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

HRID 2367643ノート

反応式

HRID 2367643 の反応式
[O-:1][CH2:2][CH3:3].[Na+].[H-].[Na+].F[C:8]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@H:23]3[CH3:28])[N:19]=[C:18]([NH:29][CH3:30])[N:17]=2)[CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11].[Cl-].[NH4+:33].[NH2:34]N.CCN(C(C)C)C(C)C>C(O)C.O.CN(C)C=O>[CH2:2]([O:1][C:8]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@H:23]3[CH3:28])[N:19]=[C:18]([NH:29][CH3:30])[N:17]=2)[CH:13]=[C:12]2[C:9]=1[C:10]([NH2:34])=[N:11][NH:33]2)[CH3:3]

参加物

10

反応物 6

HCID 9321HydrazineHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 2723922Sodium ethoxide2 回HCID 585047102,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile

生成物 1

HCID 585044784-(ethyloxy)-6-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine収率 54%

試薬・触媒・溶媒 3

HCID 702Ethanol溶媒5 回HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

実験手順

A stock solution of sodium ethoxide in ethanol was generated by the addition of ethanol (10 mL) to NaH (204 mg, 8.48 mmol), followed by stirring at room temperature for 30 mins. To a 20-mL vial was added 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (293 mg, 0.848 mmol), N,N-dimethylformamide (DMF) (1 mL) and ethanol (1.5 mL). The reaction was cooled to 0° C., and a solution of sodium ethoxide in ethanol (from 0.848 M stock solution) (1.101 mL, 0.933 mmol) was added dropwise. The reaction was stirred at room temperature for 90 min. Ammonium chloride (aq., sat., 2 mL) and water (2 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-50% EtOAc in hexanes, 10-g column) to afford a white solid which was added to a 5-mL microwave vial with hydrazine (0.259 mL, 4.48 mmol), DIEA (0.391 mL, 2.239 mmol) and ethanol (3 mL). The resulting suspension was heated for 90 min at 150° C. in a microwave reactor. The reaction mixture was concentrated and dry-loaded onto silica and purified by flash chromatography (0-10% MeOH in DCM, 25-g column) to afford the title compound (175.4 mg, 0.457 mmol, 54% yield) as an off-white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (d, 3H), 1.45 (t, J=6.95 Hz, 3H), 2.83 (d, J=4.04 Hz, 3H), 3.05-3.18 (m, 1H), 3.45 (td, J=11.75, 2.53 Hz, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.93 (dd, J=11.12, 3.03 Hz, 1H), 4.11 (d, J=12.88 Hz, 1H), 4.22 (q, J=6.99 Hz, 2H), 4.52 (d, J=4.80 Hz, 1H), 5.00 (s, 2H), 6.35-6.64 (m, 2H), 6.95 (s, 1H), 7.52 (br. s., 1H), 11.52 (s, 1H).

後処理

  1. temperatureThe reaction was cooled to 0° C.
  2. stirringThe reaction was stirred at room temperature for 90 min
  3. extractionthe mixture was extracted with ethyl acetate (3×10 mL)
  4. dry with materialThe combined organics were dried over sodium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography (0-50% EtOAc in hexanes, 10-g column)
  7. customto afford a white solid which
  8. temperatureThe resulting suspension was heated for 90 min at 150° C. in a microwave reactor
  9. concentrationThe reaction mixture was concentrated and dry-loaded onto silica
  10. custompurified by flash chromatography (0-10% MeOH in DCM, 25-g column)

出典と根拠

ORDレコード
ord-a21a3af5d32d4a3ba56defb030b56ab8
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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