tert-butyl 4-(aminomethyl)benzoate

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

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

Procedure: 2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester The reaction was partitioned between 1M HCl and dichloromethane The organic layer was dried (magnesium sulfate) filtered rotary evaporated

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

Procedure: 2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester The reaction was partitioned between 1M HCl and dichloromethane The organic layer was dried (magnesium sulfate) filtered rotary evaporated

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

Procedure: Instead of the starting material, that is, the compound S11, of Reference Example 43, tert-butyl 4-(aminomethyl)benzoate was used, and instead of (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate, the compound S45 was used for a similar reaction as in Reference Example 43 to obtain tert-butyl 4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoate (compound S47a).

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

Procedure: To a stirred solution of 2-chloro-5-fluoronicotinic acid (2.0 g, 10 mmol) and tert-butyl 4-(aminomethyl)benzoate (1.65 g, 8 mmol) in dichloromethane (25 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.88 g, 15 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (1.53 g, 10 mmol), and triethylamine (5 mL). After being stirred overnight, the reaction mixture was poured into water (100 mL). The organic layer_was separated and the aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (100 mL), dried (sodium sulfate), and evaporated. The residue was purified by flush column chromatography on silica gel (200 g) eluting with dichloromethane/ethyl acetate (20/1) to afford 2.39 g (82%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.33 (1H, d, J=3.1 Hz), 7.97 (2H, d, J=8.4 Hz), 7.91 (1H, dd, J=7.9, 3.1 Hz), 7.40 (2H, d, J=8.4 Hz), 7.04 (1H, br.s), 4.70 (2H, d, J=5.9 Hz), 1.58 (9H, s). The organic layer_was separated the aqueous layer was extracted with dichloromethane (50 mL×2) The combined organic layers were washed with brine (100 mL) dried (sodium sulfate) evaporated The residue was purified by flush column chromatography on silica gel (200 g) eluting with dichloromethane/ethyl acetate (20/1)

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

Procedure: 2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester The reaction was partitioned between 1M HCl and dichloromethane The organic layer was dried (magnesium sulfate) filtered rotary evaporated