Diisopropylethylamine → 6-Chloro-2-methyl-N4-(tetrahydro-2H-pyran-4-yl)-4,5-pyrimidinediamine

Temperature

100 °C

In a 300 mL glass pressure reactor, combine 5-amino-4,6-dichloro-2-methylpyrimidine (20.0 g, 97%, 109.0 mmol), 4-aminotetrahydropyran hydrochloride (21.0 g, 152.6 mmol), di-isopropylethylamine (57.0 mL, 326.9 mmol) and isopropyl alcohol (100 mL). Seal the pressure vessel tightly, start stirring, and adjust the set-point for heat control to 100° C. Stir the mixture at 100° C. for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and add 4-aminotetrahydropyran hydrochloride (2.25 g, 16.3 mmol). Re-seal the vessel, heat the contents to an internal temperature of 100° C., and stir for an additional 24 hours. Cool the reaction mixture to ambient temperature, vent the reactor of pressure, and transfer the contents to a recovery flask. Concentrate the mixture under reduced pressure to approximately ⅓ of its original volume. Add water (200 mL) and ethyl acetate (200 mL) and transfer the resulting mixture to a separatory funnel Separate the layers, re-extract the aqueous layer with ethyl acetate (100 mL) and combine all organics. Wash with water (2×100 mL) and brine (100 mL), then dry the organic layer over anhydrous sodium sulfate. Concentrate under reduced pressure to afford 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine as an off-white solid (25.0 g). MS (m/z): 243/245 (M+1).

1. customIn a 300 mL glass pressure reactor, combine
2. customSeal the pressure vessel tightly
3. stirringStir the mixture at 100° C. for 24 hours
4. temperatureCool the reactor contents to 60° C.
5. temperatureRe-seal the vessel, heat the contents to an internal temperature of 100° C.
6. stirringstir for an additional 24 hours
7. temperatureCool the reaction mixture to ambient temperature
8. concentrationConcentrate the mixture under reduced pressure to approximately ⅓ of its original volume
9. customSeparate the layers
10. extractionre-extract the aqueous layer with ethyl acetate (100 mL)
11. washWash with water (2×100 mL) and brine (100 mL)
12. dry with materialdry the organic layer over anhydrous sodium sulfate
13. concentrationConcentrate under reduced pressure

ORD record

ord-20eed40299d8497fa44abc97e0df538a

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08252798B2