反应详情

温度

40 °C

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride (0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo and DCM added and the concentration repeated (×2). The acid chloride intermediate was suspended in DCM (10 ml), 2,6-dimethylmorpholine (0.55 ml, 4.49 mmol) added. The reaction was stirred at RT for 0.5 hr and then concentrated in vacuo. The residue was diluted with more DCM and water and the organics extracted (2×20 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6). Elution with DCM:methanol 98:2 to 90:10 gave the mixture of cis and trans 2,6-dimethylmorpholin-4-yl compound (200 mg): 1H NMR (500 MHz, CDCl3) delta 1.21 (3H, d, J=6.2 Hz), 1.30 (3H, d, J=6.1 Hz), 2.64 (1H, dd, J=13.1, 10.8 Hz), 2.99 (1H, dd, J=13.2, 10.6 Hz), 4.84-3.26 (6H, m), 5.23 (2H, s), 7.23-7.19 (1H, m), 7.50 (1H, dd, J=8.6, 1.6 Hz), 7.98 (1H, d, J=8.6 Hz), 8.37 (1H, dd, J=5.6, 2.2 Hz), 9.01 (1H, d, J=1.2 Hz); LC-MS: m/z=+430.95/432.85 (M+H)+.

1. concentrationThe reaction mixture was concentrated in vacuo and DCM
2. additionadded
3. concentrationthe concentration
4. stirringThe reaction was stirred at RT for 0.5 hr
5. concentrationconcentrated in vacuo
6. additionThe residue was diluted with more DCM and water
7. extractionthe organics extracted (2×20 ml)
8. dry with materialThe combined organic layers were dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customCrude material purified by column chromatography, (9:1 DCM:methanol, Rf=0.6)
12. washElution with DCM:methanol 98:2 to 90:10
13. customgave