Potassium Carbonate → 4-(1-(4-Cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

HRID 541391Notes

Reaction equation

HRID 541391 reaction equation
Br[CH2:2][C:3]([C:5]1[C:6]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[CH:7][C:8]([CH3:28])=[C:9]([CH:27]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([F:18])[CH2:14][CH2:13]1)=[O:11])=O.Cl.[C:34](=[NH:37])([NH2:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:29]1([C:6]2[C:5]([C:3]3[NH:37][C:34]([CH3:35])=[N:36][CH:2]=3)=[CH:27][C:9]([C:10]([N:12]3[CH2:13][CH2:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=4)([F:18])[CH2:16][CH2:17]3)=[O:11])=[C:8]([CH3:28])[CH:7]=2)[CH2:30][CH2:31][CH2:32]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 67170Acetamidine monohydrochlorideHCID 86672542HCID 86672542, compound2×

Product 1

HCID 682887014-(1-(4-Cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrileYield 35.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH3CN (10 mL). Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 80° C. in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 13 mg (35%) of the title compound as a white solid. m/z (ES+) 457 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.78 (d, 2H), 7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers, 1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30 (m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).

Workup

  1. customTo a round-bottom flask, which was purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. temperaturecooled to ambient temperature
  4. concentrationconcentrated under reduced pressure
  5. dissolutionThe residue was dissolved in 50 mL of ethyl acetate
  6. washThe organic layer was washed with 2×20 mL of water, 2×20 mL of brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under vacuum
  9. customThe crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  10. waitmobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min
  11. waitup to 100.0% in 2 min
  12. waitdown to 29.0% in 2 min)
  13. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-dd23e8523e7445b391b90c559c9954e2
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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