Dimethylformamide → tert-butyl 3-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

HRID 1930003Notes

Reaction equation

HRID 1930003 reaction equation
[H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][NH:18][N:17]=1.S(O[CH:44]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][N:18]([CH:48]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47]2)[N:17]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 13591085tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylateHCID 178440301HCID 178440301, compound

Product 1

HCID 57929860tert-butyl 3-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a round bottom flask was added NaH (0.065 g, 1.6 mmol), DMF (4 mL) and 6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.500 g, 1.47 mmol, Example #L.1.1). The reaction mixture was stirred for about 30 min at ambient temperature. tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (0.652 g, 1.91 mmol, prepared according to US 2002/0151712, Example #34c) was added and the reaction mixture was stirred for about 30 min at ambient temperature. The reaction mixture was heated to about 75° C. for about 1 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 90:10) to give the title compound (0.446 g, 60%) as a mixture of regioisomers: LC/MS (Table 1, Method g) Rt=3.66 min; MS m/z: 510.4 (M+H)+.

Workup

  1. stirringthe reaction mixture was stirred for about 30 min at ambient temperature
  2. temperatureThe reaction mixture was heated to about 75° C. for about 1 h
  3. washwashed with water (50 mL)
  4. dry with materialdried with MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 90:10)

Sources & evidence

ORD record
ord-0283a62db6d04277b6e9cd924604557a
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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