2-O-[(Z)-1-aminoethylideneamino] 1-O-methyl 3-fluorobenzene-1,2-dicarboxylate → 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid

Temperature

-78 °C

To THF (15 mL) was added 2 M i-PrMgCl in THF (2.2 mL, 4.47 mmol). This mixture was cooled to −78° C. and the product of Step B (1.09 g, 3.58 mmol) was added dropwise in THF (20 mL). The mixture was stirred for 30 min at −78° C. and then CO2 from a lecture bottle was bubbled into the solution for 3 h while allowing the temperature to slowly rise. When the temperature reached −20° C. the dry ice bath was replaced with an ice bath, bubbling of CO2 was ceased and the mixture was allowed to come to room temperature overnight. The mixture was quenched by the addition of H2O and a small amount of Et2O. The organic layer was washed 2× with 2N aq. NaOH and the combined aqueous layers were then washed 3× with Et2O. The aqueous layer was then acidified with concentrated HCl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product as a white solid (661 mg, 83%). MS (ESI) mass calculated for C10H7FN2O3, 222.04; m/z found, 223.0. 1H NMR (500 MHz, CDCl3): 7.96 (d, J=7.8, 1H), 7.72-7.64 (m, 1H), 7.50-7.44 (m, 1H), 2.56-2.48 (m, 3H).

1. customCO2 from a lecture bottle was bubbled into the solution for 3 h
2. customreached −20° C.
3. customwas replaced with an ice bath
4. custombubbling of CO2
5. waitto come to room temperature overnight
6. customThe mixture was quenched by the addition of H2O
7. washThe organic layer was washed 2× with 2N aq. NaOH
8. washthe combined aqueous layers were then washed 3× with Et2O
9. extractionextracted with DCM
10. dry with materialThe combined organic layers were dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo

ORD record

ord-37bf1d06aa1b491b9e74462af12b0de7

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08680275B2