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

HRID 512155노트

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HRID 512155 반응식
[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

참가 물질

9

반응물 5

HCID 25517Ammonium ChlorideHCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 86716177HCID 86716177, 화합물

생성물 1

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

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매2회HCID 1140Toluene용매

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온도
110 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-8283b044f6da45b9a65240c0b9069e62
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09102591B2

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