Methanol → 6-{2-(Methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-4-(methyloxy)-1H-indazol-3-amine

HRID 2367538Notes

Reaction equation

HRID 2367538 reaction equation
F[C:2]1[CH:9]=[C:8]([C:10]2C=C(N3CCOC[C@H]3C)[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:26][O-:27].[Na+].CO.[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])[CH3:35].[OH2:40].[NH2:41][NH2:42]>C(O)C.CCOC(C)=O.CN(C=O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:41][NH:42]3)=[C:6]([O:27][CH3:26])[CH:7]=2)[CH:39]=[C:37]([N:33]2[CH2:32][CH2:31][O:40][CH2:36][C@H:34]2[CH3:35])[N:13]=1

Participants

9

Reactant 5

HCID 887MethanolHCID 24654Hydrazine hydrate (1:1)HCID 81531DiisopropylethylamineHCID 10942334Sodium MethoxideHCID 585047102,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile

Product 1

HCID 462151256-{2-(Methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-4-(methyloxy)-1H-indazol-3-amine

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 100 mL RBF was charged with sodium hydride (73.1 mg, 2.90 mmol), placed under a nitrogen atmosphere and cooled to 0° C. Then CH3OH (10 mL) was added dropwise via syringe, and the resulting mixture was stirred at this temperature for 10 minutes. Then the mixture was warmed to room temperature for 10 minutes to give a cloudy solution of sodium methoxide in CH3OH. To a 4-mL vial was added 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (100 mg, 0.290 mmol), DMF (1 mL), and 1.2 mL of the solution of sodium methoxide in CH3OH (1.2 equiv). The reaction was stirred for 2 hours at room temperature, then was poured into EtOAc (10 mL). The aqueous was extracted with EtOAc (2×10 mL) and the combined organics were dried over Na2SO4, and then concentrated. The residue was transferred to a 2-mL microwave vial, and ethanol (1.5 mL), Hunig's base (0.152 mL, 0.869 mmol) and hydrazine hydrate (0.101 mL, 1.74 mmol) were added. The resulting mixture was heated at 150° C. for 30 minutes in a microwave reactor. The reaction mixture was concentrated, and the residue purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA). The product fractions were combined, basified with Na2CO3 and extracted into EtOAc. The organic layer was concentrated and the residue lyophilized to afford the title compound (41.7 mg) as an off-white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.6 Hz, 3H), 2.83 (d, J=4.0 Hz, 3H), 3.05-3.22 (m, 1H), 3.46 (d, J=2.5 Hz, 1H), 3.62 (d, J=2.8 Hz, 1H), 3.67-3.79 (m, 1H), 3.85-4.01 (m, 4H), 4.04-4.22 (m, 1H), 4.41-4.62 (m, 1H), 5.03 (s, 2H), 6.37-6.68 (m, 2H), 6.95 (s, 1H), 7.53 (bs, 1H), 11.53 (s, 1H).

Workup

  1. extractionThe aqueous was extracted with EtOAc (2×10 mL)
  2. dry with materialthe combined organics were dried over Na2SO4
  3. concentrationconcentrated
  4. temperatureThe resulting mixture was heated at 150° C. for 30 minutes in a microwave reactor
  5. concentrationThe reaction mixture was concentrated
  6. customthe residue purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA)
  7. extractionextracted into EtOAc
  8. concentrationThe organic layer was concentrated

Sources & evidence

ORD record
ord-e5cf1054fd7245a7a9cc904cc52716b3
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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