Water → HCID 68291100, compound

HRID 1507949Notes

Reaction equation

HRID 1507949 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:20](=[O:22])[NH2:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]([C:8]1[CH:7]=[N:6][N:5]2[CH:23]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][CH:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])(=[O:22])[NH2:21]

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 66827Phenylboronic AcidHCID 68291273HCID 68291273, compound

Product 1

HCID 68291100HCID 68291100, compoundYield 60.4%

Reagents, catalysts & solvents 2

HCID 2723671Tetrabutylammonium HydroxideCatalystHCID 1140TolueneSolvent

Procedure

To a solution of methyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylbutanoate (1.0 g, 2.61 mmol) in toluene (10 ml) was added phenyl boronic acid (0.44 g, 3.91 mmol) and stirred for 10 minutes at RT. Sodium carbonate (0.553 gm, 5.22 mmol), Pd(dppf)2 (0.10 gm, 3.91 mmol), water (2.0 ml) and tetrabutyl ammonium hydroxide (1 drop) was added at room temperature under nitrogen atmosphere and the reaction mixture was degassed with nitrogen for 15 minutes. The reaction mixture was stirred at 110° C. in a CEM microwave synthesizer for 8 hours. Upon completion, the reaction mixture was cooled to room temperature and the layers were separated. The aqueous layer was washed with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhyd. sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified by column chromatography using 30% ethyl acetate in hexanes as the eluting solvent to give the title compound (600 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 1.32-1.34 (m, 6H), 1.37-1.39 (m, 3H), 3.73 (s, 3H), 4.68-4.70 (m, 1H), 7.157-7.161 (d, J=1.6 Hz, 1H), 7.27-7.31 (m, 1H), 7.41-7.44 (m, 2H), 7.62-7.65 (m, 2H), 7.87-7.88 (m, 2H). 10.60-10.63 (d, J=10 Hz, 1H).

Workup

  1. customthe reaction mixture was degassed with nitrogen for 15 minutes
  2. stirringThe reaction mixture was stirred at 110° C. in a CEM microwave synthesizer for 8 hours
  3. temperatureUpon completion, the reaction mixture was cooled to room temperature
  4. customthe layers were separated
  5. washThe aqueous layer was washed with ethyl acetate (3×50 ml)
  6. washThe combined organic layers were washed with brine (25 ml)
  7. customdried over anhyd
  8. filtrationsodium sulfate, filtered
  9. concentrationconcentrated under vacuum
  10. customThe crude compound was purified by column chromatography

Sources & evidence

ORD record
ord-58c3b2bb9cde4704803738ec6e5bf119
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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