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

HRID 718409Notes

Reaction equation

HRID 718409 reaction equation
[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([C:25]#[N:26])([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[CH2:19][CH2:20][C:21]([C:25]#[N:26])([CH3:24])[CH2:22][CH2:23]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 118307722(S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118307757(S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateYield 171.5%

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-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (670 mg, 1.58 mmol) and 0.15 mL of 70% HClO4 in DCM (15 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 (0-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 651 mg (86%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.06 (br. s, 1H), 4.93-4.89 (m, 1H), 4.03 (br. s, 1H), 3.43-3.41 (m, 2H), 3.00 (br. s, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.05 (br. s, 1H), 1.93 (br. s, 1H), 1.80-1.71 (m, 1H), 1.58 (br. s, 1H), 1.42 (s, 3H), 1.15-1.13 (m, 12H), 1.05 (d, J=6.2 Hz, 3H). UPLC (M+H)=482.4.

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 (0-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-41bb8ac60c6c4379910439e4ac10f6a1
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

Loading…