Acetic Acid → (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate

HRID 931297Notes

Reaction equation

HRID 931297 reaction equation
C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14](=[NH:18])OCC)[CH2:13][CH2:12]2)[CH:10]=1.[S].C(N(CC)CC)C.Cl.Cl.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]2)=[N:34][C:35]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]2([C:14]3[NH:18][C:35]4=[N:34][C:33]([N:37]5[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]5)=[CH:32][CH:31]=[C:30]4[N:29]=3)[CH2:12][CH2:13]2)[CH:10]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 5362487SulfurHCID 117966385ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidateHCID 131735163(R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate dihydrochloride

Product 1

HCID 178472506(R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylateYield 48.9%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Acetic acid (0.5 mL, 8.88 mmol), ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (445 mg, 1.78 mmol), a catalytic amount of sulfur, and triethylamine (0.8 mL, 5.92 mmol) were added to a suspension of (R)-ethyl 1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylate dihydrochloride (500 mg, 1.48 mmol) in ethanol (25 mL) at room temperature. The reaction mixture was heated at reflux for 18 h, then was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 25-70% ethyl acetate in petroleum ether) to afford (R)-ethyl 1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (300 mg). MS (ES+) (M+H) 415.2.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 18 h
  3. concentrationwas concentrated under reduced pressure
  4. customThe resulting residue was partitioned between ethyl acetate and water
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified via column chromatography (100-200 mesh silica gel, 25-70% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-d9294e638bdd4f86a78a51079c255d58
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

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