Diisopropylamine → 1,1-Dimethylethyl 1-oxo-3-(4-chlorophenyl)-2-cyclopropyl-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 1869226Notes

Reaction equation

HRID 1869226 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28]CC)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[N:37][CH:38]2[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[O:28]=[C:26]1[C:23]2([CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:25][CH2:24]2)[CH:36]([C:35]2[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=2)[N:37]1[CH:38]1[CH2:39][CH2:40]1

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 57986041HCID 57986041, compoundHCID 178418339Butyllithium

Product 1

HCID 249545071,1-Dimethylethyl 1-oxo-3-(4-chlorophenyl)-2-cyclopropyl-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 95%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

Cool to 0 to −10 C, a solution of diisopropylamine (6.0 mL) in THF (10 mL) and add n-butyllithium (2.5 M, 16.6 mL) dropwise. After 1 h, the reaction mixture was cooled to −78 C. Add a solution of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (1) (10 g) in anhydrous THF (20 mL) dropwise, and stir the resulting solution at −78 C for 1.5 h. Add 4-chlorobenzylidene cyclopropylamine (8) (6.69 g) in THF (40 mL) and stir for 1 h. Warm the reaction mixture to room temperature and stir overnight. Quench the reaction mixture with saturated ammonium chloride solution and extract with EtOAc. Partition the EtOAc solution with IN HCl, then salt solution. Concentrate the dried (MgSO4) EtOAc solution in vacuo to give an amber oil (13.83 g). Absorb the amber oil (12.8 g) on Purasil 60A 230-400 mesh (˜30 mL), place in a syringe cartridge, and elute onto a Redi Sep Normal Phase Disposable Column (330 g, ISCO). Elute with hexane (one column volume) then hexane/EtOAc gradient (0% to 55% EtOAc) at 65 mL/min. Collect the title compound and concentrate the fractions in vacuo to give the title compound (9) (3.49 g).

Workup

  1. temperatureCool to 0 to −10 C
  2. temperaturethe reaction mixture was cooled to −78 C
  3. stirringstir overnight
  4. customQuench the reaction mixture with saturated ammonium chloride solution
  5. extractionextract with EtOAc
  6. customPartition the EtOAc solution with IN HCl
  7. concentrationConcentrate the
  8. dry with materialdried (MgSO4) EtOAc solution in vacuo

Sources & evidence

ORD record
ord-39114aa320054d69acad0754763f16bb
Source dataset
uspto-grants-2009_12
Patent number
US07638526B2

Reaction notes

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