反应详情

温度

12.5 °C

A mixture of 1-cyclobutyl-[1,4]diazepane (prepared e.g. as in Example 13 above, 20.0 g, 129.7 mmol, 1.00 eq), water (95.2 g) and NaOH 30% aq. (34.6 g, 259.5 mmol, 2.00 eq) was cooled to 10-15° C. To the resulting mixture was added a solution of 6-chloronicotinic acid chloride (24.0 g, 136.4 mmol, 1.05 eq) in MTBE (250.0 g) at 10-15° C., over about 30-45 min, while stirring vigorously. The resulting emulsion was maintained at 10-20° C. for 45-60° C., before the layers were allowed to separate. The aqueous layer was removed and the organic layer washed with water (25.0 g). After removal of the aqueous layer, the organic layer was concentrated by distillation (140 g solvent are distilled off), ethanol (120 g) was added and additional solvent was distilled off (170 g solvent). The resulting solution was then heated to about 50-60° C. and HCl (gas, 4.8 g, 130.2 mmol) in ethanol (9.1 g) was added dropwise. The resulting solution was cooled to 43-45° C. and seeded crystals of the title compound. The product crystallized slowly at 43-45° C. when stirred for about 4-6 h. MTBE (60 g over 1.5-2 h, 120 g over 0.5-1 h) was added, the resulting mixture was then cooled to room temperature over 1-2 h and maintained for 1-2 h, before the title compound was isolated by filtration, washed with MTBE (2×40 g) and dried in vacuo at 65-75° C. for 2 days, to yield the title compound as a white solid.

1. temperatureThe resulting emulsion was maintained at 10-20° C. for 45-60° C., before the layers
2. customto separate
3. customThe aqueous layer was removed
4. washthe organic layer washed with water (25.0 g)
5. customAfter removal of the aqueous layer
6. concentrationthe organic layer was concentrated by distillation (140 g solvent are distilled off), ethanol (120 g)
7. additionwas added
8. distillationadditional solvent was distilled off (170 g solvent)
9. temperatureThe resulting solution was then heated to about 50-60° C.
10. temperatureThe resulting solution was cooled to 43-45° C.