Ammonium Chloride → 1-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

HRID 512155ノート

反応式

HRID 512155 の反応式
[CH:1]1(B(O)O)[CH2:3][CH2:2]1.Br[C:8]1[N:13]=[CH:12][C:11]([C:14]2([C:22]#[N:23])[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:8]2[N:13]=[CH:12][C:11]([C:14]3([C:22]#[N:23])[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1

参加物

9

反応物 5

HCID 25517Ammonium ChlorideHCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 86716177HCID 86716177、化合物

生成物 1

HCID 867161781-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile収率 41.6%

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒HCID 962Water溶媒2 回HCID 1140Toluene溶媒

反応条件

温度
110 °C

実験手順

A suspension of cyclopropylboronic acid (0.94 g, 11 mmol), 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.10 g, 3.67 mmol) and potassium phosphate tribasic (2.30 g, 10.8 mmol) in a mixture of toluene (16 mL) and water (4 mL) at room temperature was purged with nitrogen gas for 1 hour. Then palladium acetate (31 mg, 0.14 mmol) and tricyclohexylphosphine (51 mg, 0.18 mmol) were added and the mixture was heated at 110° C. for 18 hours. After cooling to room temperature a saturated aqueous solution of ammonium chloride was added, followed by water. The organic layer was separated and the aqueous layer was extracted again three times with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography to afford 1-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (400 mg, 27%). LC-MS (m/z) 263.0 (MH+). 11-1 NMR (400 MHz, CDCl3) δ ppm 8.59 (d, J=2.5 Hz, 1 H), 7.64 (dd, J=8.3, 2.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 2.00-2.39 (m, 9 H), 0.99-1.06 (m, 4 H).

後処理

  1. customwas purged with nitrogen gas for 1 hour
  2. additionwas added
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted again three times with AcOEt
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude product was then purified by silica gel chromatography

出典と根拠

ORDレコード
ord-8283b044f6da45b9a65240c0b9069e62
出典データセット
uspto-grants-2015_08
特許番号
US09102591B2

反応ノート

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