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

HRID 718416Notes

Reaction equation

HRID 718416 reaction equation
[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([OH:30])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Br:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:2]([CH3:7])([CH3:3])[CH3:1])[C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

3

Reactant 1

HCID 118307743(S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118307778(S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateYield 168.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.35 g, 2.84 mmol) and 0.27 mL of 70% HClO4 in DCM (25 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. 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 (0-25% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 1.27 g (84%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.30-7.27 (m, 2H), 7.20-7.18 (m, 3H), 6.12 (br. s, 1H), 4.93-4.88 (m, 1H), 3.79-3.74 (m, 1H), 3.20 (t, J=12.5 Hz, 1H), 2.97-2.95 (m, 1H), 2.74 (br. s, 1H), 2.60 (d, J=5.1 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 3H), 1.68 (br. s, 2H), 1.60-1.57 (m, 1H), 1.36-1.29 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.11 (s, 9H), 1.06 (d, J=6.2 Hz, 3H). UPLC (M+H)=533.3.

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 80 g ISCO silica gel cartridge and gradient elution (0-25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-67f60d9817bd40bf98f9e4cdce6eeb66
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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