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

HRID 2367643Notes

Reaction equation

HRID 2367643 reaction equation
[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]

Participants

10

Reactant 6

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

Product 1

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

Reagents, catalysts & solvents 3

HCID 702EthanolSolvent5×HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-a21a3af5d32d4a3ba56defb030b56ab8
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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