1-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acid → tert-butyl 4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate

HRID 1269735Notes

Reaction equation

HRID 1269735 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]3)=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1

Participants

8

Reactant 5

HCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 120962235-(Aminomethyl)-1H-indazoleHCID 178418300HCID 178418300, compound

Product 1

HCID 18447544tert-butyl 4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylateYield 25.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 1-(1H-indazol-5-yl)methanamine (291 mg) in N,N-dimethylformamide (8 ml) were added 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (507 mg, 2.21 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (578 mg, 3.02 mmol) and hydroxybenzotriazole (229 mg, 2.21 mmol), and the resulting mixture was stirred at room temperature for 14 hours. Subsequently, a saturated aqueous sodium hydrogencarbonate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=40/1). To a solution of the resulting solid in a mixture of methanol (1 ml) and tetrahydrofuran (1 ml) was added a 2N-aqueous lithium hydroxide solution (0.68 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain tert-butyl 4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (179 mg).

Workup

  1. extractionfollowed by extraction with ethyl acetate
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. distillationdistilled under reduced pressure
  4. customto remove the solvent
  5. customThe resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=40/1)
  6. additionTo a solution of the resulting solid in a mixture of methanol (1 ml) and tetrahydrofuran (1 ml)
  7. additionwas added a 2N-aqueous lithium hydroxide solution (0.68 ml)
  8. stirringthe resulting mixture was stirred at room temperature for 30 minutes
  9. additionThen, the reaction solution was poured into water
  10. extractionextracted with ethyl acetate
  11. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  12. distillationdistilled under reduced pressure
  13. customto remove the solvent
  14. customThe resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1)

Sources & evidence

ORD record
ord-e9e9dc81dde04e90bc8d5f153f7ddb5f
Source dataset
uspto-grants-2007_04
Patent number
US07199147B2

Reaction notes

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