Hydrazine → 6-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-4-(ethyloxy)-1H-indazol-3-amine

HRID 2367573Notes

Reaction equation

HRID 2367573 reaction equation
[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23](F)[C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=2)[CH:10]=1)[CH3:2].[O-:27][CH2:28][CH3:29].[Na+].[NH2:31][NH2:32].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.CC#N>[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23]3[C:20]([C:21]([NH2:22])=[N:31][NH:32]3)=[C:19]([O:27][CH2:28][CH3:29])[CH:18]=2)[CH:10]=1)[CH3:2]

Participants

8

Reactant 4

HCID 9321Hydrazine2×HCID 81531DiisopropylethylamineHCID 2723922Sodium ethoxideHCID 585044754-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile

Product 1

HCID 585044396-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-4-(ethyloxy)-1H-indazol-3-amineYield 52.3%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (690 mg, 1.92 mmol) was taken up in DMF (6 mL) followed by the addition of sodium ethoxide (1.1 M, 1.75 mL, 1.92 mmol). The reaction was then allowed to stir at room temperature. The reaction was diluted with EtOAc (20 mL) and washed with H2O (25 mL). The H2O was then back extracted with EtOAc (20 mL). The organics were dried and concentrated to afford a yellow oil that was then dissolved in CH3CN (5 mL) and transferred to a 20 mL microwave vial, followed by the addition of hydrazine (0.241 mL, 7.68 mmol) and Hunig's base (2.68 mL, 15.36 mmol). The reaction was irradiated at 140° C. for 2 hours. Another equivalent of hydrazine (0.120 mL, 3.84 mmol) was added to the reaction and it was irradiated at 140° C. for 30 minutes. The reaction was concentrated and purified via flash chromatography (0-50%, 80:20:2 CH2Cl2:CH3OH:NH4OH, 60 g). Fractions were combined and concentrated to afford the title compound (398.8 mg) as a yellow solid. LC-MS (ES) m/z=398 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, J=7.5 Hz, 3H), 1.45 (t, J=7.0 Hz, 3H), 1.60-1.80 (m, 2H), 2.79-2.85 (m, 3H), 3.06-3.15 (m, 1H), 3.40-3.48 (m, 1H), 3.49-3.55 (m, 1H), 3.81-3.87 (m, 1H), 3.87-3.92 (m, 1H), 4.17-4.25 (m, 3H), 4.34 (bs, 1H), 4.99 (s, 2H), 6.50 (bs, 2H), 6.93 (bs, 1H), 7.52 (bs, 1H), 11.52 (bs, 1H).

Workup

  1. washwashed with H2O (25 mL)
  2. extractionThe H2O was then back extracted with EtOAc (20 mL)
  3. customThe organics were dried
  4. concentrationconcentrated
  5. customto afford a yellow oil that
  6. customThe reaction was irradiated at 140° C. for 2 hours
  7. customwas irradiated at 140° C. for 30 minutes
  8. concentrationThe reaction was concentrated
  9. custompurified via flash chromatography (0-50%, 80:20:2 CH2Cl2:CH3OH:NH4OH, 60 g)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-cffc8cf472d94e368ece526d3ef7ff89
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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