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

HRID 1432665Notes

Reaction equation

HRID 1432665 reaction equation
C1COCC1.Br[C:7]1[C:8]([Cl:28])=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([CH3:26])[CH:19]=[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3=[N:14][C:13]=2[CH3:27])[S:10][CH:11]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1.Cl.CCO>C(OCC)(=O)C.[Zn].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]>[ClH:28].[Cl:28][C:8]1[C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)=[CH:11][S:10][C:9]=1[C:12]1[N:16]2[N:17]=[C:18]([CH3:26])[CH:19]=[C:20]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2=[N:14][C:13]=1[CH3:27]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 702EthanolHCID 8028TetrahydrofuranHCID 792052-Bromo-6-methylpyridineHCID 579330783-(4-Bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 1317277203-[3-Chloro-4-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine, hydrochloride saltYield 19.7%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

Reike® Zn (0.5 g/mL solution in THF (1.9 mL, 1.45 mmol) is added to a flask containing 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.73 mmol). The slurry is heated at 65° C. for 1 hour, placed in a centrifuge for 5 minutes, and the resulting solution is transferred to a flask containing 2-bromo-6-methyl-pyridine (0.12 g, 0.73 mmol) and PdCl2(dppf) (0.018 g, 0.024 mmol). The reaction is heated at 65° C. overnight, diluted with ethyl acetate (20 mL), and washed with a sat. solution of NH4Cl (15 mL). The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified by silica gel chromatography using a hexanes and ethyl acetate 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 ethyl acetate and hexanes furnish the title compound (0.033 g, 0.072 mmol, 11%). 1H-NMR (CDCl3), δ 0.95 (t, J=7.3 Hz, 6H), 1.73-2.02 (m, 4H), 2.68 (s, 3H), 2.81 (s, 3H), 3.21 (s, 3H), 3.88-3.98 (m, 1H), 7.25 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 8.09 (d, J=7.5 Hz, 1H), 8.33 (dd, J=7.5, 7.1 Hz, 1H), 9.26 (s, 1H) ppm. LC/MS (m/z): calcd. for C23H26Cl2N4S (M+H)+: 424.2; found: 424.2.

Workup

  1. customthe resulting solution is transferred to a flask
  2. temperatureThe reaction is heated at 65° C. overnight
  3. washwashed with a sat. solution of NH4Cl (15 mL)
  4. dry with materialThe organic layer is dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by silica gel chromatography
  8. dissolutionThe resulting product is dissolved in dichloromethane (5 mL)
  9. concentrationconcentrated
  10. customThe residue is recrystallized from ethyl acetate and hexanes

Sources & evidence

ORD record
ord-c6926cefbcf14f3fafd23a9510ea66e3
Source dataset
uspto-grants-2009_11
Patent number
US07612067B2

Reaction notes

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