Potassium Carbonate → tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate

HRID 338878Notes

Reaction equation

HRID 338878 reaction equation
FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[F:21][CH2:22][CH2:23][N:24]([C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:34]2[CH2:35][CH2:36][C@H:32]([N:24]([CH2:23][CH2:22][F:21])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 86707412(S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonateHCID 86707424(S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate

Product 1

HCID 86707426tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamateYield 48.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(2-fluoroethyl)amino)pyrrolidine-1-carboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate. To a solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate (0.92 g, 3.95 mmol) and K2CO3 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50° C. for 18 hours. After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes) to afford tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate (0.58 g, 48%).

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureAfter cooling to ambient temperature the mixture
  3. customwas partitioned between water (12 mL) and ethyl acetate (30 mL)
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customthe residue obtained
  10. custompurified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-73a5d55471464468a86cac119b910867
Source dataset
uspto-grants-2014_11
Patent number
US08889704B2

Reaction notes

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