4,4-Difluoropiperidine hydrochloride → 4,4-difluoro-1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}piperidine

HRID 272878Notes

Reaction equation

HRID 272878 reaction equation
[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[F:25][C:26]1([F:32])[CH2:31][CH2:30][N:29]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1

Participants

5

Reactant 2

HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 598374274-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde

Product 1

HCID 234313674,4-difluoro-1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}piperidineYield 7.5%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 702EthanolSolvent

Procedure

4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (260 mg, 0.82 mmol), 4,4-difluoropiperidine hydrochloride (323 mg, 2.05 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.209 mL, 4.09 mmol) and STAB (1.475 g, 6.96 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN:H2O:Et3N (from 29.9:70:0.1 to 94.9:5:0.1 in 13 min) to give the title compound (26 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.77-3.73 (m, 2H), 3.53-3.47 (t, 2H), 2.64 (t, 2H), 2.54 (m, 4H), 2.39 (s, 2H), 2.30-2.24 (m, 6H), 2.13 (d, 2H), 2.02 (m, 2H), 1.90-1.71 (m, 6H).

Workup

  1. customThe isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column
  2. washeluting with a gradient of MeCN

Sources & evidence

ORD record
ord-3a6b09e096274aa8847b3adeb2920df8
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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