Acetic Acid → HCID 178521019, compound

HRID 931214Notes

Reaction equation

HRID 931214 reaction equation
Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37](=N)OCC)[CH2:36][CH2:35]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:36][CH2:35]2)[CH:33]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8471TriethylamineHCID 89854051(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochlorideHCID 117966385ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate

Product 1

HCID 178521019HCID 178521019, compoundYield 94.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (5.5 g, 15.2 mmol) and acetic acid (17.4 mL, 305 mmol) in ethanol (20 mL) was added a solution of ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (3.25 g, 15.2 mmol) in ethanol (30 mL) followed by triethylamine (12.7 mL, 91.2 mmol). The resulting mixture was purged with nitrogen. The reaction mixture was stirred for 18 h at 100° C. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate and the resulting aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (6.33 g, 94%). 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; UPLC retention time 0.47 min (Method N).

Workup

  1. customThe resulting mixture was purged with nitrogen
  2. temperatureThe mixture was cooled to room temperature
  3. customthe solvent was removed under reduced pressure
  4. customThe residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL)
  5. extractionThe aqueous layer was extracted with dichloromethane (50 mL)
  6. washThe combined organics were washed with a saturated aqueous solution of sodium bicarbonate
  7. extractionthe resulting aqueous layer was extracted with dichloromethane (50 mL)
  8. washwashed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude material was purified via flash chromatography (0-5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-2b620f2119424f7d93d12872ac9f45e6
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

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