反应详情

温度

60 °C

A 12 L reactor equipped with an overhead stirrer and N2 bubbler was charged with a solution of 5-bromo-2-methyl-3-nitropyridine (945 g, 4.35 mol) in EtOAc (5.7 L, 6 vol). To the reaction mixture, Pd(PPh3)2Cl2 (15.4 g, 0.022 mol, 0.005 equiv), CuI (8.28 g, 0.0435 mol, 0.01 equiv) and Et3N (3 L, 21.75 mol, 5 equiv) were added. Nitrogen was bubbled through the solution for 15 min and 3-dimethylamino-1-propyne (556 mL, 5.22 mol, 1.2 equiv) was added. The reaction-temperature setting was increased to 60° C. stepwise. The maximum temperature attained was 66° C. The reaction was continued for 3 h at this temperature (60° C.) and was judged complete by HPLC analysis. The reaction was cooled to ambient temperature and the inorganic salts were filtered off by passing the reaction mixture through a pad of celite. The filter cake was washed with EtOAc (2 L, 2 vol). The filtrate was transferred into a 20 L separatory funnel. The EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol). The layers were separated. The EtOAc layer was then washed with 10% brine in water (5 L, 5 vol). The layers were separated and the EtOAc layer was pumped down to a low volume (ca. 2 L, 2 vol) under reduced pressure. IPA (5 L, 5 vol) was added to the solution and the solvent was again evaporated to a low volume (ca. 2 L, 2 vol). The solution of N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine was subjected to hydrogenation in two batches using the procedure described in step 2, below.

1. customA 12 L reactor equipped with an overhead stirrer
2. customNitrogen was bubbled through the solution for 15 min
3. customattained was 66° C
4. temperatureThe reaction was cooled to ambient temperature
5. filtrationthe inorganic salts were filtered off
6. washThe filter cake was washed with EtOAc (2 L, 2 vol)
7. customThe filtrate was transferred into a 20 L separatory funnel
8. washThe EtOAc layer was washed with 5% aqueous Na2CO3 solution (2×5 L, 5 vol)
9. customThe layers were separated
10. washThe EtOAc layer was then washed with 10% brine in water (5 L, 5 vol)
11. customThe layers were separated
12. additionIPA (5 L, 5 vol) was added to the solution
13. customthe solvent was again evaporated to a low volume (ca. 2 L, 2 vol)