Water → tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate

HRID 338844Notes

Reaction equation

HRID 338844 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.[NH:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CCOCC.CCCCCC.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1

Participants

9

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 1514396(3S)-(-)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 86707412(S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate

Product 1

HCID 86707413tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamateYield 77.4%

Reagents, catalysts & solvents 4

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (79.8 g, 232 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (51.9 g, 279 mmol), and K2CO3 (44.9 g, 325 mmol) in THF (500 mL) was stirred at 56° C. for 18 hours. After cooling to ambient temperature, water (200 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate) to give a thick oil. The oil was dissolved in ether (200 mL) and hexane (500 mL) was added. The solution was concentrated to about 200 mL and stirred at ambient temperature for 1 hour. Hexane (300 mL) was added, and the resulting solid was collected by filtration to give tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (68.2 g, 77.3%) as white solid. Enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 90% hexanes/10% (1:1 MeOH/EtOH) at 1.0 mL/min, >99% d.e. (R,S)-diastereomer).

Workup

  1. customThe organic layer was separated
  2. washwashed with brine
  3. dry with materialdried (sodium sulfate)
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by flash chromatography on silica gel (4:1 hexane/ethyl acetate)
  6. customto give a thick oil
  7. concentrationThe solution was concentrated to about 200 mL
  8. additionHexane (300 mL) was added
  9. filtrationthe resulting solid was collected by filtration

Sources & evidence

ORD record
ord-ce8bcf5412ce4c5491f08c34b6c4bfe2
Source dataset
uspto-grants-2014_11
Patent number
US08889704B2

Reaction notes

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