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

HRID 2367511Notes

Reaction equation

HRID 2367511 reaction equation
C(O[C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([NH:27][CH3:28])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])C.[OH2:30].[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[CH2:33]([O:30][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[CH:24]([CH3:25])[CH3:26])[N:15]=[C:14]([NH:27][CH3:28])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:31][NH:32]2)[CH3:34]

Participants

4

Reactant 3

HCID 702EthanolHCID 24654Hydrazine hydrate (1:1)HCID 585047402-(Ethyloxy)-6-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile

Product 1

HCID 585047894-(Ethyloxy)-6-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

Conditions

Temperature
100 °C

Procedure

To a solution of 2-(ethyloxy)-6-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (315 mg, 0.79 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The mixture was heated at 100° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was taken up in water (10 mL) as a suspension. The solids were collected by filtration and washed with water (3×2 mL). Further purification was carried out 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 CH3OH/NH4OH/CHCl3). The fraction containing the desired product were combined and concentrated. The resulting residue was dissolved in a solution of 5% CH3OH in CHCl3 (15 mL) and filtered. The filtrate was concentrated in vacuo, and azeotroped with 10 mL of ethanol. The resulting residue was taken up in 10 mL of water, and sonicated. A suspension formed and was filtered. The solids collected were dried under vacuum at room temperature over P2O5 for 18 hours, and then washed with hexane (3×2 mL). Further drying under vacuum at 65° C. for 20 hours gave the title compound (231 mg) as a cream-colored solid. LC-MS (ES) m/z=412 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 1.55 (t, J=7.0 Hz, 3H), 2.45-2.55 (m, 1H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.1, 3.5 Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 6.37 (s, 1H), 6.86 (s, 1H), 7.33 (s, 1H).

Workup

  1. temperaturecooled to room temperature
  2. concentrationconcentrated in vacuo
  3. filtrationThe solids were collected by filtration
  4. washwashed with water (3×2 mL)
  5. customFurther purification
  6. washelution of 1% A in CHCl3 to 75% A in CHCl3 (where
  7. additiona mixture of 800/80/3200 CH3OH/NH4OH/CHCl3)
  8. additionThe fraction containing the desired product
  9. concentrationconcentrated
  10. dissolutionThe resulting residue was dissolved in a solution of 5% CH3OH in CHCl3 (15 mL)
  11. filtrationfiltered
  12. concentrationThe filtrate was concentrated in vacuo
  13. customazeotroped with 10 mL of ethanol
  14. customsonicated
  15. customA suspension formed
  16. filtrationwas filtered
  17. customThe solids collected
  18. dry with materialwere dried under vacuum at room temperature over P2O5 for 18 hours
  19. washwashed with hexane (3×2 mL)
  20. customFurther drying under vacuum at 65° C. for 20 hours

Sources & evidence

ORD record
ord-144cb955565c41d18ef568a1a1db4520
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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