2-(5-Bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate → (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate

HRID 718395Notes

Reaction equation

HRID 718395 reaction equation
[Br:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]2)=[C:4]([CH:10]([OH:14])[C:11]([O-:13])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:22])[F:23])[CH2:17][CH2:16]2)=[C:4]([C@H:10]([O:14][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:7]([CH3:8])[CH3:2])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]

Participants

3

Reactant 1

HCID 1317341672-(5-Bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118307868(S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetateYield 178%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.9 g, 4.19 mmol) and 0.4 mL of 70% HClO4 in DCM (20 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, after which it was recooled, and an additional 0.4 mL of 70% HClO4 was added, and the reaction stirred for 24 h at rt. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-12% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 1.9 g (90%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO) δ 6.11 (br. s, 1H), 4.93-4.91 (m, 1H), 3.84 (br. s, 1H), 3.209 (br. s, 1H), 3.08 (br. s, 1H), 2.89 (br. s, 1H), 2.53 (s, 3H), 2.44 (br. s, 3H), 1.96 (br. s, 1H), 1.86 (br. s, 2H), 1.64-1.53 (m, 2H), 1.16 (d, J=6.3 Hz, 3H), 1.14 (s, 9H), 1.07 (d, J=6.3 Hz, 3H). UPLC (M+H)=511.4.

Workup

  1. customThe isobutylene gas was bubbled into a nitrogen
  2. custompurged
  3. customsealed vessel
  4. stirringthe reaction stirred for 24 h at rt
  5. washwashed with 1M Na2CO3 solution
  6. dry with materialdried over MgSO4
  7. additionThe crude product was charged (DCM)
  8. washto a 80 g ISCO silica gel cartridge and gradient elution (5-12% EtOAc/hexanes)

Sources & evidence

ORD record
ord-a16f39e761a6477a831e0c535709c6f5
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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