Hydrochloric Acid → 6-(2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine

HRID 1930048Notes

Reaction equation

HRID 1930048 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)=[C:25]2[CH2:26][CH2:27][CH2:28][N:24]2[N:23]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 2723922Sodium ethoxideHCID 866352991-(1-(2,4-Difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one

Product 1

HCID 579298816-(2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazineYield 54.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.

Workup

  1. customwas carried on without further purification
  2. customA 10 mL round-bottomed flask equipped
  3. temperaturewith reflux condenser
  4. customoutfitted with a nitrogen inlet adapter
  5. customto give a yellow solution
  6. customto give a yellow suspension
  7. temperatureThe reaction mixture was heated
  8. temperatureto reflux for about 5 h
  9. extractionThe aqueous layer was extracted with EtOAc
  10. dry with materialThe combined organic extracts were dried with MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe resulting residue was purified via silica gel chromatography
  14. washeluting with a gradient of 0-10% MeOH in DCM
  15. concentrationThe product-containing fractions were concentrated under reduced pressure
  16. customthe resulting material was crystallized from EtOAc/heptane

Sources & evidence

ORD record
ord-2897c89e19634cef991e8b2d8c9dab5f
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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