Hydrogen chloride-ethyl acetate → 6-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide dihydrochloride

HRID 1509414Notes

Reaction equation

HRID 1509414 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]2[CH2:18][C@@H:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:11])=[C:4]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:3]=1.C(OCC)(=O)C.[ClH:52]>C(O)(=O)C>[ClH:52].[ClH:52].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]3[CH2:18][C@@H:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[CH2:16][NH:15][CH2:14]3)=[O:11])[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:4]=2[CH:3]=1

Participants

4

Reactant 2

HCID 21866389Hydrogen chloride-ethyl acetateHCID 58355133tert-butyl (3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Product 1

HCID 673210346-fluoro-1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide dihydrochloride

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
80 °C

Procedure

tert-Butyl (3S,5R)-3-{[({4-fluoro-2-[(4-methoxybutyl)amino]phenyl}amino)(oxo)acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (294 mg) was dissolved in acetic acid (5 ml), and the mixture was stirred at 80° C. for 3 days. The reaction mixture was cooled to room temperature, 4M hydrogen chloride-ethyl acetate (5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added, and the mixture was concentrated again to give the object product (113 mg).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. stirringthe mixture was stirred at room temperature for 2 hr
  3. concentrationThe reaction mixture was concentrated
  4. additionthe residue was diluted with aqueous sodium bicarbonate
  5. extractionextracted with ethyl acetate
  6. washThe extract was washed with saturated brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was evaporated under reduced pressure
  9. washa fraction eluted with ethyl acetate-methanol (85:15)
  10. concentrationwas concentrated under reduced pressure
  11. dissolutionThe residue was dissolved in ethyl acetate
  12. addition4M hydrogen chloride-ethyl acetate (1 ml) was added
  13. concentrationthe mixture was concentrated again

Sources & evidence

ORD record
ord-36ecc17f8c0444b1a33c304af685689e
Source dataset
uspto-grants-2015_12
Patent number
US09221836B2

Reaction notes

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