Hydrazine hydrate (1:1) → 6-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

HRID 2367602Notes

Reaction equation

HRID 2367602 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21]O[CH2:19][C@H:18]2[CH:23]([CH3:25])[CH3:24])[N:3]=1.[OH2:26].[NH2:27][NH2:28]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:27][NH:28]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:26][CH2:19][C@H:18]2[CH:23]([CH3:24])[CH3:25])[N:3]=1

Participants

4

Reactant 2

HCID 24654Hydrazine hydrate (1:1)HCID 585046534-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile

Product 1

HCID 513571376-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 4-{2-amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (355 mg, 1.04 mmol) in EtOH (10 mL) was added hydrazine monohydrate (2 mL) in one portion at room temperature. The mixture was heated in an oil bath at 100° C. under a gentle reflux for 18 hours. LCMS showed conversion complete. The mixture was cooled to room temperature, filtered through celite, and rinsed with EtOH (20 mL). The filtrate was concentrated in vacuo. The residue was suspended in water (10 mL). The suspension was sonicated briefly, and filtered. The solids were washed with water, dried under house vacuum at room temperature for 2 hours, and then under vacuum at room temperature over P2O5 for 20 hours. These solids were washed with hexane (2×3 mL), followed by drying under vacuum at 65° C. for 24 hours to give the title compound (256 mg) as a beige solid. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.88 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 2.47-2.54 (m, 1H), 3.21-3.30 (m., 1H), 3.51-3.58 (m, 2H), 3.93 (dd, J=11.2, 3.41 Hz, 1H), 4.10 (d, J=11.6 Hz, 1H), 6.46 (s, 1H), 7.47 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.79 (s, 1H).

Workup

  1. temperaturea gentle reflux for 18 hours
  2. temperatureThe mixture was cooled to room temperature
  3. filtrationfiltered through celite
  4. washrinsed with EtOH (20 mL)
  5. concentrationThe filtrate was concentrated in vacuo
  6. customThe suspension was sonicated briefly
  7. filtrationfiltered
  8. washThe solids were washed with water
  9. customdried under house vacuum at room temperature for 2 hours
  10. washThese solids were washed with hexane (2×3 mL)
  11. customby drying under vacuum at 65° C. for 24 hours

Sources & evidence

ORD record
ord-eb363fb72f1d483dbacfe6ff09306d34
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

Loading…