Trifluoroacetic acid → Tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate

HRID 1694572Notes

Reaction equation

HRID 1694572 reaction equation
[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.FC(F)(F)C(O)=O.[C:19]([N:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:29]3[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:30]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 707665-AminoisoquinolineHCID 471360Tert-butyl 3-oxopyrrolidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 23079381Tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylateYield 82.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

A 5 L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <32° C. 1-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12 L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of <32° C. The reaction was stirred at 20-32° C. for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3 L of 5N NaOH maintaining a temperature of <45° C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3 L of 2N NaOH at 40° C. (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 40° C. (with external heating), and concentrated to ˜2 L by distillation. The resulting solution was cooled to ˜20° C. The resulting slurry was filtered, washed (3×200 mL of MTBE), and dried in a vacuum oven at ˜60° C. Approximately 536 g of tert-Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was isolated as a solid (82% yield).

Workup

  1. customA 5 L flask (Flask A) equipped with a mechanical stirrer
  2. additioninternal temperature probe and addition funnel
  3. temperaturewhile maintaining an internal temperature of <32° C
  4. customA separate 12 L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet
  5. customwas flushed with nitrogen
  6. customThe contents of Flask A were slowly transferred to Flask
  7. temperatureB while maintaining an internal temperature in Flask B of <32° C
  8. stirringThe reaction was stirred at 20-32° C. for 6 hours
  9. customall 5-aminoisoquinoline was consumed
  10. customThe reaction was quenched with 3 L of 5N NaOH maintaining a temperature of <45° C
  11. waitAfter 20 minutes
  12. customthe aqueous layer was separated
  13. washThe organic phase was washed with 3 L of 2N NaOH at 40° C.
  14. temperature(with external heating)
  15. additionThe organic phase was diluted with isopropyl acetate (2.25 L)
  16. washwashed with 1.5 L of water at 40° C.
  17. temperature(with external heating)
  18. concentrationconcentrated to ˜2 L by distillation
  19. filtrationThe resulting slurry was filtered
  20. washwashed (3×200 mL of MTBE)
  21. customdried in a vacuum oven at ˜60° C

Sources & evidence

ORD record
ord-d89cf9567afb479da0864e9f46e58c04
Source dataset
uspto-grants-2012_04
Patent number
US08158796B2

Reaction notes

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