Sodium hydride → tert-butyl 4-((1R,2R)-2-((4-bromo-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate

HRID 1468867Notes

Reaction equation

HRID 1468867 reaction equation
[H-].[Na+].[OH:3][CH2:4][C@@H:5]1[CH2:7][C@@H:6]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][C:23]=1[F:30]>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:3][CH2:4][C@@H:5]2[CH2:7][C@@H:6]2[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:24][C:23]=1[F:30]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 116661761-Bromo-4-(bromomethyl)-2-fluorobenzene2×HCID 53393314HCID 53393314, compound2×

Product 1

HCID 71116028tert-butyl 4-((1R,2R)-2-((4-bromo-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylateYield 99.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (235 mg, 5.87 mmol) was added to a stirring solution of tert-butyl 4-((1R,2R)-2-(hydroxymethyl)cyclopropyl)piperidine-1-carboxylate (Intermediate 4, 1 g, 3.92 mmol) in DMF (10 mL) that had been cooled to 0° C. in an ice bath and placed under an inert atmosphere. 10 min later 1-bromo-4-(bromomethyl)-2-fluorobenzene (Step B product of Intermediate 13, 1.1 g, 4.11 mmol) was introduced to the mixture. The ice bath was removed and the reaction warmed to rt. The reaction was aged for 1 hr then diluted with EtOAc (20 mL) and neutralized by the slow addition of saturated aqueous ammonium chloride solution (20 mL). The layers were cut and the aqueous phase extracted with EtOAc (20 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) eluting with a range of 0-20% EtOAc/Hex over 12 CV to give the desired compound (1.73 g, 91%). LC/MS (m/z): 442 (M+H)+.

Workup

  1. customThe ice bath was removed
  2. temperaturethe reaction warmed to rt
  3. additionthen diluted with EtOAc (20 mL)
  4. additionneutralized by the slow addition of saturated aqueous ammonium chloride solution (20 mL)
  5. extractionthe aqueous phase extracted with EtOAc (20 mL×2)
  6. dry with materialThe combined organic layers were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. washeluting with a range of 0-20% EtOAc/Hex over 12 CV

Sources & evidence

ORD record
ord-bc9c626640094a16ac4acb9c34ba7b92
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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