(S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate → (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate

HRID 718378Notes

Reaction equation

HRID 718378 reaction equation
[Br:1][C:2]1[C:3]([N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:19][C:20]([F:23])([F:22])[CH2:21]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]

Participants

3

Reactant 1

HCID 118307708(S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118307850(S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateYield 87%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (175 mg, 0.45 mmol) and 0.05 mL of 70% HClO4 in DCM (5 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography gave (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 88 mg (44%). 1H NMR (400 MHz, DMSO-d6) δ 5.72 (s, 1H), 5.10-5.03 (m, 1H), 4.80-4.72 (m, 2H), 4.59-4.15 (m, 2H), 2.62 (s, 3H), 2.48 (s, 3H), 1.38 (d, J=6.1 Hz, 3H), 1.20 (s, 9H), 1.19 (d, J=6.1 Hz, 3H). UPLC (M+H)=451.3.

Workup

  1. customThe isobutylene gas was bubbled into a nitrogen
  2. custompurged
  3. customsealed vessel
  4. washwashed with 1M Na2CO3 solution
  5. dry with materialdried over MgSO4
  6. additionThe crude product was charged (DCM)
  7. washto a 24 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes)

Sources & evidence

ORD record
ord-c54e72ed511940439208ed78085e3db3
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

Loading…