Trifluoroacetic acid → Bisegliptin

HRID 1099383Notes

Reaction equation

HRID 1099383 reaction equation
[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]([NH2:26])=O)=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH2:12][C:9]([NH:14][CH2:15][C:16]([N:18]3[CH2:22][C@@H:21]([F:23])[CH2:20][C@H:19]3[C:24]#[N:26])=[O:17])([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)=[O:5])[CH3:2]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 9845Trifluoroacetic anhydrideHCID 11430Potassium Carbonate2×HCID 46854534(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide

Product 1

HCID 11688894BisegliptinYield 81%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g) was dissolved in N,N-dimethylformamide (18.5 mL), and while stirring under ice-cooling, trifluoroacetic acid (0.78 mL) was added thereto at an inner temperature of 10° C. or lower. After stirring at an inner temperature of from 0 to 10° C. for 10 minutes, trifluoroacetic anhydride (1.46 mL) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into ice-water (92.5 mL), potassium carbonate (2.80 g) was added thereto in small portions at an inner temperature of 10° C. or lower and then, after gradually increasing the temperature, potassium carbonate (1.50 g) was further added thereto at an inner temperature of from 35 to 40° C. This was stirred at the same temperature for 10 minutes and then ice-cooled and stirred for 1 hour. The precipitate were collected by filtration, washed with water (37.0 mL) and then dried at 60° C. under reduced pressure, thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (obtained amount: 2.84 g, yield: 81%).

Workup

  1. temperaturecooling
  2. customat an inner temperature of 10° C.
  3. stirringAfter stirring at an inner temperature of from 0 to 10° C. for 10 minutes
  4. stirringby stirring at the same temperature for 1 hour
  5. additionwas added
  6. additionwas further added
  7. customof from 35 to 40° C
  8. stirringThis was stirred at the same temperature for 10 minutes
  9. temperatureice-cooled
  10. stirringstirred for 1 hour
  11. filtrationThe precipitate were collected by filtration
  12. washwashed with water (37.0 mL)
  13. customdried at 60° C. under reduced pressure

Sources & evidence

ORD record
ord-6e91c0d1733048cf8e4c6bd066d0cdff
Source dataset
uspto-grants-2012_03
Patent number
US08143427B2

Reaction notes

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