Trifluoroacetic anhydride → HCID 72210858, compound

To a stirred solution of 4-bromo-1-hydroxy-2,3-dimethyl-pyridin-1-ium acetate (which may be prepared as described in Description 5) (18120 mg, 69.13 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (23.89 mL, 171.9 mmol) dropwise and the reaction was stirred at room temperature for 8 hours, then additional trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was introduced. After 1 day, the reaction mixture was concentrated in vacuo to remove excess TFAA & DCM. The residue was then diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]. The resultant suspension was stirred for 3 hours and then concentrated in vacuo. The residue was then partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and trifluoroacetic anhydride (23.89 mL, 171.9 mmol) was added dropwise and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue, diluted with MeOH (200 mL) and a solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution, and the resulting suspension was stirred for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and water (200 mL). The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica (100 g SNAP), using the Isolera instrument, eluting with EtOAc: isohexane 0%-50%. Fractions containing desired product were combined and concentrated in vacuo to give (4-bromo-3-methyl-2-pyridyl)methanol (D6) (7055 mg, 34.917 mmol, 50.5% yield) as a yellow solid;

1. waitAfter 1 day
2. concentrationthe reaction mixture was concentrated in vacuo
3. customto remove excess TFAA & DCM
4. additionThe residue was then diluted with MeOH (200 mL)
5. additiona solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution [exotherms]
6. stirringThe resultant suspension was stirred for 3 hours
7. concentrationconcentrated in vacuo
8. customThe residue was then partitioned between DCM (200 mL) and water (200 mL)
9. customThe organics were separated
10. dry with materialdried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. dissolutionThe residue was dissolved in DCM (100 mL)
14. stirringthe reaction was stirred at room temperature for 16 hours
15. concentrationThe reaction mixture was concentrated in vacuo
16. additionthe residue, diluted with MeOH (200 mL)
17. additiona solution of saturated aqueous K2CO3 (approximately 100 mL) was added with caution
18. stirringthe resulting suspension was stirred for 3 hours
19. concentrationThe reaction mixture was then concentrated in vacuo
20. customthe residue was partitioned between DCM (200 mL) and water (200 mL)
21. customThe organics were separated
22. dry with materialdried over MgSO4
23. filtrationfiltered
24. concentrationconcentrated in vacuo
25. customThe residue was purified over silica (100 g SNAP)
26. washeluting with EtOAc
27. additionFractions containing desired product
28. concentrationconcentrated in vacuo

ORD record

ord-04f9f236d7e2444b881c12958972d3d7

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376436B2