1,2-Dimethoxyethane → 3-(4-(Aminomethyl)phenyl)-n-(tetrahydro-2h-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine

HRID 870630Notes

Reaction equation

HRID 870630 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=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>[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:23][CH:22]=1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 62657Potassium Phosphate, TribasicHCID 27343114-Aminomethylphenylboronic acid hydrochlorideHCID 25103082(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-(tetrahydropyran-4-yl)-amine

Product 1

HCID 668898113-(4-(Aminomethyl)phenyl)-n-(tetrahydro-2h-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amineYield 20%

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-(tetrahydro-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine (100 mg, 0.34 mmol), 4-(aminomethyl)phenylboronic acid hydrochloride (160 mg, 0.84 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (25 mg, 0.034 mmol), potassium phosphate (360 mg, 1.7 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 [3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-amine (20.5 mg, 20%) as a yellow solid: 1H NMR (400 MHz, MeOD) δ 8.24 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.74 (d, J=10 Hz, 1H), 4.13 (s, 2H), 4.06-3.92 (m, 3H), 3.61 (t, J=11.2 Hz, 2H), 2.15 (d, J=12.8 Hz, 2H), 1.65 (qd, J=11.2, 4.4 Hz, 2H); LCMS (ESI) m/e 324.2 [(M+H)+, calcd for C18H22N5O 324.2].

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-dffb1d720b75425c977bc99d78c1d700
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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