Potassium Carbonate → 2-Methyl-2-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-propionic acid

HRID 1890961Notes

Reaction equation

HRID 1890961 reaction equation
C([O:3][C:4](=[O:14])[C:5]([N:8]1[CH:12]=[C:11](I)[CH:10]=[N:9]1)([CH3:7])[CH3:6])C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][C:45]([S:49][C:50]1[N:54]3[N:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]3=[N:52][N:51]=1)=[CH:44][CH:43]=2.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O.CC(N(C)C)=O>[CH3:7][C:5]([N:8]1[CH:12]=[C:11]([C:39]2[CH:40]=[N:41][C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([S:49][C:50]2[N:54]4[N:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:53]4=[N:52][N:51]=2)=[CH:44][CH:43]=3)[CH:10]=[N:9]1)([CH3:6])[C:4]([OH:3])=[O:14]

Participants

9

Reactant 6

HCID 11430Potassium CarbonateHCID 24436Sodium SulfateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 249009763-Bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolineHCID 57911028ethyl 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanoate

Product 1

HCID 249009782-Methyl-2-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-propionic acidYield 19%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent2×

Procedure

A microwave vessel was charged with 2-(4-iodo-pyrazol-1-yl)-2-methyl-propionic acid ethyl ester (50 mg, 0.162 mmol), bis(pinacolato)diboron (50 mg, 0.195 mmol), potassium acetate (48 mg, 0.486 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (6.6 mg, 0.008 mmol), and DMA (0.6 mL). The vessel was flushed with nitrogen and capped. The reaction mixture was microwaved at 130° C. for 30 min. 3-Bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (48 mg, 0.13 mmol) and dichlorobis(triphenylphosphine) palladium(0) (5.7 mg, 0.008 mmol) were added, followed by DMA (0.4 mL) and a 2 M aqueous solution of potassium carbonate (0.5 mL). The reaction mixture was microwaved at 130° C. for 1 h. Solid sodium sulfate was added to soak up the water, and the liquid layer was filtered through a 0.45 um filter. The crude mixture was diluted to 2 mL with DMSO and purified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 11 mg of 2-methyl-2-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-propionic acid as a cream-colored solid (19% yield).

Workup

  1. customThe vessel was flushed with nitrogen
  2. customcapped
  3. customThe reaction mixture was microwaved at 130° C. for 30 min
  4. customThe reaction mixture was microwaved at 130° C. for 1 h
  5. filtrationthe liquid layer was filtered through a 0.45 um
  6. filtrationfilter
  7. additionThe crude mixture was diluted to 2 mL with DMSO
  8. custompurified directly by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier)

Sources & evidence

ORD record
ord-91c2cc5629f44a4f9c839a3d84e53902
Source dataset
uspto-grants-2013_08
Patent number
US08507489B2

Reaction notes

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