4,4-Difluoropiperidine hydrochloride → HCID 86690100, compound

HRID 520387Notes

Reaction equation

HRID 520387 reaction equation
[F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.Br[C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(#N)C>[F:1][C:2]1([F:8])[CH2:7][CH2:6][N:5]([C:11]([CH3:23])([CH3:22])[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1

Participants

4

Reactant 2

HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 12558195HCID 12558195, compound

Product 1

HCID 86690100HCID 86690100, compoundYield 11.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

A stirred mixture of 4,4-difluoropiperidine/HCl (158 mg), benzyl 2-bromo-2-methylpropanoate (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL) in a capped vial was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in ether, washed with satd. NaHCO3, water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (0-1% MeOH in DCM) to afford benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate as a viscous oil (33.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.31-7.46 (5H, m), 5.18 (2H, s), 2.66 (4H, t, J=5.40 Hz), 1.86-2.08 (4H, m), 1.36 (6H, s). Benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate was debenzylated by hydrogenation (10% Pd/C, EtOAc) to afford Cap P-16 as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s).

Workup

  1. customThe reaction mixture was evaporated to dryness
  2. dissolutionthe residue was dissolved in ether
  3. washwashed with satd
  4. dry with materialNaHCO3, water, brine and dried (MgSO4)
  5. customThe crude product was purified by silica gel FCC (0-1% MeOH in DCM)

Sources & evidence

ORD record
ord-3256d9ba70024d0293dd1e838ef5934c
Source dataset
uspto-grants-2016_05
Patent number
US09326973B2

Reaction notes

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