Potassium Phosphate, Tribasic → Tert-butyl 5-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)isoindoline-2-carboxylate

HRID 870661Notes

Reaction equation

HRID 870661 reaction equation
[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12](B(O)O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C(#N)C.O>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:27]3[CH:26]=[C:25]4[C:21](=[CH:20][CH:19]=3)[CH2:22][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]4)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 16102683N-Boc-5-bromoisoindolineHCID 86696352(6-(Butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid

Product 1

HCID 86696359Tert-butyl 5-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)isoindoline-2-carboxylateYield 66%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
145 °C

Procedure

To a mixture of (6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)boronic acid (47 mg, 0.2 mmol), tert-butyl 5-bromoisoindoline-2-carboxylate (47 mg, 0.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol) and tripotassium phosphate (41 mg, 0.3 mmol) was added 3:1 acetonitrile/water (3 mL). The resulting mixture was heated at 145° C. (microwave) for 800 s. The reaction was then filtered and concentrated. The residue was dissolved in methanol, and then filtered again. The filtration was finally purified by preparative HPLC (neutral) to afford tert-butyl 5-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)isoindoline-2-carboxylate (43 mg, 66% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.15 (d, J=10.9 Hz, 1H), 8.00-8.08 (m, 1H), 7.75 (s, 1H), 7.59 (d, J=9.6 Hz, 1H), 7.35 (t, J=9.1 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 4.69 (br. s., 4H), 3.37 (d, J=7.3 Hz, 2H), 1.65-1.78 (m, 2H), 1.56 (s, 9H), 1.45-1.53 (m, 2H), 1.02 (td, J=7.3, 2.3 Hz, 3H); LRMS (ESI) m/e 408.3 [(M+H)+, calcd for C23H30N5O2 408.2].

Workup

  1. filtrationThe reaction was then filtered
  2. concentrationconcentrated
  3. dissolutionThe residue was dissolved in methanol
  4. filtrationfiltered again
  5. filtrationThe filtration
  6. customwas finally purified by preparative HPLC (neutral)

Sources & evidence

ORD record
ord-6a93d59f5a38454fa99fe6ba8b27f21b
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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