Potassium Carbonate → (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate

HRID 931056Notes

Reaction equation

HRID 931056 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1>[N:29]1([C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])[CH2:33][CH2:32][CH2:31][CH2:30]1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 31268PyrrolidineHCID 682631,1'-CarbonyldiimidazoleHCID 6435161-(1,1-Dimethylethyl) (3R)-1,3-piperidinedicarboxylate

Product 1

HCID 28167609(R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8078CyclohexaneSolvent

Conditions

Temperature
21.5 °C

Procedure

(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (6.0 kg, 26 mol) was added in portions to a mixture of 1,1′-carbonyldiimidazole (5.1 kg, 31 mol) in tetrahydrofuran (48 L) at a temperature of 18-22° C. The mixture was held at this temperature for 3 h, then pyrrolidine (2.28 kg, 32 mol) was added while maintaining a temperature of 18-25° C., and the resulting reaction mixture was held at this temperature for 2 h. Cyclohexane (48 L) and aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water) were then added sequentially, and the mixture was stirred for 30 min before separation of the layers. The organic layer was then washed with another portion of aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water). The combined aqueous layers were extracted with cyclohexane (30 L). The combined organic layers were then washed with aqueous sodium chloride solution (prepared from 3.0 kg sodium chloride and 30 L water). The organic layer was dried over sodium sulfate (2.0 kg), then the cyclohexane was removed by distillation under reduced pressure at 45° C. Isopropanol (43 L) was added and the mixture was stirred for 30 min. The presence of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate was confirmed by HPLC analysis: HPLC retention time: 5.98 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). This material was used in the next step without further purification.

Workup

  1. customthe resulting reaction mixture
  2. waitwas held at this temperature for 2 h
  3. washThe organic layer was then washed with another portion of aqueous potassium carbonate solution (prepared from 4.8 kg potassium carbonate and 48 L water)
  4. extractionThe combined aqueous layers were extracted with cyclohexane (30 L)
  5. washThe combined organic layers were then washed with aqueous sodium chloride solution (prepared from 3.0 kg sodium chloride and 30 L water)
  6. dry with materialThe organic layer was dried over sodium sulfate (2.0 kg)
  7. customthe cyclohexane was removed by distillation under reduced pressure at 45° C
  8. additionIsopropanol (43 L) was added
  9. stirringthe mixture was stirred for 30 min
  10. waitGradient: 20% B to 90% B over 7 min
  11. waitheld for 3 min
  12. custom25° C.
  13. customThis material was used in the next step without further purification

Sources & evidence

ORD record
ord-a8e03402d37c43c19d813c60fad96f90
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

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