Water → HCID 86716500, compound

HRID 1501328Notes

Reaction equation

HRID 1501328 reaction equation
[C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].O.CO[CH2:46][CH2:47]OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=3)[N:9]=2)[N:12]=[C:13]([CH:46]=[CH2:47])[CH:14]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 86716498HCID 86716498, compound

Product 1

HCID 86716500HCID 86716500, compoundYield 92%

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Procedure

A mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.30 g, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol, 10 mol %) in 1,2-dimethoxyethane (4 mL) was stirred under an argon atmosphere for 10 min, then was sequentially treated with K2CO3 (0.075 g, 0.54 mmol, 1.0 eq), water (1.5 mL) and vinylboronic acid anhydride pyridine complex (prepared as described in J. Org. Chem. 2002, 67, 4968; 0.13 g, 0.54 mmol, 1.0 eq). The resulting mixture was heated at the reflux temperature for 16 h, then was added to water (15 mL). The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min) to give tert-butyl {1-[4-(8-methoxy-3-phenyl-6-vinylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.25 g, 92%):

Workup

  1. customwas prepared in a manner analgous to
  2. temperatureThe resulting mixture was heated at the reflux temperature for 16 h
  3. extractionThe resulting mixture was extracted with EtOAc (2×25 mL)
  4. washThe combined organic phases were washed with water (25 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting material was purified
  8. customMPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 1.5 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 4.0 min, gradient to 100% EtOAc 4.5 min, 100% EtOAc 7.7 min)

Sources & evidence

ORD record
ord-dcc240a7df8545b591fd630ab4a41ba3
Source dataset
uspto-grants-2015_12
Patent number
US09206185B2

Reaction notes

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