反应详情

Phosgene (20% in toluene, 0.54 mL, 1.0 mmol, 2.0 equiv) is added to a solution of 2,4-dichloro-5-methoxy-3-trifluoromethylaniline (156 mg, 0.60 mmol, 1.2 equiv) in dioxane (2 mL), under a nitrogen atmosphere. The mixture is heated to reflux, stirred for 75 min, allowed to cool to RT, and concentrated in vacuo. The resulting solid 2,4-dichloro-5-methoxy-3-trifluoromethyl-phenylisocyanate is added portion-wise to a boiling solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (156 mg, 0.50 mmol; preparation see Step 25.5) in 6 ml of toluene under a nitrogen atmosphere. The reaction mixture is stirred at 110° C. for 3.3 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated off and extracted twice with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Trituration of the resulting solid with 2 portions of MeOH yields the title compound: ESI-MS: 598/600 [MH]+; tR=5.1 min (purity: 97%, system 1).

1. temperatureThe mixture is heated
2. temperatureto reflux
3. concentrationconcentrated in vacuo
4. stirringThe reaction mixture is stirred at 110° C. for 3.3 h
5. temperatureto cool to RT
6. customThe aqueous layer is separated off
7. extractionextracted twice with DCM
8. washThe organic phase is washed with brine
9. dry with materialdried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated