Tetrahydro-4H-pyran-4-one → 5-Fluoro-6-methyl-1-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one

HRID 2064207Notes

Reaction equation

HRID 2064207 reaction equation
[F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1

Participants

6

Reactant 3

HCID 121599Tetrahydro-4H-pyran-4-oneHCID 5003444Sodium cyanoborohydrideHCID 598502105-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one

Product 1

HCID 160710185-Fluoro-6-methyl-1-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-1,3-dihydrobenzimidazol-2-one

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 887MethanolSolvent

Procedure

5-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D30) (0.64 mmol, 160 mg) in methanol (3 mL) was treated under argon at room temperature with tetrahydro-4H-pyran-4-one (1.28 mmol, 128 mg, 2 eq), then titanium tetra-isopropoxide (1.28 mmol, 364 mg, 2 eq). The mixture was stirred under argon for 1.5 h, then sodium cyanoborohydride (1.28 mmol, 80.4 mg, 2 eq) was added and stirred for 1.5 h. The mixture was loaded on an SCX cartridge, washed with 6 CV methanol and eluted with 6 CV 2M ammonia in methanol and dichloromethane. The eluate was concentrated under reduced pressure and purified 5-100% 2 m NH3 in MeOH/DCM to give 5-fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was transformed into the corresponding HCl salt (0.27 mmol, 100 mg, 42% yield), using 1M HCl in diethyl ether. M+H=334.12

Workup

  1. stirringstirred for 1.5 h
  2. washwashed with 6 CV methanol
  3. washeluted with 6 CV 2M ammonia in methanol and dichloromethane
  4. concentrationThe eluate was concentrated under reduced pressure
  5. custompurified 5-100% 2 m NH3 in MeOH/DCM

Sources & evidence

ORD record
ord-7224edfe646e4cf9a3b535ce631fac82
Source dataset
uspto-grants-2012_10
Patent number
US08288412B2

Reaction notes

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