反应详情

温度

-65 °C

To a solution of tert-butyl dimethylcarbamate (57.8 g) in N,N,N′,N′-tetramethylethylenediamine (70 ml) and MTBE (485 g) was added sec-butyl lithium (1.4 M in cyclohexane, 300 ml) over 0.5 h while maintaining the temperature below −65° C. The mixture was stirred at −65° C. for 0.5 h, then magnesium bromide diethyl etherate (111.07 g) was added with an exotherm to −60° C. The resultant slurry was allowed to warm to −11° C. over 0.5 h then cooled to −72° C. The slurry was cannulated into a −72° C. solution of N-methoxy-N-methylpyrimidine-2-carboxamide (27.2 g) in methylene chloride (400 ml) with an exotherm to −60° C. and rinsed in with MTBE (25 ml). The mixture was warmed to 0° C. over 45 min then cooled to −27° C. Acetone (30.5 ml) was added. The mixture was cooled to −29° C., then a solution of acetic acid (63.7 g) in water (303 ml) was added with an exotherm to 11° C. The mixture was warmed to 20° C. and the phases separated. The organic layer was washed with saturated aq. sodium bicarbonate (250 ml) and the aqueous phases serial back extracted with MTBE (350 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a net weight of 85 g. Toluene (200 ml) was added and the mixture concentrated to 128 g net weight. Branched octanes (205 g) was added to the cloud point, the mixture seeded and the product allowed to precipitate for 15 minutes with stirring. The slurry was cooled to −19° C. and the precipitate collected by vacuum filtration, washed with branched octanes (82 g) and dried in a nitrogen stream to afford 29.27 g of the title compound as a solid. Physical characteristics are as follows: 1H NMR (400 MHz, CDCl3) δ 1.38, 1.49, 3.00, 4.83, 4.92, 7.50, 8.94; 13C NMR (100 MHz, CDCl3) δ 28.11, 28.30, 35.57, 35.71, 56.11, 56.61, 79.96, 123.25, 123.36, 157.56, 157.65.

1. temperaturewhile maintaining the temperature below −65° C
2. temperatureto warm to −11° C. over 0.5 h
3. temperaturethen cooled to −72° C
4. customwas cannulated into a −72° C.
5. customto −60° C.
6. washrinsed in with MTBE (25 ml)
7. temperatureThe mixture was warmed to 0° C. over 45 min
8. temperaturethen cooled to −27° C
9. additionAcetone (30.5 ml) was added
10. temperatureThe mixture was cooled to −29° C.
11. additiona solution of acetic acid (63.7 g) in water (303 ml) was added with an exotherm to 11° C
12. temperatureThe mixture was warmed to 20° C.
13. customthe phases separated
14. washThe organic layer was washed with saturated aq. sodium bicarbonate (250 ml)
15. extractionthe aqueous phases serial back extracted with MTBE (350 ml)
16. dry with materialThe combined organics were dried (MgSO4)
17. concentrationconcentrated in vacuo to a net weight of 85 g
18. additionToluene (200 ml) was added
19. concentrationthe mixture concentrated to 128 g net weight
20. additionBranched octanes (205 g) was added to the cloud point
21. customto precipitate for 15 minutes
22. stirringwith stirring
23. temperatureThe slurry was cooled to −19° C.
24. filtrationthe precipitate collected by vacuum filtration
25. washwashed with branched octanes (82 g)
26. customdried in a nitrogen stream