Hydrochloric Acid → (5R)-3-{4-[(3-chloro-5-fluorophenyl)oxy]phenyl}-5-methyl-2,4-imidazolidinedione

Temperature

100 °C

To triphosgene (0.052 g, 0.177 mmol) was added a solution of 4-[(3-chloro-5-fluorophenyl)oxy]aniline (Intermediate 6, 0.12 g) in toluene (1 mL) and triethylamine (0.16 g) with shaking. A thick slurry immediately formed and additional toluene (1 mL) was added. The mixture was stirred for 3 hours at room temperature and then D-alanine (0.067 g, 0.757 mmol) in N,N-dimethylformamide (2 mL) and water (ca. 2 mL) (barely dissolved) was rapidly added via pipette. A two-layer system formed that was vigorously stirred for 2 hours and kept overnight at room temperature. Volatiles were evaporated, hydrochloric acid (2 mL, 24.35 mmol) added and the heterogeneous mixture heated at 100° C. for 2 hours, then allowed to cool to room temperature. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give the title compound as colourless solid (7 mg).

1. customA thick slurry immediately formed
2. stirringThe mixture was stirred for 3 hours at room temperature
3. additionwas rapidly added via pipette
4. customA two-layer system formed
5. stirringthat was vigorously stirred for 2 hours
6. customVolatiles were evaporated
7. temperatureto cool to room temperature
8. customthe residue dried under vacuum
9. customThe residue was purified by silica gel chromatography (Biotage instrument, 10 g column)
10. washeluting with 0-100% EtOAc/cHex

ORD record

ord-8f159bd6faa74bb7ad01744a0703a865

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08722695B2