Water → HCID 135921415, compound

Temperature

-30 °C

(S)-tert-Butyl 3-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.259 g, 0.616 mmol) (prepared by methods analogous to those described in Synthesis 2) was dissolved in DMF (6.16 mL) and cooled to −30° C. NaH (60% dispersion in mineral oil, 0.041 mg, 0.678 mmol) was added and the mixture was stirred at −30° C. for 15 minutes. The mixture was cooled to −78° C. and iodomethane (0.046 mL, 0.727 mmol) was added dropwise. The solution was warmed to room temperature over 2 hours. Water (5 mL) was added and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (1.3 mL) and 1 M boron tribromide in dichloromethane (1.3 mL). The solution was stirred at room temperature for 18 hours. Methanol (5 mL) was added and the mixture was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. Further purification by silica column chromatography, eluting with a gradient from 3% to 30% methanol in dichloromethane, gave the title compound as a yellow solid (0.028 g, 66%).

1. customthose described in Synthesis 2)
2. temperatureThe mixture was cooled to −78° C.
3. temperatureThe solution was warmed to room temperature over 2 hours
4. extractionthe aqueous phase was extracted with dichloromethane (3×20 mL)
5. dry with materialThe combined organic phases were dried (MgSO4)
6. concentrationconcentrated in vacuo
7. customThe residue was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g)
8. washeluting with methanol
9. customThe solvents were removed in vacuo
10. dissolutionthe residue was dissolved in dichloromethane (1.3 mL)
11. stirringThe solution was stirred at room temperature for 18 hours
12. additionMethanol (5 mL) was added
13. customthe mixture was purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g)
14. washeluting with methanol
15. customFurther purification by silica column chromatography
16. washeluting with a gradient from 3% to 30% methanol in dichloromethane

ORD record

ord-8e4ff77109d44044b7b37c9da0f75d07

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08324226B2