Cyclobutanone → 6-Chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine

HRID 1369435

Reaction equation

HRID 1369435 reaction equation
[Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:22]2([OH:26])[CH2:25][CH2:24][CH2:23]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1

Participants

5

Reactant 2

HCID 14496CyclobutanoneHCID 154861756-Chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-[1,2,4]triazolo[4,3-b]pyridazine

Product 1

HCID 226099106-Chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazineYield 26%

Reagents, catalysts & solvents 2

HCID 1784490421-Butanaminium, N,N,N-tributyl-, (TB-5-11)-difluorotriphenylstannate(1-) (1:1)Catalyst2×HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (1.04 g, 3.24 mmol) in anhydrous THF (15 ml) under nitrogen was added cyclobutanone (1.21 ml, 16.2 mmol), followed by solid tetrabutylammonium difluorotriphenylstannate (0.410 g, 0.650 mmol). The flask was evaporated and refilled with nitrogen four times, then stirred at room temperature for 5.75 h. More tetrabutylammonium difluorotriphenylstannate (0.403 g, 0.639 mmol) was added and the mixture was stirred for a further 36 h. The mixture was then partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was extracted further with dichloromethane (2×50 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in, vacuo. The residue was purified by flash chromatography (silica gel. 70-100% EtOAc/hexane) to give 0.2634 g (26%) of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) δ1.81 (1H, m), 2.27 (1H, m), 2.52 (2H, m), 2.72 (2H, m), 2.87 (1H, s), 7.30 (1H, t, J=9.3 Hz), 7.36 (1H, t, J=7.5 Hz), 7.58 (1H, m), 7.88 (1H, td, J=7.3 and 1.8 Hz), 8.12 (1H, s); MS (ES+) m/e 319/321 [MH]+, 249.

Workup

  1. customThe flask was evaporated
  2. additionrefilled with nitrogen four times
  3. stirringthe mixture was stirred for a further 36 h
  4. customThe mixture was then partitioned between dichloromethane (75 ml) and water (75 ml)
  5. extractionThe aqueous layer was extracted further with dichloromethane (2×50 ml)
  6. dry with materialthe combined organic extracts were dried (Na2SO4)
  7. customevaporated in, vacuo
  8. customThe residue was purified by flash chromatography (silica gel. 70-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-919582391af54c99846fe6dfd078cb24
Source dataset
uspto-grants-2003_06
Patent number
US06579875B1

Linked notes

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