Acetic Acid → tert-Butyl trans(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-pyrrolidin-1-ylpiperidine-1-carboxylate

HRID 1425314Notes

Reaction equation

HRID 1425314 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C:18]2=O)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1.CO>[Cl:6][C:7]1[N:8]=[C:9]([C:14]([NH:16][C@@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][C@H:18]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])[NH:10][C:11]=1[CH2:12][CH3:13]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 31268Pyrrolidine2×HCID 5003444Sodium cyanoborohydrideHCID 68406285tert-Butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate

Product 1

HCID 86648779tert-Butyl trans(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-pyrrolidin-1-ylpiperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Pyrrolidine (45 μL, 0.539 mmol) and 3 Å molecular sieves (100 mg) were added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (100 mg, 0.270 mmol) in tetrahydrofuran (3 mL), and the mixture was heated at 50° C. for four hours. Methanol (3 mL), pyrrolidine (45.0 μL, 0.539 mmol), sodium cyanoborohydride (51 mg, 0.809 mmol) and acetic acid (154 μL, 2.70 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain two isomers of the title compound, 21 mg of the cis isomer (18%) and 9 mg of the trans isomer (8%), as pale yellow oily substances.

Workup

  1. concentrationThe reaction solution was concentrated under reduced pressure
  2. additionSaturated aqueous sodium bicarbonate solution was added to the residue
  3. extractionfollowed by extraction with ethyl acetate
  4. washThe resulting organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customthe insoluble matter was separated by filtration
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customthe resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v)

Sources & evidence

ORD record
ord-1f96549dc81e49629cc3458d42a82ff4
Source dataset
uspto-grants-2015_01
Patent number
US08927588B2

Reaction notes

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