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

HRID 2367537Notes

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]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:25][NH2:26].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:7]=[C:6]3[C:3]([C:4]([NH2:5])=[N:25][NH:26]3)=[CH:2][CH:9]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1

Participants

Conditions

Temperature: 150 °C

Procedure

To a 5-mL microwave vial was added 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (270 mg, 0.824 mmol), hydrazine (0.31 mL, 9.9 mmol), Hunig's base (0.576 mL, 3.30 mmol), and ethanol (3 mL). The reaction mixture was heated at 150° C. for 70 minutes in a microwave reactor. LCMS analysis indicated good conversion, so the reaction mixture was concentrated, dissolved in DMSO and purified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA). The product fractions were pooled, then basified with NaHCO3 and extracted with EtOAc. The organic layer was dried and concentrated to afford the title compound (117 mg). LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.23 (m, 3H), 2.84 (d, J=4.0 Hz, 3H), 3.02-3.20 (m, 1H), 3.38-3.51 (m, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.87-3.98 (m, 1H), 4.07-4.19 (m, 1H), 4.45-4.57 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.61 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.98 (bs, 1H), 11.51 (s, 1H).

Workup

concentrationso the reaction mixture was concentrated
dissolutiondissolved in DMSO
custompurified by RP-HPLC (8-32% CH3CN in water, 0.1% TFA)
extractionextracted with EtOAc
customThe organic layer was dried
concentrationconcentrated

Sources & evidence

ORD record: ord-7783f96164a1484e83c1636772821033
Source dataset: uspto-grants-2014_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08697685B2

Reaction notes

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