Hydrochloric Acid → 4-(2,5-Difluoro-phenoxy)-piperidine hydrochloride
Reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].CCOCC>O1CCOCC1>[ClH:23].[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1Participants
Procedure
To a stirred solution of 2,5-difluorophenol (1.0 g, 0.0076 mole) in DMF (20 mL) was added cesium carbonate (12.4 g, 0.038 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 0.076 mole). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (10% ethyl acetate in hexane) to afford 1.5 g (63.0%) of 4-(2,5-Difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 85%. 1H NMR (CDCl3): δ 7.0 (m, 1H), 6.6 (m, 1H), 6.5 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.4 (m, 4H), 2 (m, 2H), 1.9 (m, 2H). 1.5 (s, 9H). A solution of 4-(2,5-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.0047 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 1 hour. Ether was then added, and the resulting precipitate was isolated by filtration and dried to afford 0.65 g (65%) of 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride. LCMS: 214.1 (M+1)+, 100%. 1H NMR (CDCl3): δ 9.2 (bs, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.2 (m, 2), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H).
Workup
- customthe resulting precipitate was isolated by filtration
- customdried
Sources & evidence
- ORD record
- ord-20d0a0ce0c87421b8fc49f283e14dab9
- Source dataset
- uspto-grants-2012_03
- Patent number
- US08129376B2
Reaction notes
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