Methylamine → N4-Methyl-6-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazole-3,4-diamine

HRID 2367540Notes

Reaction equation

HRID 2367540 reaction equation
F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[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][NH2:27].[NH2:28][NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][NH:27][C:6]1[C:3]2[C:4]([NH2:5])=[N:28][NH:29][C:2]=2[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 6329Methylamine2×HCID 9321HydrazineHCID 81531DiisopropylethylamineHCID 585047102,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile

Product 1

HCID 58504485N4-Methyl-6-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazole-3,4-diamineYield 37.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a 20-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 methylamine (2 M in THF, 0.174 mL, 0.347 mmol). The reaction was stirred overnight at room temperature. An additional 0.6 equiv of methylamine solution (2 M in THF) was added and the reaction stirred at room temperature for 3 days over the weekend. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ethanol (1.5 mL), and hydrazine (0.101 mL, 1.737 mmol) and Hunig's base (0.152 mL, 0.869 mmol) were added. The reaction was heated at 150° C. for 60 minutes in a microwave reactor. The reaction mixture was concentrated, and the residue dissolved in DMSO and purified by RPHPLC. The product fractions were combined, basified with NaHCO3 and extracted with EtOAc. The organics were combined, dried and concentrated to afford the title compound (40.5 mg) as a brown solid. LC-MS (ES) m/z=369 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 6H), 3.03-3.15 (m, 1H), 3.39-3.52 (m, 1H), 3.62 (d, J=2.5 Hz, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.01-4.15 (m, 1H), 4.41-4.55 (m, 1H), 5.07 (s, 2H), 5.59-5.74 (m, 1H), 6.26-6.62 (m, 3H), 7.14 (br. s., 1H), 11.35 (s, 1H).

Workup

  1. stirringthe reaction stirred at room temperature for 3 days over the weekend
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was dissolved in ethanol (1.5 mL)
  4. temperatureThe reaction was heated at 150° C. for 60 minutes in a microwave reactor
  5. concentrationThe reaction mixture was concentrated
  6. dissolutionthe residue dissolved in DMSO
  7. custompurified by RPHPLC
  8. extractionextracted with EtOAc
  9. customdried
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-c632d20c0c934d13b0414dfb07776e57
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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