Preparation method of teduglutide
A technology of teduglutide and peptide fragments, which is applied in the field of polypeptide drug preparation to achieve the effects of high yield, short construction period and simple operation
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Embodiment 1
[0037]Example 1: Synthesis of fully protected 1-3 peptide fragment Boc-His(Trt)-Gly-Asp(OtBu)-OH
[0038]Weigh CTC Resin (100.00 g, loading: 1.0 mmol / g), wash it once with 800 mL of dry DMF, drain it, and swell with 800 mL of dry DMF for 2 hours and drain it.
[0039]Weigh 82.29g Fmoc-Asp(OtBu)-OH, add 77.54g DIEA to the solution under ice bath, and pour it into the reaction column. Stir the reaction at room temperature for 8 hours, add 100 mL of methanol, continue the reaction for 0.5 hours, remove the reaction solution, wash with 800 mL DMF 3 times, and then wash 3 times with 500 mL MeOH and 500 mL / time DCM, take out the resin, and dry to obtain Fmoc-Asp (OtBu)-CTC Resin 136.5g, substitution degree 0.586mmol / g.
[0040]Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 800mL / time, 5min+15min. After deprotection, wash with DMF 6 times, 800 mL / time / min, drain, and detect with ninhydrin, K+.
[0041]Weigh 47.57g Fmoc-Gly-OH, 23.78g HOBt dissolved in 800mL DMF, add 26.25g DIC...
Embodiment 2
[0045]Example 2: Synthesis of fully protected 4-8 peptide fragment Fmoc-Gly-Ser(tBu)-Phe-Ser(tBu)-Asp(OtBu)-OH
[0046]Weigh CTC Resin (100.00 g, loading: 1.0 mmol / g), wash it once with 800 mL of dry DMF, drain it, and swell with 800 mL of dry DMF for 2 hours and drain it.
[0047]Weigh 82.29g Fmoc-Asp(OtBu)-OH, add 77.54g DIEA to the solution under ice bath, and pour it into the reaction column. Stir the reaction at room temperature for 8 hours, add 100 mL of methanol, continue the reaction for 0.5 hours, remove the reaction solution, wash with 800 mL DMF 3 times, and then wash 3 times with 500 mL MeOH and 500 mL / time DCM, take out the resin, and dry to obtain Fmoc-Asp (OtBu)-CTC Resin 138.6g, substitution degree 0.58mmol / g.
[0048]Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 800mL / time, 5min+15min. After deprotection, wash with DMF 6 times, 800 mL / time / min, drain, and detect with ninhydrin, K+.
[0049]Weigh 61.35g Fmoc-Ser(tBu)-OH, 23.78g HOBt dissolved in 800mL D...
Embodiment 3
[0052]Example 3: Synthesis of fully protected 9-13 peptide fragment Fmoc-Glu(OtBu)-Met-Asn(Trt)-Thr(tBu)-Ile-OH
[0053]Weigh CTC Resin (100.00 g, loading: 1.0 mmol / g), wash it once with 800 mL of dry DMF, drain it, and swell with 800 mL of dry DMF for 2 hours and drain it.
[0054]Weigh 70.68g Fmoc-Ile-OH, add 51.70g DIEA to the solution under ice bath, and pour it into the reaction column. The reaction was stirred at room temperature for 8 hours, 100 mL of methanol was added, and the reaction was continued for 0.5 hours. The reaction solution was removed and washed with 800 mL of DMF for 3 times, and then washed with 500 mL of MeOH and 500 mL of DCM for 3 times. The resin was taken out and dried to obtain Fmoc-Ile. -CTC Resin 130.60g, substitution degree 0.61mmol / g.
[0055]Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 800mL / time, 5min+15min. After deprotection, wash with DMF 6 times, 800 mL / time / min, drain, and detect with ninhydrin, K+.
[0056]Weigh 63.59g Fmoc-Th...
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