Azetidine-1-carbothiohydrazide → 6-(2-(2,4-Difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine

HRID 1930043Notes

Reaction equation

HRID 1930043 reaction equation
Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[N:25]1([C:29](=S)[NH:30][NH2:31])[CH2:28][CH2:27][CH2:26]1>CC(O)=O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[C:2]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=3)[N:18]=2)=[C:29]2[NH:25][CH2:26][CH2:27][CH2:28][N:30]2[N:31]=1

Participants

4

Reactant 2

HCID 57929853Azetidine-1-carbothiohydrazideHCID 579298612-Bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone

Product 1

HCID 1361368236-(2-(2,4-Difluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazineYield 26.3%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.61 g, 1.54 mmol; Preparation #A.2) and azetidine-1-carbothiohydrazide (0.29 g, 2.20 mmol) in HOAc (5 mL) was stirred at about 55° C. for about 1-2 h. The reaction mixture was cooled to ambient temperature overnight and partitioned between DCM and water. The aqueous layer was basified with a saturated aqueous solution of Na2CO3 and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by chromatography on silica gel using DCM/MeOH (gradient, 100:0 to 90:10), stirred overnight with Et2O/DCM (100:10), and collected by vacuum filtration to give the title compound (0.16 g, 26%): LC/MS (Table 1, Method a) Rt=2.98 min; MS m/z: 396.2 (M+H)+; 1H NMR (CDCl3) δ 7.76 (d, J=9.89 Hz, 1H), 7.56-7.51 (m, 1H), 7.11-6.99 (m, 1H), 6.98-6.87 (m, 1H), 6.73 (dd, J=9.89, 1.83 Hz, 1H), 6.44 (s, 1H, broad), 4.2 (t, J=6.08 Hz, 2H), 3.61-3.58 (m, 2H), 3.56-3.52 (m, 1H), 2.36-2.24 (m, 2H), 1.58 (d, J=6.99 Hz, 6H).

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature overnight
  2. custompartitioned between DCM and water
  3. extractionextracted with DCM
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting crude material was purified by chromatography on silica gel
  8. stirringstirred overnight with Et2O/DCM (100:10)
  9. filtrationcollected by vacuum filtration

Sources & evidence

ORD record
ord-a02589ee6ffd48a9b3be3b86de0a3de5
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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