Water → tert-butyl 4-((1R,2R)-2-{[(5-bromopyridin-2-yl)methoxy]}cyclopropyl)piperidine-1-carboxylate

HRID 1468818Notes

Reaction equation

HRID 1468818 reaction equation
OC[C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36]Br)=[N:34][CH:35]=1.[OH2:38]>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:38][C@@H:3]2[CH2:5][C@@H:4]2[CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[N:34][CH:35]=1

Participants

6

Reactant 4

HCID 962WaterHCID 2724254Sodium bis(trimethylsilyl)amideHCID 234380625-Bromo-2-(bromomethyl)pyridineHCID 53393314HCID 53393314, compound2×

Product 1

HCID 86717775tert-butyl 4-((1R,2R)-2-{[(5-bromopyridin-2-yl)methoxy]}cyclopropyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 4: 3.5 g, 13.71 mmol) in THF (40 mL) was added NaHMDS (16.45 mL of a 1.0M soln in THF, 16.45 mmol) followed by the product of step A (4.13 g, 16.45 mmol) and the resulting mixture heated at reflux overnight. The mixture was cooled and poured into water (100 mL) and extracted with EtOAc (2×75 mL); combined EtOAc layers washed with sat. NaCl, dried over MgSO4, filtered and evaporated in vacuo. Residue purified by silica gel column chromatography (eluent: gradient 0-25% EtOAc in Hexanes) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 8.82 (d, J 2.0 Hz, 1H), 7.84 (dd, J 8.0 & 2.0 Hz, 1H), 7.38 (d, J 8.0 Hz, 1H), 4.65 (d, J 13.5 Hz, 1H), 4.57 (d, J 13.5 Hz, 1H), 4.18-3.97 (br m, 2H), 3.64-3.58 (m, 1H), 3.58-3.52 (m, 1H), 2.74-2.58 (m, 2H), 1.86-1.79 (m, 1H), 1.77-1.69 (m, 1H), 1.47 (s, 9H), 1.36-1.20 (m, 3H), 0.98-0.89 (m, 1H), 0.79-0.68 (m, 2H), 0.07-0.03 (m, 1H).

Workup

  1. temperaturethe resulting mixture heated
  2. temperatureat reflux overnight
  3. temperatureThe mixture was cooled
  4. extractionextracted with EtOAc (2×75 mL)
  5. washcombined EtOAc layers washed with sat. NaCl
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customResidue purified by silica gel column chromatography (eluent: gradient 0-25% EtOAc in Hexanes)

Sources & evidence

ORD record
ord-3fd22df6fc6e4e8e8f31378d0c9842b2
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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