The mixture was concentrated the residue was diluted with ethyl acetate and 1 N HCl solution The organic layer was separated washed with brine, saturated aq NaHCO3 solution dried over MgSO4 concentrated to give a glassy material which was purified by flash silica gel column chromatography on silica gel (ISCO

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

Procedure: To a solution of 3,5-dichlorobenzaldehyde (3.9 g, 22.3 mmol) in 2-propanol (20 mL) and CH2Cl2 (20 mL) was added 4-fluorobenzylamine (2.93 mL, 25.6 mmol). The resulting mixture was stirred at rt for 1 h. The mixture was cooled to ice bath temperature and was treated with sodium triacetoxyborohydride (7.56 g, 35.7 mmol) under N2 atmosphere. The resulting mixture was stirred at rt for 22 h. To the reaction mixture was added saturated aq NaHCO3 solution and it was stirred for 0.2 h, and concentrated in vacuo. The residue was mixed with ethyl acetate and saturated aq NaHCO3 solution. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash silica gel column chromatography on silica gel to obtain (ISCO. Condition: 40 g column. Eluents: 0-6% of B, gradient, solvent A: CH2Cl2, solvent B: ethyl acetate (5% 2 M ammonia in MeOH). 35 min run. The desired product peak came from 5 min to 15 min) the desired product as a colorless oil (5.6 g, 80%). 1H NMR (CDCl3): δ 7.34-7.27 (m, 5H), 7.08-7.03 (m, 2H), 3.78 (s, 2H), 3.77 (s, 2H), 1.85 (bs, 1H); MS (ESI): [M+H]+=284.0. The mixture was cooled to ice bath temperature The resulting mixture was stirred at rt for 22 h was stirred for 0.2 h concentrated in vacuo The residue was mixed with ethyl acetate and saturated aq NaHCO3 solution The organic layer was separated washed with brine dried over MgSO4 concentrated The residue was purified by flash silica gel column chromatography on silica gel to obtain (ISCO 35 min

Conditions: temp:0.00; pressure:0.00; stir: