Potassium Carbonate → 2-(8-Fluoro-2-{3-formyl-4-[1-methyl-5-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-1-oxo-1,2dihydro-isoquinolin-6-yl)-2-methyl-propionitrile

HRID 337324Notes

Reaction equation

Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[C:14]3[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:78][C:79]1[CH:80]=[C:81]([C:99]([CH3:103])([CH3:102])[C:100]#[N:101])[CH:82]=[C:83]2[C:88]=1[C:87](=[O:89])[N:86]([C:90]1[C:95]([CH:96]=[O:97])=[C:94](I)[CH:93]=[CH:92][N:91]=1)[CH:85]=[CH:84]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[F:78][C:79]1[CH:80]=[C:81]([C:99]([CH3:103])([CH3:102])[C:100]#[N:101])[CH:82]=[C:83]2[C:88]=1[C:87](=[O:89])[N:86]([C:90]1[C:95]([CH:96]=[O:97])=[C:94]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:20]=[C:14]5[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][N:13]5[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH:93]=[CH:92][N:91]=1)[CH:85]=[CH:84]2

Participants

Conditions

Temperature: 100 °C

Procedure

6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (511 mg, 1.73 mmol, 1 equiv.), bis(pinacolato)diboron (485 mg, 1.91 mmol, 1.1 equiv.) and potassium acetate (511 mg, 5.2 mmol, Eq: 3) were suspended in dioxane (25 ml). The reaction mixture was degassed under argon. X-PHOS (124 mg, 260 μmol, Eq: 0.15) and palladium(II) acetate (19.5 mg, 86.7 μmol, 0.05 equiv.) were added and the reaction mixture was stirred at 100° C. (external temperature) for 40 min. under an argon atmosphere until reaction was complete. Bath temperature was reduced to 80° C. Flask was raised out of the heating bath, but continued stirring. 2-(8-fluoro-2-(3-formyl-4-iodopyridin-2-yl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile (800 mg, 1.73 mmol, 1.0 equiv.) and potassium carbonate (719 mg, 5.2 mmol, 3 equiv.) were added, followed by 2.5 mL H2O. Tricyclohexylphosphine (48.6 mg, 173 μmol, 0.1 equiv.) and bis(dibenzylideneacetone)palladium (49.9 mg, 86.7 μmol, 0.05 equiv.) were added. The reaction mixture was heated with vigorous stirring at 80° C. and stirred for 1.5 h. The reaction mixture was poured onto water. Some brine was added to break up the emulsion and the mixture was extracted with DCM (4 times). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated by adding 10 mL EtOAc followed by 75 mL ether. The solid was collected by filtration and washed several times with ether to give a pale green/grey solid (800 mg). (M+H)+=594 m/e. The product was used as is in the next step without further purification.

Workup

customThe reaction mixture was degassed under argon
customuntil reaction
customBath temperature was reduced to 80° C
temperatureFlask was raised out of the heating bath
stirringcontinued stirring
temperatureThe reaction mixture was heated
stirringwith vigorous stirring at 80° C.
stirringstirred for 1.5 h
additionThe reaction mixture was poured onto water
extractionthe mixture was extracted with DCM (4 times)
dry with materialThe combined organic extracts were dried over Na2SO4
concentrationconcentrated in vacuo
customThe resulting solid was triturated
additionby adding 10 mL EtOAc
filtrationThe solid was collected by filtration
washwashed several times with ether

Sources & evidence

ORD record: ord-d279e380f28b482fab26307d61f6567c
Source dataset: uspto-grants-2014_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08889682B2

Reaction notes

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