Triethylamine → Tert-butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate

HRID 1616084Notes

Reaction equation

HRID 1616084 reaction equation
[C:1]([CH:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH:4]=O)#[N:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=O)=O.[C:31]([O:34][CH2:35][CH2:36]S)(=[O:33])C.[O-]CC.[Na+]>ClCCl.C(Cl)(Cl)Cl>[NH2:2][C:1]1[C:3]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[CH:4][S:27][C:26]=1[C:31]([O:34][CH2:35][CH3:36])=[O:33]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 98505Ethanol, 2-mercapto-, 1-acetateHCID 2723922Sodium ethoxideHCID 86681870Tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate

Product 1

HCID 86681876Tert-butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylateYield 22%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolvent2×HCID 6344DichloromethaneSolvent2×

Procedure

The tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (926 mg, 3.68 mmol) obtained in Step 4 of Example 1 was dissolved in dichloromethane (8 mL), a solution of triethylamine (0.66 mL, 4.78 mmol) and methanesulfonyl chloride (0.31 mL, 4.05 mmol) in dichloromethane (2 mL) was added dropwise under ice-cooling, followed by stirring under ice-cooling for 1 hour. The reaction liquid was diluted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (1.58 g) was dissolved in dichloromethane (20 mL), 1,8-diazabicyclo[4,3,0]-7-undecene (2.13 mL, 17.2 mmol) and 2-mercaptoethyl acetate (0.31 mL, 4.05 mmol) were added under ice-cooling, followed by stirring under ice-cooling for 3 hours. The reaction liquid was diluted with chloroform, and washed with a 1 N aqueous hydrochloric acid solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (3.26 g) was dissolved in ethanol (20 mL), and then sodium ethoxide (2.0 g, 29.4 mmol) was added, followed by heating under reflux for 3 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=50:1→30:1) to give tert-butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (287 mg, 22.0%) as a pale yellow amorphous.

Workup

  1. temperaturecooling
  2. temperaturecooling for 1 hour
  3. customThe reaction liquid
  4. washthe organic layer was washed with saturated brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under a reduced pressure
  7. dissolutionThe obtained residue (1.58 g) was dissolved in dichloromethane (20 mL)
  8. temperaturecooling
  9. stirringby stirring under ice-
  10. temperaturecooling for 3 hours
  11. customThe reaction liquid
  12. washwashed with a 1 N aqueous hydrochloric acid solution
  13. washThe organic layer was washed with saturated brine
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationconcentrated under a reduced pressure
  16. dissolutionThe obtained residue (3.26 g) was dissolved in ethanol (20 mL)
  17. temperatureby heating
  18. temperatureunder reflux for 3 hours
  19. customThe reaction liquid
  20. concentrationwas concentrated under a reduced pressure
  21. dissolutionthe obtained residue was dissolved in chloroform
  22. washThe organic layer was washed with saturated brine
  23. dry with materialdried over anhydrous sodium sulfate
  24. concentrationconcentrated under a reduced pressure
  25. customThe obtained residue was purified

Sources & evidence

ORD record
ord-607d37be9a2343559bb2826c231b5a7f
Source dataset
uspto-grants-2014_07
Patent number
US08765771B2

Reaction notes

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