Ethyl Acetate → HCID 178518680, compound

HRID 2358269Notes

Reaction equation

HRID 2358269 reaction equation
Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[C:31]([F:38])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[Cl-].[Na+].O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:34]5[C:29]([F:28])=[N:30][C:31]([F:38])=[CH:32][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 2762713(2,6-Difluoropyridin-3-yl)boronic acidHCID 178518678HCID 178518678, compound

Product 1

HCID 178518680HCID 178518680, compound

Reagents, catalysts & solvents 1

HCID 57417360Sodium chloride; waterSolvent

Procedure

A sealed tube was charged with the intermediate from Example 1 Step E (230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6 mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added, followed by the addition of 2.0M aqueous sodium carbonate solution (2.6 mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., and stirred for 3 hours. The reaction mixture was then cooled and poured into a mixture of ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo. Purification via flash chromatography (silica, 0-20% methanol/dichloromethane) was followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43 (q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was not observed [M+H]+ 476. τR: 9.44 min (analytical chiral HPLC, AD column, 0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).

Workup

  1. customThe tube was evacuated
  2. additionFully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added
  3. customThe tube was sealed
  4. customplaced in an oil bath at 90° C.
  5. temperatureThe reaction mixture was then cooled
  6. extractionThe aqueous layer was extracted twice with ethyl acetate
  7. dry with materialthe combined organics were dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification via flash chromatography (silica, 0-20% methanol/dichloromethane)
  11. customwas followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic)

Sources & evidence

ORD record
ord-d03891dd115347b5ae7dba3363a08de6
Source dataset
uspto-grants-2010_07
Patent number
US07763634B2

Reaction notes

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