Hydrochloric Acid → tert-Butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-methoxypiperidine-1-carboxylate

HRID 1617385Notes

Reaction equation

HRID 1617385 reaction equation
[C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8](OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1.[CH3:22][O:23][CH:24]1C(=O)[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([CH:3]=[C:4]1[CH2:5][N:6]([C@H:8]2[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][C@H:24]2[O:23][CH3:22])[CH2:7]1)#[N:2]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 5049666Sodium triacetoxyborohydrideHCID 457892161-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidineHCID 57363786tert-Butyl 3-methoxy-4-oxopiperidine-1-carboxylate

Product 1

HCID 67392031tert-Butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-methoxypiperidine-1-carboxylateYield 60.7%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (3.0 g, 15 mmol) in tetrahydrofuran (8 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol). After being stirred at room temperature for two hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate (3.58 g, 15.62 mmol) and triethylamine (3.126 g, 30.89 mmol) were added. After being stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (8.184 g, 38.61 mmol) was added. The mixture was stirred at room temperature overnight. The resulting solution was diluted with aqueous NaHCO3 and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated. Purification with combi-flash (20-100% EtOAc in hexanes) afforded 2.8 g (60% yield) of the desired product. LC/MS found: 308.1 (M−56)+.

Workup

  1. concentrationthe reaction mixture was concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in tetrahydrofuran (20 mL)
  3. stirringAfter being stirred at room temperature for 30 minutes
  4. stirringThe mixture was stirred at room temperature overnight
  5. customThe organic layer was separated
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customPurification with combi-flash (20-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-2458027ea61e4843a87e6e33ef498428
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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