Potassium Fluoride → 2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide

Participants

Role	Name	HCID	Charge
Reactant	Potassium Fluoride	HCID 522689	—
Reactant	(4-Fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate	HCID 58043634	—
Reactant	N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)-2-cyanoacrylamide	HCID 118116912	—
Catalyst	Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)	HCID 178418228	—
Solvent	Water	HCID 962	—
Solvent	Acetonitrile	HCID 6342	—
Product	2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide	HCID 118116974	15.7%

Reaction Conditions

Temperature	75 °C

Reaction Steps

A mixture of 117a (300 mg, 0.72 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (430 mg, 0.86 mmol), Pd(dppf)Cl2 (52 mg, 0.072 mmol), KF (125 mg, 2.16 mmol) in acetonitrile (10 mL) and H2O (2 mL) was stirred at 75° C. for 3 h under nitrogen. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (PE/EA=1/3) to give 2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide 117b (80 mg, 15%) as white solid. ESI-LCMS: m/z=709.8

Provenance & Evidence

DOI	10.6084/m9.figshare.5104873.v1
Patent number	US09260415B2
Source dataset	uspto-grants-2016_02
ORD ID	ord-956edc7abc294dc999f53f989886398d
Source note	uspto-grants-2016_02