Hydrochloric Acid → 3-(3-Chloro-4-pyridin-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine, hydrochloride salt

HRID 1432672Notes

Reaction equation

HRID 1432672 reaction equation
Br[C:2]1[C:3]([Cl:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.CCO>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[ClH:23].[Cl:23][C:3]1[C:2]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:6][S:5][C:4]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 702EthanolHCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 2734379(Pyridin-4-yl)boronic acidHCID 579330783-(4-Bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 1317277223-(3-Chloro-4-pyridin-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine, hydrochloride saltYield 111.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 10311-PropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A solution of 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.61 mmol), 4-pyridyl-boronic acid (0.82, 0.67 mmol), a 2 M solution of Na2CO3 (0.5 mL, 0.91 mmol), and n-PrOH (2.5 mL) are degassed with nitrogen for 10 minutes. Pd(OAc)2 (0.0027 g, 0.012 mmol) and PPh3 (0.0095 g, 0.036 mmol) are added, and the solution heated at a 90° C. overnight. The solution is diluted with ethyl acetate (40 mL) and washed with a 10% solution of Na2CO3 (30 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by ISCO flash chromatography (20%-30% EtOAc gradient). The resulting product is dissolved in dichloromethane (5 mL), treated with a 1 M solution of HCl in EtOH (0.35 mL, 0.35 mmol), and concentrated. The residue is recrystallized from acetonitrile and ethyl acetate furnish the title compound (0.15 g, 0.34 mmol, 56%). 1H-NMR (CDCl3), δ 0.95 (t, J=7.5 Hz, 6H), 1.73-1.88 (m, 2H), 1.89-2.04 (m, 2H), 2.68 (s, 3H), 2.82 (s, 3H), 3.87-3.97 (m, 1H), 7.28 (s, 1H), 8.26-8.34 (m, 3H), 8.95 (d, J=5.3 Hz, 2H) ppm. LC/MS (m/z): calcd. for C22H24Cl2N4S (M+H)+: 411.1; found: 411.2.

Workup

  1. washwashed with a 10% solution of Na2CO3 (30 mL)
  2. dry with materialThe organic layer is dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue is purified by ISCO flash chromatography (20%-30% EtOAc gradient)
  6. dissolutionThe resulting product is dissolved in dichloromethane (5 mL)
  7. concentrationconcentrated
  8. customThe residue is recrystallized from acetonitrile and ethyl acetate

Sources & evidence

ORD record
ord-c98fc304ec4241928de6c0b5160ae377
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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