Ethanol → 3-[5-(2,6-Difluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamide

HRID 2097592

Reaction equation

HRID 2097592 reaction equation
N1[CH:6]=[CH:5][C:4]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])=[N:3]C=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[B-](F)(F)F.[K+].CCO.[CH2:38]([N:40](CC)CC)C>C(Cl)Cl>[N:40]1[CH:38]=[CH:6][CH:5]=[C:4]([NH:7][C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[CH:17][N:16]=3)[CH2:13]2)=[O:9])[N:3]=1

Participants

6

Reactant 4

HCID 702EthanolHCID 8471TriethylamineHCID 23677741Potassium (2,6-difluorophenyl)trifluoroboranuide2×HCID 667101533-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrimidin-4-ylamide

Product 1

HCID 442190533-[5-(2,6-Difluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridazin-3-ylamideYield 17%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
80 °C

Procedure

3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyrimidin-4-ylamide (50 mg, 0.126 mmol), potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), triethylamine (0.05 ml, 0.38 mmol) 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and EtOH (108 mg, 0.786 mmol) were combined and heated at 80° C. for 16 h. The reaction had not gone to completion so further potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and triethylamine (0.05 ml, 0.38 mmol) were added and the mixture heated for a further 5 h. The reaction mixture was allowed to cool before being passed through a pad of celite and washed through with EtOAc and MeOH. These organics were evaporated in vacuo, to afford a crude oil, which was purified by flash chromatography, eluting with a gradient of 0 to 4% MeOH in CH2Cl2 to a afford still impure product as a brown oil. This was purified by HPLC (pH 4, HCO2NH4/HCO2H/H2O/MeCN) to afford the desired product as a white solid (8 mg, 17%)

Workup

  1. additionwere added
  2. temperaturethe mixture heated for a further 5 h
  3. temperatureto cool
  4. washwashed through with EtOAc and MeOH
  5. customThese organics were evaporated in vacuo
  6. customto afford a crude oil, which
  7. customwas purified by flash chromatography
  8. washeluting with a gradient of 0 to 4% MeOH in CH2Cl2 to
  9. customa afford still impure product as a brown oil
  10. customThis was purified by HPLC (pH 4, HCO2NH4/HCO2H/H2O/MeCN)

Sources & evidence

ORD record
ord-d6bbf01691e945e5a7c744976b124826
Source dataset
uspto-grants-2013_05
Patent number
US08450346B2

Linked notes

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