1,2-Dimethoxyethane → 6-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one

HRID 870648Notes

Reaction equation

HRID 870648 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:16]=[C:17]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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].O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[C:17](=[O:16])[NH:18][CH2:19][CH2:20]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 62657Potassium Phosphate, TribasicHCID 49835905(1-Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acidHCID 866963223-Bromo-6-(butylamino)imidazo[1,2-b]pyridazine

Product 1

HCID 866963446-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydro-2H-isoquinolin-1-oneYield 44%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
160 °C

Procedure

A mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (160 mg, 0.61 mmol), (1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (200 mg, 0.73 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (50 mg, 0.06 mmol), potassium phosphate (250 mg, 1.2 mmol), DME (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 360 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford 6-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (90 mg, 44%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.11-8.20 (m, 2H), 7.94 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.57 (d, J=9.7 Hz, 1H), 6.67 (d, J=9.7 Hz, 1H), 3.50 (t, J=6.7 Hz, 2H), 3.34 (t, J=7.2 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 1.60-1.75 (m, 2H), 1.36-1.50 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); LCMS (ESI) m/e 336.2 [(M+H)+, calcd for C19H22N6O 336.2].

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous layer was extracted with ethyl acetate (2 mL)
  3. concentrationThe combined organic layers were concentrated under reduced pressure
  4. customto afford an oil that
  5. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-66bc815b85ac429f92cb259ddb4de555
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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