Diethyl (cyanomethyl)phosphonate → 4-[3-(Cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide

HRID 1049140Notes

Reaction equation

HRID 1049140 reaction equation
[C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[F:18][C:19]1[CH:33]=[C:32]([N:34]2[CH2:37][C:36](=O)[CH2:35]2)[C:31]([F:39])=[CH:30][C:20]=1[C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22]>O1CCCC1>[C:1]([CH:3]=[C:36]1[CH2:37][N:34]([C:32]2[C:31]([F:39])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[C:19]([F:18])[CH:33]=2)[CH2:35]1)#[N:2]

Participants

5

Reactant 3

HCID 75676Diethyl (cyanomethyl)phosphonateHCID 23665647Potassium tert-butoxideHCID 1176967892,5-Difluoro-4-(3-oxoazetidin-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide

Product 1

HCID 1177001494-[3-(Cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamideYield 63.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

Diethyl cyanomethylphosphonate (1.95 mL, 11.8 mmol) was added drop-wise to a cooled (ice bath) solution of 1.0 M potassium tert-butoxide in THF (11.8 mL, 11.8 mmol) which was diluted with tetrahydrofuran (12 mL). The bath was removed and the reaction was warmed to room temperature, and stirred for 90 min. The reaction solution was cooled with an ice bath again. The above prepared solution was then added over 12 min to a cooled (ice-bath) solution of 2,5-difluoro-4-(3-oxoazetidin-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (4.00 g, 12.4 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 30 min. The ice bath was removed, and the reaction was stirred at room temperature overnight, then quenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0% to 30%) to yield the desired product (2.6 g). 1H NMR (400 MHz, DMSO-d6) δ 8.59-8.37 (m, 1H), 7.33 (dd, J=12.5, 6.4 Hz, 1H), 6.59 (dd, J=12.0, 7.4 Hz, 1H), 5.88 (m, 1H), 4.94-4.75 (m, 4H), 4.76 (m, 1H), 1.31 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C15H13F5N3O (M+1)+: m/z=346.1. Found: 346.1.

Workup

  1. customThe bath was removed
  2. temperatureThe reaction solution was cooled with an ice bath again
  3. customThe above prepared solution
  4. additionwas then added over 12 min to
  5. stirringThe reaction mixture was stirred for 30 min
  6. customThe ice bath was removed
  7. stirringthe reaction was stirred at room temperature overnight
  8. customquenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL)
  9. customThe organic layer was separated
  10. extractionThe aqueous layer was extracted with ethyl acetate (50 mL)
  11. dry with materialThe combined organic layers were dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0% to 30%)

Sources & evidence

ORD record
ord-f28ac49a39db4bfeaf1ba85f888382d6
Source dataset
uspto-grants-2016_07
Patent number
US09382231B2

Reaction notes

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