Cyclopropanecarboxaldehyde → 3-Cyclopropyl-6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine

HRID 1930083Notes

Reaction equation

HRID 1930083 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:24][CH2:23][CH2:22][N:12]2[C:13]=1[C:14]1[N:15]=[N:16][C:17]([NH:20][NH2:21])=[CH:18][CH:19]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH:25]1([C:28]2[N:16]3[N:15]=[C:14]([C:13]4[N:12]5[CH2:22][CH2:23][CH2:24][C:11]5=[N:10][C:9]=4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH:19]=[CH:18][C:17]3=[N:20][N:21]=2)[CH2:27][CH2:26]1

Participants

5

Reactant 3

HCID 123114CyclopropanecarboxaldehydeHCID 12217721Iodo benzene diacetateHCID 579298742-(2,4-Difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

Product 1

HCID 579299343-Cyclopropyl-6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazineYield 64.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2 °C

Procedure

The 2-(2,4-difluorophenyl)-3-(6-hydrazinylpyridazin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (5.00 g, 15.2 mmol, Example #35, Step E) was reacted with cyclopropanecarbaldehyde (1.60 g, 22.8 mmol) overnight at ambient temperature in DCM (300 mL). The reaction mixture was cooled to about 0-4° C. Iodobenzene diacetate (5.4 g, 16.75 mmol) was added and the reaction mixture stirred at about 0-4° C. for about 30 min and then at ambient temperature for about 3 h. The reaction mixture was partitioned between DCM and a saturated aqueous Na2CO3 solution. The aqueous phase was back-extracted with of DCM (2×50 mL). The combined organics were dried over MgSO4, filtered, concentrated and purified by chromatography on silica gel using DCM/MeOH (gradient, 100:0 to 95:5) and subsequently triturated with a 90:10 mixture of DCM/Et2O to give the title compound (3.7 g, 64%): LC/MS (Table 1, Method a) Rt=2.22 min; MS m/z: 379.3 (M+H)+; 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.66 (m, 1H), 7.08-7.00 (m, 1H), 6.95-6.85 (m, 2H), 4.55-4.45 (m, 2H), 3.12-3.01 (m, 2H), 2.78 (m, 2H), 2.53-2.42 (m, 1H), 1.45-1.38 (m, 2H), 1.28-1.19 (m, 2H).

Workup

  1. waitat ambient temperature for about 3 h
  2. customThe reaction mixture was partitioned between DCM
  3. extractionThe aqueous phase was back-extracted with of DCM (2×50 mL)
  4. dry with materialThe combined organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified by chromatography on silica gel
  8. customsubsequently triturated with a 90:10 mixture of DCM/Et2O

Sources & evidence

ORD record
ord-a4bbeea53abf488b8a6a64ec8ae16049
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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