Hydrochloric Acid → 2-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol

HRID 1027301Notes

Reaction equation

HRID 1027301 reaction equation
[N:1]1[CH:2]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]4[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)=[CH:18][CH:17]=3)=[C:12]([O:34]C)[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.B(Br)(Br)Br.Cl>C(Cl)Cl>[CH3:33][N:22]([CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)[C:19]1[N:20]=[N:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:3]3[N:4]4[CH2:9][CH2:8][NH:7][CH2:6][C:5]4=[N:1][CH:2]=3)=[CH:11][C:12]=2[OH:34])=[CH:17][CH:18]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 25134Boron tribromideHCID 867107286-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine

Product 1

HCID 1362530362-(6-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenolYield 8.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Example 42-3, 50 mg, 0.1 mmol) in DCM (2 mL) was added 1 M solution of BBr3 in DCM (0.52 mL) dropwise at 78° C. The crude reaction mixture was warmed to RT and stirred overnight. The reaction was quenched with NaHCO3 aq solution at 0° C. and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was acidified to pH 3 using 1N HCl and purified by catch and release using SiliaBond Propylsulfonic Acid® (1 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). After evaporation, the material was purified via reverse phase HPLC to afford 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol (4 mg). MS: 462.4 [M+H+]; LCMS Rt=0.36 min [Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.03 (d, J=10.11 Hz, 1H), 7.74 (d, J=9.09 Hz, 1H), 7.22 (d, J=10.11 Hz, 1H), 6.96 (s, 2H), 6.99 (s, 1H), 5.02 (br. s., 1H), 3.88-4.09 (m, 4H), 3.11 (t, J=5.31 Hz, 2H), 2.92 (s, 3H), 1.62 (d, J=12.63 Hz, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.31 (s, 6H), 1.16 (s, 6H).

Workup

  1. customThe crude reaction mixture
  2. customThe reaction was quenched with NaHCO3 aq solution at 0° C.
  3. extractionextracted with DCM
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude product
  8. custompurified by catch and release
  9. customAfter evaporation
  10. customthe material was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-bd4b8a5d7a2346aaa6bcdbe338213626
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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