Potassium Carbonate → HCID 178437942, compound

HRID 541408Notes

Reaction equation

HRID 541408 reaction equation
[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:30])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH:13]=2)=[N:6][N:7]=1)[CH3:2].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:33]1([C:9]2[C:8]([C:5]3[NH:4][C:3]([CH2:1][CH3:2])=[N:7][N:6]=3)=[CH:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[CH2:20][CH2:21]3)=[O:15])=[C:11]([CH3:30])[CH:10]=2)[CH2:36][CH2:35][CH2:34]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 12308726Azetidine hydrochlorideHCID 1784379414-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile2×

Product 1

HCID 178437942HCID 178437942, compoundYield 20%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

To a 10-mL sealed tube was added a solution of 4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile (compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equiv) in 1,4-dioxane (5 mL). Azetidine hydrochloride (93.0 mg, 0.990 mmol, 5.00 equiv) was added to the reaction in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0 equiv) was also added to the above mixture. The resulting solution was stirred overnight at 105° C. behind a blast shield, then cooled to rt. The reaction was quenched with 20 mL of water. The mixture was extracted with 30 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product (80 mg) was further 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 50 mL NH4CO3 and CH3CN (41.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 41.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18.0 mg (20%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d, J=6.3 Hz, 2H), 7.48 (d, J=5.7 Hz, 2H), 7.24 & 7.13 (2 singlets, amide rotamers, Ar—H, 1H), 6.52 (s, 1H), 4.91-7.77 (m, 1H partially obscured by water peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz, 4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H), 2.45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7 Hz, 3H).

Workup

  1. customTo a 10-mL sealed tube
  2. temperaturecooled to rt
  3. customThe reaction was quenched with 20 mL of water
  4. extractionThe mixture was extracted with 30 mL of ethyl acetate
  5. dry with materialthe organic layer was dried over anhydrous sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe product (80 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  8. waitmobile phase, water with 50 mL NH4CO3 and CH3CN (41.0% CH3CN up to 43.0% in 8 min
  9. waitup to 100.0% in 2 min
  10. waitdown to 41.0% in 2 min)
  11. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-b3e8bf4b7a0748dbad9a51c13a03b518
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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