Preparation method of semaglutide
A peptide, fully protected technology, applied in the field of preparation of semaglutide, can solve the problems of high cost, excessive consumption of solid phase carrier, cumbersome operation of peptide fragments, etc.
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[0043] According to specific embodiments of the present invention, the preparation method of semaglutide provided by the present invention comprises steps:
[0044] (1) The first fully protected peptide obtained by solid-phase synthesis:
[0045] R-His(R1)-Aib-Glu(R2)-Gly-Thr(R3)-Phe-Thr(R3)-Ser(R3)-Asp(R2)-Val-Ser(R3)-Ser(R3)- Tyr(R3)-Leu-Glu(R2)-Gly-Gln(R1)-Ala-COOH;
[0046] (2) Solid phase synthesis of fully protected second peptide:
[0047] NH 2 -Ala-Lys[AEEA-AEEA-γ-Glu(R2)-Otc(R2)]-Glu(R2)-Phe-Ile-Ala-Trp(R4)-Leu-Val-Arg(R5)-Gly-Arg (R5)-Gly-R6;
[0048] (3) Mixing the fully protected first peptide segment with the fully protected second peptide segment for a condensation reaction to obtain a fully protected semaglutide intermediate;
[0049] (4) cutting the fully protected semaglutide intermediate with a cleavage reagent to obtain a cleavage solution so as to obtain crude semaglutide;
[0050] Wherein, R is selected from any one of Boc, Fmoc, Alloc, and Cbz;
[...
Embodiment 1
[0078] Embodiment 1 Preparation of the first peptide segment of semaglutide
[0079] The first peptide was synthesized by the following method: Boc-His(Trt)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser (tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-COOH.
[0080]1) Weigh 2-Cl-trityl resin (1.2mmol / g, 16.6g, 20mmol) into a reaction tube, add 200mL DMF / DCM, and swell the resin for 1 hour. Fmoc-Ala-OH (12.4g, 40mmol) was weighed and dissolved in 200mL DMF, and DIEA (13.2mL, 80mmol) was added, mixed well, added to the above swollen resin, and reacted at room temperature for 12 hours. After the reaction was completed, 10 mL of methanol was added. After continuing to react for 30 minutes, drain the resin, wash the resin with DMF and DCM, and finally use methanol to shrink the resin to obtain dry Fmoc-Ala-2-Cl-trityl resin, and the measured resin replacement value is 0.50 mmol / g;
[0081] 2) Weigh Fmoc-Ala-2-Cl-trityl resin (0.50mmol / g, 20g, 10mmol) i...
Embodiment 2
[0083] Synthesis of Example 2 Branched R2-Otc-γ-Glu(R2)-AEEA-AEEA-COOH
[0084] 1) Weigh 2-Cl-trityl resin (1.2mmol / g, 8.3g, 10mmol) into a reaction tube, add 100mL of DMF / DCM, and swell the resin for 1 hour. Weigh Fmoc-AEEA-OH (7.7g, 20mmol) and dissolve it in 100mL DMF, add DIEA (6.6mL, 40mmol), mix well, add to the above swollen resin, and react at room temperature for 12 hours. After the reaction was completed, 5 mL of methanol was added. After continuing to react for 30 minutes, drain the resin, wash the resin with DMF and DCM, and finally use methanol to shrink the resin to obtain dry Fmoc-AEEA-2-Cl-trityl resin, and the measured resin substitution value is 0.58mmol / g;
[0085] 2) Weigh Fmoc-AEEA-2-Cl-trityl resin (0.58mmol / g, 8.6g, 5mmol) into a reaction tube, add 200mL DMF / DCM, and swell the resin for 1 hour. Drain the resin and add 100 mL of 20% piperidine / DMF to remove Fmoc. The stripping reaction was performed twice for 15 minutes each. The dereacted resin was w...
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