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

HRID 2367538ノート

反応式

HRID 2367538 の反応式
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

参加物

9

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 702Ethanol溶媒HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-e5cf1054fd7245a7a9cc904cc52716b3
出典データセット
uspto-grants-2014_04
特許番号
US08697685B2

反応ノート

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