Dimethylformamide → HCID 58483266, compound

Temperature

0 °C

To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).

1. temperatureThen the reaction mixture was cooled to −78° C.
2. additionwas added to the reaction mixture
3. temperaturegradually warmed to 0° C. over 1 h
4. customThe reaction mass was quenched with 10% aq. AcOH
5. extractionwas extracted with EtOAc
6. washThe organic layer was washed with water and brine
7. customseparated
8. customdried
9. filtrationfiltered
10. concentrationconcentrated

ORD record

ord-528bb333d0db4f9b9e625213b4b309d4

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006257B2