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Preparation method of semaglutide full-protection peptide resin and preparation method of semaglutide

A fully protected, peptide resin technology, applied in the field of peptide synthesis, can solve problems such as increased production costs, difficulty in obtaining high-quality crude products, and affecting product quality

Active Publication Date: 2022-01-04
浙江肽昇生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to sequence reasons, when using conventionally protected amino acids for step-by-step connection, the connection is difficult due to resin polycondensation, which affects product quality
It is difficult to obtain high-quality crude products, resulting in increased production costs

Method used

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  • Preparation method of semaglutide full-protection peptide resin and preparation method of semaglutide
  • Preparation method of semaglutide full-protection peptide resin and preparation method of semaglutide
  • Preparation method of semaglutide full-protection peptide resin and preparation method of semaglutide

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preparation example Construction

[0021] The invention provides a preparation method of semaglutide fully protected peptide resin, comprising the following steps: according to the sequence of semaglutide, taking Fmoc-Gly 31 -resin, sequentially coupled with the amino acid shown in formula I or the dipeptide fragment shown in formula II and the raw material that provides the remaining amino acids in the semaglutide sequence to obtain a semaglutide fully protected peptide resin, the formula I is Fmoc-N(R)-AA 1 -OH, the formula II is Fmoc-AA 2 -N(R)-AA 1 -OH, R in the formula I and II is Dmb or Hmb, AA in the formula I and II 1 for Gly 29、Leu 26 、Ala 24 、Ala 19 、Ala 18 、Gly 16 、Leu 14 One or more of the AA 2 is Arg(Pbf) 28 、Trp(Boc) 25 、Ile 23 、Ala 18 、Gln(Trt) 17 、Glu(OtBu) 15 、Tyr(tBu) 13 In one or more of the above, the raw material that provides the remaining amino acids in the semaglutide sequence includes amino acids and / or peptide fragments, and the amino acids and / or peptide fragments hav...

Embodiment 1

[0082] Weigh 17.24g of Wang Resin with a degree of substitution of 0.58mmol / g, add it to the synthesis reactor, add DMF to swell for 30min, and remove the DMF solution; weigh Fmoc-Gly 31 Add 4.46g of -OH and 2.05g of HoBt into the synthesis reactor, dissolve with DMF, blow nitrogen, add DIC2.310ml, react for 10min, weigh 0.366g of DMAP and add to the above reaction mixture, continue the reaction for 3h, pump out the reaction mixture solution, washed the resin 5 times with DMF, capped with 200ml acetic anhydride / NMM / DMF for 3h, washed 2 times with DMF, 2 times with MeOH, 2 times with DCM, 2 times with MeOH, dried in vacuum to constant weight, and obtained Fmoc -Gly 31 - WangResin 31.82g, the measured substitution degree is 0.31mmol / g.

[0083] Weigh Fmoc-Gly with a substitution degree of 0.31mmol / g 31 -Wang Resin 3.26g, added to the synthesis reactor, swollen with DMF for 60min, pumped out the DMF solution, added 20% PIP / DMF solution to remove Fmoc, washed the resin 5 times w...

Embodiment 2

[0090] Weigh 17.24g of Wang Resin with a degree of substitution of 0.58mmol / g, add it to the synthesis reactor, add DMF to swell for 30min, and remove the DMF solution; weigh Fmoc-Gly 31 Add 4.46g of -OH and 2.05g of HoBt into the synthesis reactor, dissolve with DMF, blow nitrogen, add 2.310ml of DIC, react for 10min, weigh 0.366g of DMAP and add to the above reaction mixture, continue the reaction for 3h, pump out the reaction mixture solution, washed the resin 5 times with DMF, capped with 200ml acetic anhydride / NMM / DMF for 3h, washed 2 times with DMF, 2 times with MeOH, 2 times with DCM, 2 times with MeOH, dried in vacuum to constant weight, and obtained Fmoc -Gly 31 - WangResin 31.82g, the measured substitution degree is 0.31mmol / g.

[0091] Weigh Fmoc-Gly with a substitution degree of 0.31mmol / g 31 -Wang Resin 3.23g, added to the synthesis reactor, swelled with DMF for 60min, pumped out the DMF solution, added 20% PIP / DMF solution to remove Fmoc, washed the resin 5 tim...

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Abstract

The invention provides a preparation method of semaglutide and relates to the technical field of polypeptide synthesis. According to the preparation method provided by the invention, amino acid as shown in a formula I or a dipeptide fragment as shown in a formula II is adopted, and through steric hindrance of a raw material structure, polycondensation caused by beta folding in a semaglutide full-protection peptide resin coupling process can be improved, the difficulty of coupling of semaglutide resin is lowered, so that missing impurities, inserted impurities and racemization impurities are effectively avoided. Therefore, the preparation method provided by the invention has the advantages that the quality of a semaglutide crude product can be improved, the yield of the semaglutide is increased, and the preparation method is low in cost, simple to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of semaglutide fully protected peptide resin and a preparation method of semaglutide. Background technique [0002] Semaglutide (CAS: 910463-68-2), a novel glucagon-like peptide-1 (GLP-1) receptor agonist, is effective for glycemic control and weight loss in type 2 diabetes mellitus (T2DM) significant effect. [0003] In humans, semaglutide is chemically similar to glucagon-like peptide-1 (GLP-1). The structure of Semaglutide is that the 8-position Aib on the GLP-1 (7-37) chain replaces Ala, the 34-position Arg replaces Lys, and the 26-position Lys is connected to an octadecanedioic acid fatty chain, glutamic acid and a short chain PEG modification. After PEG modification, it can not only bind tightly with albumin, cover the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, prolong the biological half-life and achieve long-ter...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/10C08F8/32
CPCC07K14/605C08F8/32Y02P20/55
Inventor 纪东亮罗瑞昌李雪豪龚裕录
Owner 浙江肽昇生物医药有限公司
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