Ethyl chloroformate → 6-Chloro-5-(difluoromethyl)-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride

HRID 2064222Notes

Reaction equation

HRID 2064222 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[CH:22]([F:24])[F:23].C(N(CC)C(C)C)(C)C.Cl[C:35](OCC)=[O:36]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[C:3]([CH:22]([F:24])[F:23])=[CH:4][C:5]2[NH:21][C:35](=[O:36])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1

Participants

5

Reactant 3

HCID 10928Ethyl chloroformateHCID 81531DiisopropylethylamineHCID 598501795-Chloro-4-(difluoromethyl)-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,2-benzenediamine

Product 1

HCID 692365546-Chloro-5-(difluoromethyl)-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochlorideYield 87.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
150 °C

Procedure

A stirred solution of 5-chloro-4-(difluoromethyl)-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,2-benzenediamine (D98, 180 mg, 0.50 mmol) in tetrahydrofuran (8 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (0.18 ml, 1.0 mmol) followed by ethyl chloroformate (65 mg, 0.60 mmol) and maintained for 1 hr. The solution was concentrated under vacuum and the residue dissolved in dimethylformamide (5 ml) and heated at 150° C. under argon for 1.5 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid, which was washed with diethyl ether. The remaining solid was converted to its HCl salt, which was again washed with diethyl ether to afford the HCl salt of the title compound as a pale yellow solid (92 mg, 47%).

Workup

  1. temperaturemaintained for 1 hr
  2. concentrationThe solution was concentrated under vacuum
  3. dissolutionthe residue dissolved in dimethylformamide (5 ml)
  4. concentrationThe solution was concentrated under vacuum
  5. additionthe residue treated with 10% Na2CO3 solution
  6. extractionextracted with ethyl acetate
  7. customThe extract was dried
  8. concentrationconcentrated under vacuum
  9. customto leave an orange solid, which
  10. washwas washed with diethyl ether
  11. washwas again washed with diethyl ether

Sources & evidence

ORD record
ord-69b087f87c0f44fdaaa9b95267c488f3
Source dataset
uspto-grants-2012_10
Patent number
US08288412B2

Reaction notes

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