Potassium Phosphate, Tribasic → N-[(1S)-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]-1-methyl-ethyl]prop-2-enamide

HRID 1774648Notes

Reaction equation

HRID 1774648 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]([F:46])=[CH:33][C:32]=1[N:47]1[C:59](=[O:60])[C:58]2[S:57][C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[C:50]=2[CH:49]=[N:48]1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[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]>[F:46][C:34]1[CH:33]=[C:32]([N:47]2[C:59](=[O:60])[C:58]3[S:57][C:56]4[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=4[C:50]=3[CH:49]=[N:48]2)[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:35]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 58043634(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 acetateHCID 118116485(S)-N-(1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)propan-2-yl)acrylamide

Product 1

HCID 118117062N-[(1S)-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]-1-methyl-ethyl]prop-2-enamideYield 27.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of (S)—N-(1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)propan-2-yl)acrylamide 107d (150 mg, 0.37 mmol), 108c (200 mg, 0.40 mmol), Pd(dppf)Cl2(27 mg, 10 mol %) and K3PO4(235 mg, 1.11 mmol) in acetonitrile (20 mL) and water (5 ml) was stirred at 85° C. for 4 h under nitrogen. The reaction mixture was cooled to rt and concentrated. The residue was purified by prep-TLC (DCM/MeOH=30/1) to give 108d (70 mg crude) as yellow solid

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. concentrationconcentrated
  3. customThe residue was purified by prep-TLC (DCM/MeOH=30/1)

Sources & evidence

ORD record
ord-ff7455d3665d4a0c8766c1c596c6eb23
Source dataset
uspto-grants-2016_02
Patent number
US09260415B2

Reaction notes

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