| 5.2 g |
With 5%-palladium/activated carbon; hydrogen; acetic acid at 20℃; |
1 Example 1. Synthesis of the peptide Ac-Asp-Glu-OH (AcDE) (SEQ ID NO: 1)
16.5 ml (150 mmol) of NMM and 19.5 ml (150 mmol) of isobutylchloroformate were added to the solution of Boc-Asp (Bzl)-OH 48.5 g (150 mmol) cooled down to -20°C in 300 ml of DMF and agitated for 15 minutes. The mixture was agitated at the same temperature for 20 minutes. A solution, cooled down to -20°C, and comprising 74.5 g. (155 mmol) of the aminocomponent H-Glu (Bzl)-OBzl x Tos in 200 ml of DMF, containing 17 ml of NMM (155 mmol), was further added. The reaction mixture was agitated for 1 hour at -10°C, and for 2 hours at room temperature. Once evaporated, the residue was dissolved in ethyl acetate (500 ml) and sequentially washed with 5% NaHCO3, H2O, 2% H2SO4, H2O (twice, with 200 ml of each), boiled down, and boiled down again with isopropyl alcohol. 500 ml of hexane and 50 ml of ester were added to the resulting oil, and the resulting oil was ground until the formation of solid particles. (0024) The product is crystallized in a refrigerator. The sediment is filtered, washed with hexane on the filter, and dried. 89 g (89%) of a chromatographically homogeneous product were obtained. (0025) 12.64 g (20 mmol) of the protected dipeptide 1 (Asp-Glu peptide) were dissolved in 100 ml of chloroform, added to this solution at 0°C were 100 ml of trifluoroacetic acid, the mixture was kept for 1 hour at room temperature, and the solvents were evaporated in vacuum. The residue was dissolved in 300 ml of ethyl acetate and washed with 5% solution of bicarbonate 3 times, 200 ml each time. The organic layer was separated and dried over water-free Na2SO4, and the ethyl acetate was boiled down. The residue was dissolved in 300 ml of dimethyl formamide, added to the resulting solution were 3.6 g (20 mmol) of paranitophenyl ester of acetic acid. The mixture was left for 15 hours at room temperature. The solvent was boiled down, the residue was dissolved in ethyl acetate and washed with a 5% water solution of ammonia until traces of pararnitrophenol disappeared (control with TLC), and with water to pH 6-7; the organic layer was separated and dried, and ethyl acetate was boiled down. The residue was dissolved in 80% acetic acid and hydrated above 5% PdC at room temperature. Once the hydration was completed the catalyst was filtered out, the filtrate was boiled down, the residue was dissolved in 300 ml water, again boiled down to half of the volume, and lyophilized. 5.2 g (85.8%) of the target acyl derivative dipeptide were obtained. According to HPLC, the product's purity was over 95 %. (0026) In the PMR spectrum: Asp - 4.62 (α-CH); 2.70, 2.53 (β-CH2); 8.63 (NH) Glu - 4.20 (α-CH); 1.97, 1.78 (β-CH2); 2.26(γ-CH2); 8.19 (NH) Ac - 1.96 (3H, -COCH3) |
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