Potassium Carbonate → HCID 68288596, compound

HRID 541389Notes

Reaction equation

HRID 541389 reaction equation
Br[CH2:2][C:3]([C:5]1[C:6]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[CH:7][C:8]([CH3:27])=[C:9]([CH:26]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=O.Cl.[C:33](=[NH:37])([NH2:36])[CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:28]1([C:6]2[C:5]([C:3]3[NH:36][C:33]([CH2:34][CH3:35])=[N:37][CH:2]=3)=[CH:26][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:8]([CH3:27])[CH:7]=2)[CH2:31][CH2:30][CH2:29]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 12301253Propionimidamide hydrochlorideHCID 86672541HCID 86672541, compound2×

Product 1

HCID 68288596HCID 68288596, compoundYield 45.2%

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)piperidin-4-yl)benzonitrile (compound 235.2, 100 mg, 0.210 mmol, 1.00 equiv) in CH3CN (5 mL). Propionimidamide hydrochloride (22.8 mg, 1.00 equiv) and potassium carbonate (86.6 mg, 0.63 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 80° C., then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 20 mL of water. The mixture was extracted with 2×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (˜100 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 7 min, up to 100.0% in 3 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 43 mg (44%) of the title compound as a white solid. m/z (ES+) 453 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d with fine structure, J=7.8 Hz, 2H), 7.56-7.53 (m, 4H), 7.30 and 7.20 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 3.84-3.70 (m, 1H), 3.70-3.53 (m, 1H), 3.33-3.19 (m, 1H partially obscured by methanol solvent peak), 3.13-2.92 (m, 4H), 2.48 & 2.38 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.29-2.11 (m, 4H), 2.11-1.93 (m, 2H), 1.93-1.72 (m, 3H), 1.72-1.53 (m, 1H), 1.45 (t, 3H).

Workup

  1. customTo a round-bottom flask, which was purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. temperaturecooled to room temperature
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in 20 mL of water
  6. extractionThe mixture was extracted with 2×20 mL of ethyl acetate
  7. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customThe crude product (˜100 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 7 min
  11. waitup to 100.0% in 3 min
  12. waitdown to 29.0% in 2 min)
  13. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-eea9744b38bc4df4a43513eb9d64cbfb
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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