Tetrahydro-4H-pyran-4-one → 6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one

HRID 2064215Notes

Reaction equation

HRID 2064215 reaction equation
Cl.[CH3:2][C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:2][C:3]1[C:4]([C:19]([F:20])([F:22])[F:21])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1

Participants

6

Reactant 3

HCID 121599Tetrahydro-4H-pyran-4-one2×HCID 5049666Sodium triacetoxyborohydride2×HCID 69171370HCID 69171370, compound

Product 1

HCID 160711346-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 8471TriethylamineSolvent2×

Procedure

6-Methyl-1-(4-piperidinyl)-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D60) (2.2 mmol), was dissolved in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added in that order at room temperature and the mixture was stirred at room temperature for 2 hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved again in 1,2-dichloroethane (50 ml) and triethylamine (7 ml), tetrahydro-4H-pyran-4-one (7 eq., 15.4 mmol, 1.4 ml), sodium triacetoxyborohydride (7 eq., ˜3.2 g) were added at room temperature and the mixture was stirred at room temperature for three hours. Reaction mixture was quenched with 10 ml of NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one, 240 mg, 30%, M++H=384, which was subsequently converted into the hydrochloride salt using HCl solution (1M in diethyl ether, 2 eq).

Workup

  1. customReaction mixture
  2. customwas quenched with 10 ml of NaHCO3 (saturated solution)
  3. additiondiluted with dichloromethane
  4. customthe two phases were separated
  5. customthe organic solvent was evaporated
  6. customto afford the crude product
  7. customThe crude obtained
  8. stirringthe mixture was stirred at room temperature for three hours
  9. customReaction mixture
  10. customwas quenched with 10 ml of NaHCO3 (saturated solution)
  11. additiondiluted with dichloromethane
  12. customthe two phases were separated
  13. customthe organic solvent was evaporated
  14. customto afford the crude product that
  15. customwas purified by chromatography (methanol-NH3-dichloromethane)

Sources & evidence

ORD record
ord-ea2cdb18ae2d46b4b5644911bb00abc4
Source dataset
uspto-grants-2012_10
Patent number
US08288412B2

Reaction notes

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