Pyridine → (2S,4S)-4-Fluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonate

HRID 2374635Notes

Reaction equation

HRID 2374635 reaction equation
C(OC([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([NH2:12])=O)=O)(C)(C)C.C(OC(C)C)(=O)C.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>O>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[F:16][C@@H:14]1[CH2:15][NH:8][C@H:9]([C:10]#[N:12])[CH2:13]1

Participants

7

Reactant 5

HCID 1049PyridineHCID 6101p-Toluenesulfonic acidHCID 7915Isopropyl AcetateHCID 9845Trifluoroacetic anhydrideHCID 497605222-Methyl-2-propanyl (2S,4S)-2-carbamoyl-4-fluoro-1-pyrrolidinecarboxylate

Product 1

HCID 72699082(2S,4S)-4-Fluoropyrrolidine-2-carbonitrile 4-methylbenzenesulfonateYield 68%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
20 °C

Procedure

The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.

Workup

  1. temperaturemaintaining the temperature at approx. 20° C
  2. stirringThe reaction solution was stirred an additonal 1 hour at approx. 20° C
  3. stirringthe reaction mixture was stirred for 15 minutes
  4. customto separate
  5. concentrationThe organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume
  6. additionThe reaction was diluted back up to 5 volumes with isopropyl acetate
  7. temperatureThe reactor contents were cooled to 20° C.
  8. stirringThe reaction was stirred for 2 hours
  9. customconsumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide
  10. concentrationThe reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol
  11. additionwere added
  12. concentrationThe reaction was concentrated to a final volume of 4 volumes
  13. temperatureThe reaction was cooled to 0° C.
  14. filtrationThe solids were collected by filtration
  15. washwashed with isopropyl alcohol (1 vol)
  16. customdried under vacuum at approx. 50° C. to constant weight

Sources & evidence

ORD record
ord-9d2eed99f9164b9284004b430ec035a9
Source dataset
uspto-grants-2008_12
Patent number
US07462641B2

Reaction notes

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