A kind of preparation method of teduglutide
A technology for teduglutide and peptide fragments, which is applied in the field of polypeptide drug preparation and achieves the effects of high yield, simple operation and broad market prospects
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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 (100.00g, loading: 1.0mmol / g) and wash it once with 800mL dry DMF, drain it, swell it with 800mL dry DMF for 2h, and drain it.
[0039] Weigh 82.29g Fmoc-Asp(OtBu)-OH, add 77.54g DIEA into the solution under ice cooling, and pour it into the reaction column. Stir the reaction at room temperature for 8 hours, add methanol 100mL, continue the reaction for 0.5 hours, remove the reaction solution, wash 3 times with 800mL DMF, then wash 3 times with 500mLMeOH and 500mL / time DCM respectively, 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, 800 mL each time, 5min+15min. After deprotection is completed, wash with DMF 6 times, 800 mL / time / min, drain, and detect ninhydrin, K+.
[0041] Weigh 47.57g Fmoc-Gly-OH, dissolve 23.78g ...
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 (100.00g, loading: 1.0mmol / g) and wash it once with 800mL dry DMF, drain it, swell it with 800mL dry DMF for 2h, and drain it.
[0047] Weigh 82.29g Fmoc-Asp(OtBu)-OH, add 77.54g DIEA into the solution under ice cooling, and pour it into the reaction column. Stir the reaction at room temperature for 8 hours, add methanol 100mL, continue the reaction for 0.5 hours, remove the reaction solution, wash 3 times with 800mL DMF, then wash 3 times with 500mLMeOH and 500mL / time DCM respectively, 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, 800 mL each time, 5min+15min. After deprotection is completed, wash with DMF 6 times, 800 mL / time / min, drain, and detect ninhydrin, K+.
[0049] Weigh 61.35g Fmoc-Ser(tBu)-OH...
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 (100.00g, loading: 1.0mmol / g) and wash it once with 800mL dry DMF, drain it, swell it with 800mL dry DMF for 2h, and drain it.
[0054] Weigh 70.68g of Fmoc-Ile-OH, add 51.70g of DIEA into the solution under ice cooling, and pour it into the reaction column. Stir the reaction at room temperature for 8 hours, add methanol 100mL, continue the reaction for 0.5 hours, remove the reaction liquid, wash 3 times with 800mL DMF, then wash 3 times with 500mLMeOH and 500mL / time DCM respectively, take out the resin, and dry to obtain Fmoc-Ile -CTC Resin 130.60g, substitution degree 0.61mmol / g.
[0055] Add 20% piperidine / DMF solution (DBLK solution) for deprotection twice, 800 mL each time, 5min+15min. After deprotection is completed, wash with DMF 6 times, 800 mL / time / min, drain, and detect ninhydrin, K+.
[0056] Weigh 63.59g Fmoc-Thr(tBu)-OH, diss...
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