Dimethylformamide → HCID 90080030, compound

In a 100 mL round-bottomed flask was added 4,4-difluoropentanoic acid (1.7 g, 12.31 mmol) and DMF (0.019 mL, 0.246 mmol) in DCM (9 mL) to give a colorless solution. Oxalyl chloride (1.077 mL, 12.31 mmol) was added slowly and the resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated to dryness. A separate 100 mL round-bottomed flask was charged with (S)-4-benzyloxazolidin-2-one (2.181 g, 12.31 mmol) in THF (23 mL) and then cooled to −78° C. Next, n-BuLi (4.92 mL, 12.31 mmol) was added slowly over 5 min. A solution of the above acid chloride in THF (10 mL) was slowly added to the reaction at −78° C. The reaction mixture was stirred at −78° C. for about 1 h and then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was quenched with about 60 mL of saturated aqueous NH4Cl solution. The resulting mixture was diluted with 200 mL of EtOAc and about 60 mL of water. The layers were separated and the aqueous layer was extracted with 250 mL of EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give a dark yellowish oil. The crude material was purified by silica gel chromatography (80 g ISCO column. A: hexane, B: DCM, 20% to 100% elution) to give Intermediate S-5A (1.65 g, 5.55 mmol, 45.1% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.23-7.39 (3 H, m), 7.17-7.24 (2 H, m), 4.67 (1 H, ddd, J=9.85, 3.69, 3.41 Hz), 4.13-4.26 (2 H, m), 3.29 (1 H, dd, J=13.42, 3.30 Hz), 3.16 (2 H, ddd, J=13.98, 8.47, 6.82 Hz), 2.77 (1 H, dd, J=13.31, 9.57 Hz), 2.19-2.41 (2 H, m), 1.53-1.75 (3 H, m).

1. customto give a colorless solution
2. concentrationThe resulting mixture was concentrated to dryness
3. temperaturecooled to −78° C
4. stirringThe reaction mixture was stirred at −78° C. for about 1 h
5. temperatureto warm to room temperature
6. stirringstirred under nitrogen overnight
7. customThe reaction mixture was quenched with about 60 mL of saturated aqueous NH4Cl solution
8. additionThe resulting mixture was diluted with 200 mL of EtOAc and about 60 mL of water
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with 250 mL of EtOAc
11. dry with materialThe combined EtOAc extracts were dried (MgSO4)
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto give a dark yellowish oil
15. customThe crude material was purified by silica gel chromatography (80 g ISCO column
16. washA: hexane, B: DCM, 20% to 100% elution)
17. customto give Intermediate S-5A (1.65 g, 5.55 mmol, 45.1% yield)

ORD record

ord-14b928067fcc47c484096e4ba97a3493

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242940B2