Reaction #5076

Reaction equation

H-Pro-OBzl.HCl

Boc-(D)Phe-OH

N-methylmorpholine

Triethylamine

isobutyl chloroformate

→

Boc-(D)Phe-Pro-OBzl

Yield 89.1%

Solvents

chloroform

THF

Conditions

Workup

1. 1
   Otherremoving the ester by catalytic hydrogenation
2. 2
   TemperatureThe solution was cooled to -20°
3. 3
   Temperaturecooled to -20°
4. 4
   workup.ADDITIONwas added
5. 5
   FiltrationThe reaction mixture was filtered
6. 6
   Otherthe filtrate evaporated
7. 7
   workup.DISSOLUTIONThe residue was dissolved in ethyl acetate
8. 8
   Washwas washed with 0.2N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride
9. 9
   DryingThe organic phase was dried over anhydrous sodium sulfate
10. 10
    Filtrationfiltered
11. 11
    Otherevaporated

Procedure

Boc-(D)Phe-Pro-OH was produced by first preparing the dipeptide benzyl ester and then removing the ester by catalytic hydrogenation. Boc-(D)Phe-OH (10.0 g, 37.7 mmoles) was dissolved in 50 mL of THF and N-methylmorpholine (4.14 mL, 37.7 mmoles) was added. The solution was cooled to -20° and isobutyl chloroformate (4.90 mL, 37.7 mmoles) was added. After 5 min, H-Pro-OBzl.HCl (9.11 g, 37.7 mmoles), dissolved in 50 mL of chloroform and cooled to -20°, was added. Triethylamine (5.25 mL, 37.7 mmoles) was added and the mixture was stirred for 1 h at -20° and 2 h at room temperature. The reaction mixture was filtered and the filtrate evaporated. The residue was dissolved in ethyl acetate and was washed with 0.2N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to yield 15.2 g of Boc-(D)Phe-Pro-OBzl as an oil. The benzyl ester (15.2 g) was dissolved in 100 mL of methanol and it was hydrogenated at an initial pressure of 40 psi on a Parr apparatus in the presence of 0.5 g of 10% Pd/C. The reaction solution was filtered through Celite™ and evaporated to yield a solid. This solid material was isolated and was washed with ethyl acetate and then by ether to yield 10.0 g of the desired product (mp 176.5°-177°).

Source