Triethylamine → ethyl (S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate

HRID 2296909Notes

Reaction equation

HRID 2296909 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:31][CH2:30]1>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([N:29]1[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 62493Pivaloyl chlorideHCID 85082Tert-butoxycarbonylalanineHCID 71357176Ethyl (piperidin-4-yloxy)-acetate hydrochloride

Product 1

HCID 59923219ethyl (S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetateYield 95.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
2.5 °C

Procedure

47.3 g (250 mmol) of (S)-2-tert.-butoxycarbonylamino-propionic acid (Fluka) were dissolved in 560 ml of ethyl acetate (Fluka) while stirring and under argon, cooled to 0-5° C. and treated with 31.0 ml (250 mmol) of pivaloyl chloride (d=98; Fluka). The light yellowish solution was treated dropwise within 30 minutes with 35.0 ml (250 mmol) of triethylamine (d=0.726; Fluka), with the temperature being held in the range of 0-5° C. A white suspension formed. The white precipitate was filtered off through a pre-cooled, sintered glass filter (G3) and the filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C.). To the combined filtrates, a light yellow solution, were added 55.9 g (17. HCl; 250 mmol) of ethyl (piperidin-4-yloxy)-acetate hydrochloride and 66.6 g of K3PO4.3H2O (250 mmol; Merck). The white suspension was treated with 500 ml of deionised water at 5 to 10° C. under argon and while stirring vigorously, with the temperature rising to 20° C. The colourless two-phase system was stirred at 20 to 25° C. for two hours. The aqueous phase was separated and the organic phase was washed with 500 ml of a 1M sodium bicarbonate solution. The organic phase was dried over about 50 g of sodium sulphate, filtered and the filter cake was washed with about 100 ml of ethyl acetate. The combined filtrates were evaporated in a rotary evaporator at 50°/20 mbar, giving 85.5 g (95 wt. %) of ethyl (S)-[1-(2-tert.-butoxycarbonylamino-propionyl)-piperidin-4-yloxy]-acetate as a crude product in the form of a clear, yellowish oil (HPLC analysis: 88.9% (area).

Workup

  1. custombeing held in the range of 0-5° C
  2. customA white suspension formed
  3. filtrationThe white precipitate was filtered off through a pre-cooled, sintered glass
  4. filtrationfilter (G3)
  5. washthe filter cake was washed with 140 ml of cold ethyl acetate (0 to 5° C.)
  6. stirringwhile stirring vigorously, with the temperature
  7. customrising to 20° C
  8. stirringThe colourless two-phase system was stirred at 20 to 25° C. for two hours
  9. customThe aqueous phase was separated
  10. washthe organic phase was washed with 500 ml of a 1M sodium bicarbonate solution
  11. dry with materialThe organic phase was dried over about 50 g of sodium sulphate
  12. filtrationfiltered
  13. washthe filter cake was washed with about 100 ml of ethyl acetate
  14. customThe combined filtrates were evaporated in a rotary evaporator at 50°/20 mbar

Sources & evidence

ORD record
ord-de74780410fb4132aead65a3594cfb89
Source dataset
uspto-grants-2002_12
Patent number
US06489479B1

Reaction notes

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