Isobutylene → Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-YL)-2,6-dimethylpyridin-3-YL)-2-(tert-butoxy)acetate

HRID 718369Notes

Reaction equation

HRID 718369 reaction equation
[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([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].[CH3:26][C:27](=[CH2:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:27]([CH3:29])([CH3:28])[CH3:26])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]

Participants

5

Reactant 3

HCID 8255IsobutyleneHCID 10340Sodium CarbonateHCID 118307841Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-YL)-2,6-dimethylpyridin-3-YL)-2-hydroxyacetate

Product 1

HCID 118307891Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-YL)-2,6-dimethylpyridin-3-YL)-2-(tert-butoxy)acetateYield 60.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A stirred ice-cold yellow mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 16.21 mmol) and 70% HClO4 (2.2 mL, 25.6 mmol) in dichloromethane (400 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). The reaction mixture was cloudy sealed in a seal tube, stirred for 24 h at rt. The reaction mixture was recooled in a −10° C. bath, bubbled additional isobutylene (˜15 min). The reaction mixture became a clear solution at this point. The tube was sealed and stirred at rt for 16 h. LCMs at this point showed incomplete reaction. So, the reaction mixture was cooled down to −30° C. and bubbled isobutene (˜15 min). After 24 h, reaction mixture was neutralized with sat. Na2CO3 (20 mL), organic layer separated and aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified on a ISCO 120 g column (EtOAc/hex: 0 to 40%) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (5.43 g, 9.83 mmol, 60.7% yield) as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.26 (br. s., 1H), 5.09-4.97 (m, 1H), 4.06 (br. s., 1H), 3.51 (br. s., 1H), 2.90 (br. s., 1H), 2.65 (s, 3H), 2.56 (s, 3H), 1.72-1.54 (m, 3H), 1.47 (br. s., 1H), 1.37 (br. s., 1H), 1.23-1.20 (m, 12H), 1.15 (d, J=6.1 Hz, 3H), 1.09 (br. s., 3H), 1.04 (br. s., 3H). LCMS (M+H)=471.3.

Workup

  1. customby bubbling through the reaction mixture (10 min)
  2. customThe reaction mixture was cloudy sealed in a seal tube
  3. customwas recooled in a −10° C.
  4. custombubbled additional isobutylene (˜15 min)
  5. customThe tube was sealed
  6. stirringstirred at rt for 16 h
  7. customreaction
  8. temperatureSo, the reaction mixture was cooled down to −30° C.
  9. custombubbled isobutene (˜15 min)
  10. waitAfter 24 h
  11. customreaction mixture
  12. customseparated
  13. extractionaqueous layer was extracted with CH2Cl2 (25 mL)
  14. dry with materialThe combined organic layers were dried (MgSO4)
  15. filtrationfiltered
  16. concentrationconcentrated
  17. custompurified on a ISCO 120 g column (EtOAc/hex: 0 to 40%)

Sources & evidence

ORD record
ord-40cc1f2f731e48c0be0c9a23698f7f7f
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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