Water → 4-(3-Bromo-5-methoxyphenoxy)-1-methylpiperidine

HRID 1888403Notes

Reaction equation

HRID 1888403 reaction equation
[H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[C:16](F)[CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([O:19][CH3:20])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 660484-Piperidinol, 1-methyl-HCID 108220943-Bromo-5-fluoroanisole

Product 1

HCID 582663084-(3-Bromo-5-methoxyphenoxy)-1-methylpiperidineYield 50%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300.

Workup

  1. stirringthe reaction mixture was stirred at 65° C. for 24 h
  2. extractionextracted with ethyl acetate (2×100 mL)
  3. washwas then washed with acetonitrile
  4. washthen eluted with 2N ammonia in methanol

Sources & evidence

ORD record
ord-5db21eb151f84a34af0dfd4d59e356e0
Source dataset
uspto-grants-2013_08
Patent number
US08501765B2

Reaction notes

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