Trifluoroacetic acid → HCID 86679013, compound

HRID 2203376Notes

Reaction equation

HRID 2203376 reaction equation
[NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28]N)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:9]=2)[N:7]=1.FC(F)(F)C(O)=O.N(OC(C)(C)C)=O.N[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>C1COCC1>[NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:9]=2)[N:7]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 100093-AminopyridineHCID 10906Tert-Butyl nitriteHCID 86679014HCID 86679014, compound

Product 1

HCID 86679013HCID 86679013, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a THF solution (2 mL) of the intermediate from Step A (227 mg, 0.521 mmol) at 0° C. was added trifluoroacetic acid (0.044 mL, 0.574 mmol) and tert-butyl nitrite (0.186 mL, 1.564 mmol). After stirring at 0° C. for 30 minutes, the mixture was concentrated in vacuo, ensuring that the temperature was maintained below 40° C. The residue was suspended in acetonitrile (3 mL), cooled to 0° C., and 3-aminopyridine (245 mg, 2.61 mmol) was added in one portion. The resultant mixture was heated to 40° C. for one hour, and then stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, suspended in EtOAc and washed sequentially with water (4×), saturated aqueous ammonium chloride solution (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using DCM/MeOH (with 0.5% NH4OH) gradient provided the title compound. Chiral separation using SFC on a Chiralpak IC column provided both enantiomers of the title compound, 1H NMR (500 MHz, DMSO-d6): δ 9.53 (1H, s), 9.05 (1H, dd, J=8.08, 1.58 Hz), 8.77 (1H, d, J=2.48 Hz), 8.63 (1H, dd, J=4.47, 1.58 Hz), 8.28 (1H, d, J=4.69 Hz), 8.00 (1H, d, J=8.47 Hz), 7.36 (2H, ddd, J=21.65, 8.21, 4.57 Hz), 6.86 (2H, s), 4.85-4.77 (2H, m), 3.06-2.95 (2H, m), 1.72 (3H, s). m/z=498.2 (M+H).

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. temperaturewas maintained below 40° C
  3. temperaturecooled to 0° C.
  4. stirringstirred at ambient temperature for 16 hours
  5. concentrationThe mixture was concentrated in vacuo
  6. washwashed sequentially with water (4×), saturated aqueous ammonium chloride solution (2×), and brine
  7. dry with materialThe organic layer was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by silica gel column chromatography

Sources & evidence

ORD record
ord-e2cb2311924142ef9a80679ca737fb43
Source dataset
uspto-grants-2016_06
Patent number
US09365574B2

Reaction notes

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