反应详情

A solution of dimethyl 2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (612 mg, 1.50 mmol) in a mixture of tetrahydrofuran (24 ml), MeOH (8 ml) and 1 N aqueous sodium hydroxide (2.4 ml, 2.4 mmol) was stirred at room temperature for 30 minutes and then neutralized with 1 N aqueous HCl. The organic solvents were removed on the rotary evaporator and the residue was dissolved in water and acidified to about pH 3 with 1 N aqueous HCl. This was chilled in an ice bath and the precipitate was collected by filtration and dried. LC/MS indicated that the major component of this was 2-(3-fluoro-4-methoxyphenyl)-7-(methoxycarbonyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid [MS (ESI) m/z 395.0 (M+H); retention time 2.75 min; Xbridge S10 4.6×50 mm column; flow rate=4 mL/min; gradient from 0% B to 100% B over 3 min; Solvent A=0.1% TFA/95% water/5% methanol, Solvent B=0.1% TFA/5% water 95% methanol]. Dimethylformamide (5 mL) was added to a mixture of a portion of this material (400 mg, about 1.01 mmol), ammonium chloride (0.163 gm, 3.04 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0.583 g, 3.04 mmol), and 1-hydroxybenzotriazole hydrate (0.411 g, 3.04 mmol). After stirring for a few minutes, triethylamine (0.42 mL, 3.0 mmol) was added and the reaction was left stirring overnight. It was diluted with EtOAc, washed with water and dried with sodium sulfate. The solvent was removed and the residue was suspended in warm (40° C.) methylene chloride for 10 minutes and then filtered to gave methyl 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylate (0.35 g) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 11.90 (1H, s), 8.64 (1H, br. s.), 8.51 (1H, s), 8.44 (1H, s), 8.39 (1H, d, J=8.24 Hz), 8.09-8.22 (2H, m), 7.97 (1H, br. s.), 7.89 (1H, d, J=8.24 Hz), 7.36 (1H, t, J=8.70 Hz), 3.95 (3H, s), 3.93 (3H, s).

1. customThe organic solvents were removed on the rotary evaporator
2. dissolutionthe residue was dissolved in water
3. temperatureThis was chilled in an ice bath
4. filtrationthe precipitate was collected by filtration
5. customdried
6. customindicated that the major component of this was 2-(3-fluoro-4-methoxyphenyl)-7-(methoxycarbonyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid [MS (ESI) m/z 395.0 (M+H); retention time 2.75 min; Xbridge S10 4.6×50 mm column; flow rate=4 mL/min; gradient from 0% B to 100% B over 3 min; Solvent A=0.1% TFA/95% water/5% methanol, Solvent B=0.1% TFA/5% water 95% methanol]
7. stirringAfter stirring for a few minutes
8. waitthe reaction was left
9. stirringstirring overnight
10. washwashed with water
11. dry with materialdried with sodium sulfate
12. customThe solvent was removed
13. temperaturein warm (40° C.) methylene chloride for 10 minutes
14. filtrationfiltered