Ammonia → Pentanamide, 5,5,5-trifluoro-2-[[(1R)-1-phenylethyl]amino]-, (2R)-

HRID 418398Notes

Reaction equation

HRID 418398 reaction equation
[F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:6]#[N:7].S(=O)(=O)(O)[OH:20].N>ClCCl>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]([NH2:7])=[O:20]

Participants

5

Reactant 3

HCID 222AmmoniaHCID 1118Sulfuric AcidHCID 66649793Pentanenitrile, 5,5,5-trifluoro-2-[[(1R)-1-phenylethyl]amino]-

Product 1

HCID 66649707Pentanamide, 5,5,5-trifluoro-2-[[(1R)-1-phenylethyl]amino]-, (2R)-

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-2.5 °C

Procedure

5,5,5-Trifluoro-2-(1-phenylethylamino)pentanenitrile (crude mixture of diastereomers from Step B, 1.10 kg) was dissolved in dichloromethane (5.5 L) in a suitable vessel equipped with mechanical stirring, ice bath for cooling and maintained under a blanket of nitrogen. Stirring was started and the reaction mixture was cooled to 0 to −5° C. Concentrated sulfuric acid (1.75 L) was added dropwise over a period of 1 hour into the above mixture, maintaining the temperature below 0° C.; a clear solution was obtained after the addition was complete. The temperature of the reaction mixture was raised to 25 to 27° C. and stirred overnight (12-14 h). Completion of the reaction was determined by HPLC. The reaction mixture was poured slowly over crushed ice (˜15.0 kg) and was neutralized with aqueous ammonia (˜25% by volume). The aqueous layer was separated and extracted with dichloromethane (2×3.0 L). The combined dichloromethane layer was washed with water (1×12.0 L) followed by brine (1×3.0 L). The product rich organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 0.85 kg (72.0%) of the crude title compound 1H NMR (CDCl3) (400 MHz) (Mixture of diastereomers) δ 1.36 (d&m, 4H, CH3 (J=8.0 Hz & 1H of CH2), 1.90 (m, 1H of CH2), 2.15 & 2.35 (two m, 1H each of CH2—CF3), 2.80-2.90 (m, 1H, CH-Ph), 3.60-3.70 (m, 1H, —(CONH2)CH(NH), 5.90 & 6.45 (1H each of CONH2 with minor peaks for other diastereomer), 7.20-7.40 (m, 6H, Ar+NH).

Workup

  1. customequipped with mechanical stirring, ice bath
  2. temperaturefor cooling
  3. temperaturemaintained under a blanket of nitrogen
  4. temperaturemaintaining the temperature below 0° C.
  5. customa clear solution was obtained
  6. additionafter the addition
  7. temperatureThe temperature of the reaction mixture was raised to 25 to 27° C.
  8. stirringstirred overnight (12-14 h)
  9. additionThe reaction mixture was poured slowly
  10. customThe aqueous layer was separated
  11. extractionextracted with dichloromethane (2×3.0 L)
  12. washThe combined dichloromethane layer was washed with water (1×12.0 L)
  13. dry with materialThe product rich organic layer was dried over sodium sulfate
  14. concentrationconcentrated under reduced pressure
  15. customto yield

Sources & evidence

ORD record
ord-37789cb30d0f4663a74c2086eb00aa31
Source dataset
uspto-grants-2012_01
Patent number
US08093276B2

Reaction notes

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