Acetic Acid → HCID 178451827, compound

HRID 1749055Notes

Reaction equation

HRID 1749055 reaction equation
C(O)(=O)C.[NH2:5]/[C:6](/[C:24]1[CH:29]=[N:28][C:27]([NH2:30])=[C:26]([C:31]2[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=2)[N:25]=1)=[N:7]\[NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O>O1CCOCC1>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:6]2[NH:7][N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:5]=2)=[N:25][C:26]=1[C:31]1[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=1

Participants

4

Reactant 2

HCID 176Acetic AcidHCID 90283740tert-butyl 4-[[(Z)-[amino-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]methylidene]amino]carbamoyl]piperidine-1-carboxylate

Product 1

HCID 178451827HCID 178451827, compoundYield 70%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

Acetic acid (200 mL) was added to dioxane (500 mL) in a 3 L fixed double jacketed vessel and the solution was heated to 70° C. under nitrogen. (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)-piperidine-1-carboxylate (74.5 g, 152.80 mmol) was added portionwise to the warm mixture. After 10 minutes the temperature was increased to 100° C. (slight reflux). The reaction mixture was stirred at 100° C. for 1.5 hours (suspension) then held at 80° C. overnight (solution formed after overnight hold). The resulting solution was concentrated under reduced pressure, then diluted with toluene, evaporated to dryness, taken up with toluene and concentrated again. The residual oil was mixed with some ethyl acetate and concentrated to dryness. A solid crystallised from solution which was triturated with MTBE (200 mL) and isolated by filtration. The filter cake was washed with water and MTBE to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (50 g, 70%) as a grey solid. The filtrate was concentrated under reduced pressure to give a yellow solid. This material was triturated with MTBE and filtered. The filter cake was washed with ethyl acetate and then MTBE to give a second crop as a pale yellow solid (4.93 g, 7%). This material was identical to the first crop: 1H NMR Spectrum: (DMSO-d6) 1.17 (9H, s), 1.22 (9H, s), 1.29-1.47 (2H, m), 1.67-1.78 (2H, m), 2.57-2.87 (3H, m), 3.57-3.92 (2H, m), 7.56 (2H, br), 8.56 (1H, s), 13.47 (2H, br s); Mass Spectrum [M+H]+=470.

Workup

  1. temperatureAfter 10 minutes the temperature was increased to 100° C.
  2. temperature(slight reflux)
  3. waitthen held at 80° C. overnight
  4. custom(solution formed after overnight hold)
  5. concentrationThe resulting solution was concentrated under reduced pressure
  6. additiondiluted with toluene
  7. customevaporated to dryness
  8. concentrationconcentrated again
  9. additionThe residual oil was mixed with some ethyl acetate
  10. concentrationconcentrated to dryness
  11. customA solid crystallised from solution which
  12. customwas triturated with MTBE (200 mL)
  13. customisolated by filtration
  14. washThe filter cake was washed with water and MTBE

Sources & evidence

ORD record
ord-b065444b755a41578e9ffc02af3c033e
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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