Method for preparing polypeptide with high-fidelity end group by initiating polymerization of NPCA (N-phenoxycarbonyl protected alpha-amino acid precursor) through protonated amino group
A technology of protonation and initiator, applied in the field of preparing polypeptides
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Embodiment 1
[0088] Embodiment 1: the synthesis of NBDab
[0089]
[0090] A solution mixture of Boc-Gln-OH (15.0 g, 60.9 mmol, 1.0 eq) in THF (320 mL) and water (80 mL) was prepared and pre-cooled to ~4°C. PIDA (23.54g, 73.09mmol, 1.2eq) was added. After stirring for 8 hours, the reaction mixture was evaporated to dryness, the residue was dissolved in water (250 mL) and extracted with EA (3 x 60 mL). The organic layer was discarded, and the aqueous layer was evaporated to dryness. The residue was washed 3 times with cold chloroform and dried under vacuum, and the obtained pale yellow solid NB-1 was directly used in the next step (9.91 g, yield: 74.56%).
[0091] Synthesis of NB-2. To stirred NB-1 (8.0g, 36.7mmol, 1.0eq) and H in an ice-water bath 2 Aqueous NaOH (1.0 M) was added dropwise to a solution of O (100 mL) to adjust the pH of the solution to about 10. Freshly synthesized o-nitrobenzyl chloroformate (9.48 g, 43.99 mmol, 1.2 eq) was added and the reaction mixture was stirre...
Embodiment 2
[0094] Embodiment 2: the synthesis of NBO
[0095]
[0096] To a round bottom flask was added L-ornithine hydrochloride (15.0 g, 88.97 mmol, 1.0 eq) and deionized water (500 mL). To this mixture was slowly added sodium hydroxide (7.11 g, 177.9 mmol, 2.0 eq) at 0°C. Next, add CuSO 5 hydrate 4 (11.12g, 44.5mmol, 0.5eq), the reaction mixture was stirred at room temperature for 6h, then it was cooled to 0°C. In an ice-water bath, o-nitrobenzyl chloroformate (23.01 g, 106.8 mmol, 1.2 eq) in THF (80 mL) and sodium bicarbonate (8.96 g, 106.8 mmol, 1.2 eq) were added. It was stirred overnight at room temperature, and the blue solid residue formed was collected by filtration, washed with water, dried, and used immediately in the subsequent step. The above intermediate was dispersed in 700 mL of water at 80 °C in a vigorously stirred in suspension. At 90 °C, EDTA (25.72 g, 76.51 mmol, 0.86 eq) was added and the reaction mixture was stirred for a few minutes until most of the solid ...
Embodiment 3
[0098] Embodiment 3: the synthesis of 4-[(tert-butoxycarbonylamino) methyl] benzoyl azide
[0099]
[0100] 4-(Aminomethyl)benzoic acid (5.0 g, 32.02 mmol, 1.0 eq) and Boc anhydride (7.69 g, 35.22 mmol, 1.1 eq) were stirred in a mixture of THF (200 mL) and water (50 mL). After cooling to 0 °C in an ice-water bath, add saturated NaHCO 3 aqueous solution until the pH of the solution changes to ~8. The reaction mixture was stirred at ambient temperature for 16 hours, TLC showed complete consumption of starting material. After removal of THF under reduced pressure, 200 mL of water was added, the pH of the solution was adjusted to ~2-3 using 2M HCl, and the formed precipitate was collected by suction filtration and washed with water (100 mL) and diethyl ether (3x100 mL). It was then dried in vacuo to obtain the title compound as a white solid (7.51 g, yield: 90.6%).
[0101] To a stirred suspension of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid (7.0 g, 27.86 mmol, 1.0 eq...
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