3-(Azidomethyl)-6-(2,6-difluorophenyl)pyridazine → N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine

HRID 716195Notes

Reaction equation

HRID 716195 reaction equation
[N:1]([CH2:4][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[CH:9][CH:10]=1)=[N+]=[N-].[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[N:26]=[C:27]=S>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH:26][C:27]1[N:6]2[N:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=[CH:10][C:5]2=[CH:4][N:1]=1

Participants

5

Reactant 2

HCID 709823613-(Azidomethyl)-6-(2,6-difluorophenyl)pyridazineHCID 891577604-Chloro-3-isothiocyanatopyridine

Product 1

HCID 70982735N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amineYield 54%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine PMe3 (0.62 mL of 1.0 M solution in THF, 0.62 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 140 mg, 0.57 mmol) in THF (2.5 mL) at RT. The reaction turned purple and an evolution of gas was observed. It was stirred for 15 min at RT. A solution of 4-chloro-3-isothiocyanatopyridine (Preparation XXIV, 106 mg, 0.62 mmol) in THF (1 mL) was added. After 15 min at RT, the reaction was diluted with EtOAc (50 mL) and washed with H2O (10 mL). The aqueous phase was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide N-(4-chloro-3-pyridinyl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine (110 mg, 54% yield) as an orange crystalline solid. MS (ESI, pos. ion) m/z: 350.8 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (s, 1 H), 8.17 (d, J=5.09 Hz, 1 H), 7.79 (d, J=9.59 Hz, 1 H), 7.64 (s, 1 H), 7.40-7.51 (m, 1 H), 7.37 (s, 1 H), 7.32 (d, J=5.09 Hz, 1 H), 7.07 (m, 2 H), 6.57 (dt, J=9.44, 1.64 Hz, 1 H).

Workup

  1. waitAfter 15 min at RT
  2. washwashed with H2O (10 mL)
  3. extractionThe aqueous phase was extracted with EtOAc (2×15 mL)
  4. washThe combined organic layers were washed with brine (15 mL)
  5. dry with materialdried over anh. Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-84c286e8bf4342f4833437faf5fab5e0
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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