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

HRID 2367603ノート

反応式

HRID 2367603 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]([NH2:17])[N:3]=1.[C:18]([C:20]1[C:25]([F:26])=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:30])#[N:19].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>[NH2:17][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[C:25]([F:26])[C:20]([C:18]#[N:19])=[C:21]([F:30])[CH:22]=2)[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]=1

参加物

8

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acidHCID 585047754-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

生成物 1

HCID 585048264-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2,6-difluorobenzonitrile収率 88.4%

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-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (2.36 g, 9.19 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (2.52 g, 13.19 mmol, 1.5 equiv), tricyclohexylphosphine (0.39 g, 1.38 mmol, 0.15 equiv), Pd2(dba)3 (0.63 g, 0.69 mmol, 0.075 equiv), and K3PO4 (3.32 g, 15.63 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 nitrogen, which was repeated five times. The mixture was heated in an oil bath at 100° C. for 20 hours. LCMS showed conversion complete. The mixture was filtered through celite and rinsed with EtOAc (100 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and brine (50 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, providing the title compound (2.92 g) as a yellowish foam. LC-MS (ES) m/z=360 [M+H]+.

後処理

  1. customThe mixture was degassed
  2. customback flushed with nitrogen, which
  3. filtrationThe mixture was filtered through celite
  4. washrinsed with EtOAc (100 mL)
  5. concentrationThe filtrate was concentrated in vacuo
  6. customThe residue was partitioned between EtOAc (200 mL) and brine (50 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-1c9d01f50ddd4fbf895777dbb922da80
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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