Hydrochloric Acid → 2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-B][1,4]diazepin-6(7H)-one

Temperature

60 °C

Compound ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate (1.0 g, 2.7 mmol) was dissolved in AcOH (10 mL) and then cooled in an ice bath. Iron powder (296 mg, 5.3 mmol) was added followed by the slow addition of HCl (1.5 mL, conc.). After 10 minutes the reaction was transferred to a heat bath and left to stir at 60° C. for 5 hours. The reaction was then cooled, the stir bar and unreacted iron removed by filtration through paper, and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water (15 mL) and EtOAc (20 mL), the layers separated, the aqueous layer washed with EtOAc (2×30 mL), the organic extracts combined, washed with sat. NaHCO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated to yield a brown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) was used to coax out a light yellow solid (535 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.96 (m, 8H) 3.98 (t, J=11.49 Hz, 2H) 4.87 (q, 1H) 8.12 (s, 1H) 11.06 (br. s., 1H). [M+H] calc'd for C12H13ClF2N4O, 303. found 303.

1. temperaturecooled in an ice bath
2. waitleft
3. temperatureThe reaction was then cooled
4. customthe stir bar and unreacted iron removed by filtration through paper
5. additionThe mixture was then diluted with ice water (15 mL) and EtOAc (20 mL)
6. customthe layers separated
7. washthe aqueous layer washed with EtOAc (2×30 mL)
8. washwashed with sat. NaHCO3 (20 mL), brine (20 mL)
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. customto yield a brown syrup

ORD record

ord-3f830631a7ae498a9c7c349d512969b8

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026234B2