反应详情

温度

-2 °C

A suspension of (methoxymethyl)triphenyl-phosphonium chloride (11, 276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to −2° C. and 1M KOtBu in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 hr at −2 to −3° C. The deep red-orange mixture was stirred for 1 hr at −2 to −3° C. 4-Amino-6-chloropyrimidine-5-carbaldehyde (10, 115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from −3 to 13° C. and a brown color developed. When the reaction temperature dropped to 10° C., the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred 42 hr. The reaction mixture was cooled to −2° C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2N HCl (4×250 mL) followed by 3N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 hr. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 hr to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12, 72.3 g, 136.2 g theoretical, 53.1%). The crude 12 was used in the following reaction without further purification. A sample of crude 12 (2.3 g) was purified by chromatography on silica gel, eluting with 0-35% EtOAc/heptane to give 1.7 g of pure 12 as a white solid, which is a 1:2 mixture of E/Z isomers. For 12: 1H NMR (DMSO-d6, 300 MHz) for E-isomer: δ ppm 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) and for Z-isomer: δ ppm 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H); C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H).

1. washto rinse the container and funnel
2. additionDuring the addition the reaction temperature
3. temperatureincreased from −3 to 13° C.
4. additionWhen the reaction temperature dropped to 10° C.
5. customthe cooling bath was removed
6. temperatureto warm to room temperature
7. stirringstirred 42 hr
8. temperatureThe reaction mixture was cooled to −2° C.
9. custombefore being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL)
10. concentrationThe mixture was concentrated under reduced pressure
11. customto remove most of the THF
12. customThe residue was partitioned between EtOAc (3 L) and H2O (1 L)
13. filtrationThe organic phase was filtered
14. customto remove insoluble material at the interface
15. extractionextracted with 2N HCl (4×250 mL)
16. extractionThe combined HCl extracts were back-extracted with EtOAc (500 mL)
17. filtrationthen filtered through Celite
18. customto remove insoluble material
19. temperatureThe filtrate was cooled in an ice/brine bath
20. extractionextracted with EtOAc (3×1 L)
21. washThe combined EtOAc extracts were washed with brine (1 L)
22. dry with materialdried over Na2SO4
23. stirringstirred with charcoal (10 g) and silica gel (10 g) for 1 hr
24. filtrationThe mixture was filtered through Celite
25. washwashing the Celite pad with EtOAc (1 L)
26. concentrationThe filtrate was concentrated
27. waitThe resulting tan solid was pumped under high vacuum for 2 hr
28. customto afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12, 72.3 g, 136.2 g theoretical, 53.1%)
29. customThe crude 12 was used in the following reaction without further purification
30. customA sample of crude 12 (2.3 g) was purified by chromatography on silica gel
31. washeluting with 0-35% EtOAc/heptane