Cesium fluoride → HCID 136408033, compound

HRID 1501333Notes

Reaction equation

HRID 1501333 reaction equation
Br[C:2]1[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1B(O)O.[F-].[Cs+]>COCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:6]1[CH:7]=[C:2]([C:37]2[NH:36][CH:40]=[CH:39][N:38]=2)[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 450736021H-Imidazol-2-ylboronic acidHCID 86716502HCID 86716502, compound

Product 1

HCID 136408033HCID 136408033, compoundYield 37%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8020DimethoxymethaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7.1 (0.78 g, 1.42 mmol), 1H-imidazol-2-ylboronic acid (0.024 g, 2.13 mmol, 1.5 equiv.), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride CDM complex (0.12 g, 0.14 mmol, 0.1 equiv.) and cesium fluoride (0.65 g, 4.25 mmol, 3.0 equiv.) in dimethoxymethane (12 mL) was bubbled with Ar, then placed under an argon atmosphere in a sealed vial, and was heated at 100° C. for 3 days. The reaction mixture was then added to ice water (50 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (4×50 mL). The combined organics were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 50% hexane/20% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.5 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min) to give tert-butyl (1-{4-[6-chloro-8-(1H-imidazol-2-yl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.28 g, 37%):

Workup

  1. customwas prepared in a manner analgous to
  2. customwas bubbled with Ar
  3. additionThe reaction mixture was then added to ice water (50 mL)
  4. extractionThe aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (4×50 mL)
  5. dry with materialThe combined organics were dried (Na2SO4 anh.)
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting material was purified
  8. customMPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 50% hexane/20% EtOAc 3.5 min, 50% hexane/50% EtOAc 4.5 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 8.7 min)

Sources & evidence

ORD record
ord-ad9380c572344d2db8f6c6d7ead6d886
Source dataset
uspto-grants-2015_12
Patent number
US09206185B2

Reaction notes

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