Reaction #4593

Reaction equation

L-phenylalanine methyl ester hydrochloride

N-methyl morpholine

N-Methylmorpholine

isobutyl chloroformate

L-pyroglutamic acid

→

L-Pyroglutamyl-L-phenylalanine Methyl Ester

Solvents

EtOAc AcOH

DMF

THF DMF

Conditions

Workup

1. 1
   workup.ADDITIONwas added to the reaction mixture
2. 2
   workup.WAITto proceed at this temperature for 30 minutes
3. 3
   Otherat room temperature
4. 4
   FiltrationThe reaction mixture was then filtered
5. 5
   Otherto remove fines
6. 6
   Otherthe filtrate was evaporated in vacuo
7. 7
   workup.DISSOLUTIONThe resulting yellow liquid was dissolved in 100 ml of ethyl acetate
8. 8
   Washthe ethyl acetate solution was washed with 5% citric acid saturated with sodium chloride (50 ml) and 5% sodium bicarbonate saturated with NaCl (50 ml)
9. 9
   DryingThe separated organic layer was dried over anhydrous sodium sulfate
10. 10
    Otherevaporated in vacuo
11. 11
    Otherto yield quantitative amounts of a pale yellow liquid which
12. 12
    Otherquenching

Procedure

N-Methylmorpholine (2.02 g, 0.020 mol) and isobutyl chloroformate (2.73 g, 0.020 mol) were added to a solution of L-pyroglutamic acid (2.58 g, 0.020 mol) in 100 ml of THF/DMF (6:1) at -15° C. After a 2 minute coupling period, a mixture of L-phenylalanine methyl ester hydrochloride (4.31 g, 0.020 mol) (suspension) and N-methyl morpholine (2.02 g, 0.020 mol) in 50 ml of DMF was added to the reaction mixture. The reaction was allowed to proceed at this temperature for 30 minutes and then at room temperature for 1 additional hour. The reaction mixture was then filtered to remove fines and the filtrate was evaporated in vacuo to incipient dryness. The resulting yellow liquid was dissolved in 100 ml of ethyl acetate, and the ethyl acetate solution was washed with 5% citric acid saturated with sodium chloride (50 ml) and 5% sodium bicarbonate saturated with NaCl (50 ml). The separated organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield quantitative amounts of a pale yellow liquid which was used directly for the following step. TLC: Rf =0.22 in EtOAc/AcOH (100:1), detected by UV quenching; IR (neat, cm-1) 3300 (NH), 3020-3060 (C6H5), 2860-2960 (alkyl), 1650-1750 (C=O); NMR (Silanor C, δ from TMS) 7.25 (fused s, C6H5 --), 5.5-5.7 and 6.6-6.8 (broad, NH's), 4.6-5.1 (g, --NH--CH--C=O), 3.0-3.2 (q, --CH2 --C6H5), 1.6-2.5 (m, cycl. O=C--CH2 --CH2).

Source