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

HRID 1774668Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([C:24]#[N:25])=[CH2:23])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][C:35]([F:47])=[CH:34][C:33]=1[N:48]1[C:60](=[O:61])[C:59]2[S:58][C:57]3[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=3[C:51]=2[CH:50]=[N:49]1)(=[O:29])[CH3:28].[F-].[K+]>C(#N)C.O.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]>[C:24]([C:22](=[CH2:23])[C:21]([NH:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:37]3[CH:36]=[C:35]([F:47])[CH:34]=[C:33]([N:48]4[C:60](=[O:61])[C:59]5[S:58][C:57]6[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=6[C:51]=5[CH:50]=[N:49]4)[C:32]=3[CH2:31][O:30][C:27](=[O:29])[CH3:28])[CH:3]=2)[N:16]=1)=[O:26])#[N:25]

Participants

Conditions

Temperature: 75 °C

Procedure

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

Workup

concentrationThe reaction mixture was concentrated
customthe residue was purified by silica gel chromatography (PE/EA=1/3)

Sources & evidence

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

Reaction notes

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