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

HRID 2367605Notes

Reaction equation

HRID 2367605 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](OC)[C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH:25]([CH3:27])[CH3:26])[N:3]=1.[OH2:28].[NH2:29][NH2:30].[CH2:31](O)C>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:29][NH:30]3)=[C:14]([O:28][CH3:31])[CH:15]=2)[CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@H:20]2[CH:25]([CH3:26])[CH3:27])[N:3]=1

Participants

4

Reactant 3

HCID 702EthanolHCID 24654Hydrazine hydrate (1:1)HCID 585043924-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluoro-6-(methyloxy)benzonitrile

Product 1

HCID 585045996-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-4-(methyloxy)-1H-indazol-3-amine

Conditions

Temperature
100 °C

Procedure

To a solution of 4-{2-amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluoro-6-(methyloxy)benzonitrile (276 mg, 0.74 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2 mL) in one portion. The mixture was heated at 100° C. for 20 hours. LCMS showed conversion complete. The mixture was cooled to room temperature and concentrated in vacuo. The solid residue was partitioned between EtOAc (2×40 mL) and water (15 mL). The organic was concentrated in vacuo, and the residue was purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 75% A in CHCl3, where A was a mixture of 800/80/3200 (v/v/v) CH3OH/NH4OH/CHCl3. The collected fractions were concentrated in vacuo. The residue was redissolved in CHCl3 and EtOAc, followed by filtration. The filtrate was concentrated in vacuo, and azeotroped with EtOH. The residue was taken up in water (8 mL) as a suspension. The solids were collected by filtration and washed with water (2×2 mL), followed with drying under house vacuum at room temperature for 1 hour and then vacuum at room temperature over P2O5 for 20 hours. The solids were washed with hexane (2×3 mL), and dried under vacuum at 65° C. for 20 hours to give the title compound (125 mg) as an off-white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.88 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 3.20-3.30 (m, 1H), 3.48-3.60 (m, 2H), 3.93 (dd, J=11.4, 3.3 Hz, 1H), 4.04 (s, 3H), 4.10 (d, J=11.6 Hz, 1H), 6.43 (s, 1H), 6.85 (s, 1H), 7.31 (s, 1H).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. customThe solid residue was partitioned between EtOAc (2×40 mL) and water (15 mL)
  4. concentrationThe organic was concentrated in vacuo
  5. customthe residue was purified by silica gel column chromatography
  6. washelution of 1% A in CHCl3 to 75% A in CHCl3
  7. additiona mixture of 800/80/3200 (v/v/v) CH3OH/NH4OH/CHCl3
  8. concentrationThe collected fractions were concentrated in vacuo
  9. dissolutionThe residue was redissolved in CHCl3
  10. filtrationEtOAc, followed by filtration
  11. concentrationThe filtrate was concentrated in vacuo
  12. customazeotroped with EtOH
  13. filtrationThe solids were collected by filtration
  14. washwashed with water (2×2 mL)
  15. customwith drying under house vacuum at room temperature for 1 hour
  16. washThe solids were washed with hexane (2×3 mL)
  17. customdried under vacuum at 65° C. for 20 hours

Sources & evidence

ORD record
ord-6c0c08b8c6524ce481c8a6df3a4cd00f
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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