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

HRID 1617387Notes

Reaction equation

HRID 1617387 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.[F:22][CH:23]1C(=O)[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]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[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][C@H:23]2[F:22])[CH2:7]1)#[N:2]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 5049666Sodium triacetoxyborohydrideHCID 10560711TERT-BUTYL 3-FLUORO-4-OXOPIPERIDINE-1-CARBOXYLATEHCID 457892161-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine

Product 1

HCID 67392594tert-Butyl cis-4-[3-(Cyanomethylene)azetidin-1-yl]-3-fluoropiperidine-1-carboxylateYield 66%

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 solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL). To it were added tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (3.392 g, 15.62 mmol) and triethylamine (3.126 g, 30.89 mmol). 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 and diluted with aqueous NaHCO3 and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification with combi-flash (20-100% EtOAc in hexanes) afforded 0.5 g (66% yield) of the desired product. LC/MS found: 240.1 (M−56)+.

Workup

  1. concentrationthe solution 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 under reduced pressure
  9. customPurification with combi-flash (20-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-71eac8d5a1c94086b02a3a0de7f60b4b
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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