Potassium Phosphate, Tribasic → 2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile

HRID 2367507ノート

反応式

HRID 2367507 の反応式
Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[C:26]([F:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:31])#[N:20].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:27][C:26]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:23]=[C:22]([F:31])[C:21]=1[C:19]#[N:20]

参加物

8

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acidHCID 585044624-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

生成物 1

HCID 585046702,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile収率 69.9%

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

4-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (1.70 g, 6.28 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (1.72 g, 9.42 mmol, 1.5 equiv), tricyclohexylphosphine (0.264 g, 0.94 mmol, 0.15 equiv), Pd2(dba)3 (0.431 g, 0.47 mmol, 0.075 equiv), and K3PO4 (2.27 g, 10.67 mmol, 1.7 equiv) were charged into a 250 mL RB flask, followed by addition of 1,4-dioxane (30 mL) and water (10 mL). The mixture was degassed and back flushed with argon (5×). The mixture was heated in an oil bath at 100° C. for 20 hours. LCMS showed complete conversion. The mixture was filtered through celite and rinsed with EtOAc (150 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (150 mL) and brine (40 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, to afford the title compound (1.64 g) as a yellow foam. LC-MS (ES) m/z=374 [M+H]+.

後処理

  1. customThe mixture was degassed
  2. customback flushed with argon (5×)
  3. filtrationThe mixture was filtered through celite
  4. washrinsed with EtOAc (150 mL)
  5. concentrationThe filtrate was concentrated in vacuo
  6. customThe residue was partitioned between EtOAc (150 mL) and brine (40 mL)
  7. dry with materialThe organic was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel column chromatography
  11. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

出典と根拠

ORDレコード
ord-98881d701efc428aa69ae0d9ead8ef32
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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