反应详情

温度

-78 °C

tert-butyl (25)-4-(4-bromo-5-methyl-thiazol-2-yl)-2-isobutyl-piperazine-1-carboxylate (921 mg, 1.737 mmol) in THF (10 mL) was cooled to −78° C. before BuLi (729.6 μL, 2.5 M in hexanes, 1.824 mmol) was added dropwise over approx. 10 mins (temperature kept below −70° C. during addition). Once added, mixture stirred at −78° C. for 30 mins before a solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (319.9 mg, 1.737 mmol) in THF (3 mL) was added dropwise at −78° C. at such a rate that temperature did not exceed −70° C. (−5 mins). Mixture then stirred at −78° C. for 2 h allowed to warm to room temperature over the weekend (3.5 days). Reaction quenched with water, diluted with EtOAc and organic layer separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a yellow solid (208 mg, 26%); 1H NMR DMSO-d6 δ 0.85 (d, 6H), 1.40-1.35 (m, 12H), 2.63 (s, 3H), 2.97-2.94 (m, 2H), 3.10 (dd, 1H), 3.58 (d, 2H), 3.87-3.80 (m, 1H), 4.20-4.13 (m, 1H), 7.49-7.46 (m, 1H), 8.17-8.12 (m, 1H), 8.39 (dd, 1H); ES+ 463.22.

1. additionwas added dropwise over approx. 10 mins
2. addition(temperature kept below −70° C. during addition)
3. additionOnce added
4. additionwas added dropwise at −78° C. at such a rate that temperature
5. customdid not exceed −70° C.
6. custom(−5 mins)
7. temperatureto warm to room temperature over the weekend (3.5 days)
8. customReaction
9. customquenched with water
10. additiondiluted with EtOAc and organic layer
11. customseparated
12. washwashed with brine
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customCrude product purified by flash chromatography (80 g SiO2, 0 to 15% EtOAc/petrol)