反应详情

A 25 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-pyridine-2-carbaldehyde (400 mg, 1.201 mmol) and t-butanol (6 mL). Rapid stiffing and warming with a heat gun failed to dissolved all of the aldehyde. Additional t-butanol (2 mL) was added, but still failed to form a homogeneous solution. The mixture was treated with H2O (2 mL), 2-methyl-2-butene (1 mL), sodium phosphate dibasic dihydrate (Na2HPO4; 341 mg, 2.402 mmol, 2 equiv) and finally sodium chlorite (326 mg, 3.60 mmol, 3 equiv) was added in one portion. The mixture was stirred at room temperature for 5 min and then placed in an oil bath and heated to 85° C. After stiffing at 85° C. for 60 min, the reaction mixture finally became a light yellow, homogenous solution. After stirring at 83° C. overnight (12 h), an aliquot of the reaction mixture was partitioned between EtOAc and 1 molar (M) hydrochloric acid (HCl) and analyzed by HPLC and LC-MS. HPLC analysis showed that all of the starting material had been consumed and one major, slightly more polar product formed along with multiple minor products. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream-colored solid. The crude material was stirred with Et2O (5 mL). After stiffing for 3 h, the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, 83%) was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.47 (dd, J=8.5, 1.4 Hz, 1H), 7.31 (dd, J=8.4, 7.1 Hz, 1H), 7.04 (s, 2H), 3.93 (s, 4H); 19F NMR (376 MHz, DMSO-d6) δ −129.10 (d, J=28.3 Hz), −138.56 (d, J=28.4 Hz); ESIMS m/z 349 ([M+H]+), 347 ([M−H]−).

1. customA 25 mL round bottom flask equipped with a magnetic stir bar
2. temperaturereflux condenser
3. temperaturewarming with a heat gun
4. customto form a homogeneous solution
5. additionwas added in one portion
6. customplaced in an oil bath
7. temperatureheated to 85° C
8. waitAfter stiffing at 85° C. for 60 min
9. stirringAfter stirring at 83° C. overnight (12 h)
10. customan aliquot of the reaction mixture was partitioned between EtOAc and 1 molar (M) hydrochloric acid (HCl)
11. customhad been consumed
12. customone major, slightly more polar product formed along with multiple minor products