Dicyclohexylcarbodiimide → 1-Benzyl-3(S)-n-butylpiperazine-2,5-dione

HRID 342112Notes

Reaction equation

HRID 342112 reaction equation
C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:29]([OH:31])=O)[CH2:25][CH2:26][CH2:27][CH3:28])([O:18]C(C)(C)C)=O.[CH2:32]([NH:39][CH2:40]C(OCC)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([N:39]1[CH2:40][C:16](=[O:18])[NH:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[C:29]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

Participants

5

Reactant 3

HCID 10868DicyclohexylcarbodiimideHCID 80908N-Benzylglycine ethyl esterHCID 2733747N-tert-Butoxycarbonyl-L-norleucine

Product 1

HCID 600090831-Benzyl-3(S)-n-butylpiperazine-2,5-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus dicyclohexylcarbodiimide (9.33 g, 45.2 mmol) in methylene chloride (0.5M) was added to methylene chloride (250 mL). This solution was cooled to 0° C. under nitrogen and Boc-L-norleucine (10.5 g, 45.2 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (8.72 g, 45.2 mmol) was added. The reaction was stirred for 2 h at 0° C., then at 20° C. overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tic. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude diketopiperazine was triturated with hexane to give the title compound as a white powder. 1HNMR (300 MHz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H, br s), 4.07 (1H, dt, J=3, 6 Hz), 3.87 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).

Workup

  1. customThe title compound was prepared
  2. stirringThe reaction was stirred for 2 h at 0° C.
  3. customat 20° C.
  4. customovernight
  5. customThe precipitate was removed by filtration, and hydrogen chloride gas
  6. custombubbled through the methylene chloride solution for 2-4 h, until the reaction
  7. customThe solvent was removed in vacuo
  8. customthe residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL)
  9. washThe organic phase was washed with saturated sodium chloride
  10. filtrationfiltered
  11. customevaporated
  12. customThe crude diketopiperazine was triturated with hexane

Sources & evidence

ORD record
ord-e2a9be3b924446a28d9ac7780615dd39
Source dataset
uspto-grants-1999_01
Patent number
US05856326

Reaction notes

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