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

HRID 718401Notes

Reaction equation

HRID 718401 reaction equation
[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][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[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]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 118307770(S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118307896(S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetateYield 142%

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-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (2.25 g, 5.63 mmol) and 0.53 mL of 70% HClO4 in DCM (30 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 72 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 (0-12% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 1.82 g (71%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.16 (s, 1H), 4.93-4.90 (m, 1H), 3.82-3.77 (m, 1H), 3.24 (t, J=10.6 Hz 1H), 2.98 (d, J=9.9 Hz, 1H), 2.74 (br. s, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 1.73 (br. s, 1H), 1.62 (br. s, 1H), 1.49 (br. s, 1H), 1.28-1.23 (m, 2H), 1.16-1.14 (m, 12H), 1.07 (d, J=6.2 Hz, 3H), 0.97 (d, J=6.2 Hz, 3H). UPLC (M+H)=457.3.

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 (0-12% EtOAc/hexanes)

Sources & evidence

ORD record
ord-f0d8e846419646c78da58abb4ea0309f
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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