| 51% |
Stage #1: 4-amino-2,5-dimethylbenzoic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 24℃; for 1h;
Stage #2: (2,6-dimethoxyphenyl)methanamine In N,N-dimethyl-formamide for 18h; |
8B Example 8B: Preparation of 4-amino-N-(2,6-dimethoxybenzyl)-2,5-dimethylbenzamide.
In a 20 mL vial equipped with a stir bar in open air, 4-amino-2,5-dimethylbenzoic acid (281 mg, 1.70 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (276 mg, 2.04 mmol), and EDCI (392 mg, 2.04 mmol) were dissolved in DMF (10.0 mL). DIPEA (0.357 mL, 2.04 mmol) was then added. The vial was capped, and the dark orange solution was stirred for an hour at room temperature. After 1 h, (2,6-dimethoxyphenyl)methanamine (397 mg, 2.04 mmol) was added and the mixture was stirred overnight. The reaction was judged complete after 18 h as determined by UPLC analysis. The reaction mixture was diluted with EtOAc (15 mL) and was washed with deionized water (5x). The organic layer was washed with saturated aqueous sodium bicarbonate (NaHCO3), dried over MgSO4, filtered, and concentrated under reduced pressure to afford a dark yellow solid. The resulting material was purified by flash column chromatography (SiO2, 0% ^40% 3:1 EtOAc:EtOH in hexanes) to afford the title compound (270 mg, 51% yield) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.57 (d, J = 8.3 Hz, 2H), 6.45 (s, 1H), 6.08 (br s, 2H), 4.77 - 4.59 (m, 2H), 3.85 (s, 6H), 3.67 (s, 1H), 2.36 (s, 3H), 2.09 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.58, 158.87, 145.97, 135.69, 130.00, 129.05, 126.96, 119.02, 117.00, 114.51, 103.99, 56.00, 32.99, 19.99, 16.83; ESIMS m/z 315 ([M+H]+). |
| 51% |
Stage #1: 4-amino-2,5-dimethylbenzoic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 24℃; for 1h;
Stage #2: (2,6-dimethoxyphenyl)methanamine In N,N-dimethyl-formamide for 18h; |
8B Example 8B: Preparation of 4-amino-N-(2,6-dimethoxybenzyl)-2,5-dimethylbenzamide.
In a 20 mL vial equipped with a stir bar in open air, 4-amino-2,5-dimethylbenzoic acid (281 mg, 1.70 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (276 mg, 2.04 mmol), and EDCI (392 mg, 2.04 mmol) were dissolved in DMF (10.0 mL). DIPEA (0.357 mL, 2.04 mmol) was then added. The vial was capped, and the dark orange solution was stirred for an hour at room temperature. After 1 h, (2,6-dimethoxyphenyl)methanamine (397 mg, 2.04 mmol) was added and the mixture was stirred overnight. The reaction was judged complete after 18 h as determined by UPLC analysis. The reaction mixture was diluted with EtOAc (15 mL) and was washed with deionized water (5x). The organic layer was washed with saturated aqueous sodium bicarbonate (NaHCO3), dried over MgSO4, filtered, and concentrated under reduced pressure to afford a dark yellow solid. The resulting material was purified by flash column chromatography (SiO2, 0% ^40% 3:1 EtOAc:EtOH in hexanes) to afford the title compound (270 mg, 51% yield) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.57 (d, J = 8.3 Hz, 2H), 6.45 (s, 1H), 6.08 (br s, 2H), 4.77 - 4.59 (m, 2H), 3.85 (s, 6H), 3.67 (s, 1H), 2.36 (s, 3H), 2.09 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.58, 158.87, 145.97, 135.69, 130.00, 129.05, 126.96, 119.02, 117.00, 114.51, 103.99, 56.00, 32.99, 19.99, 16.83; ESIMS m/z 315 ([M+H]+). |
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