Preparation method of somaglutide

A peptide resin and resin technology, applied in the field of peptide synthesis, can solve the problems of increasing the difficulty of side chain coupling, high production costs, and increasing the amount of racemized impurities

Inactive Publication Date: 2021-01-22
浙江肽昇生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, there are two main methods for the synthesis of semaglutide: one is to gradually couple the main chain, then remove the Lys side chain protecting group, and then gradually couple the side chain, but this method increases the difficulty of coupling the side chain , and in the process of gradually coupling the side chain to remove the protecting group, the amount of His racemic impurities increases and the yield is low; the second is to remove the Lys side chain protecting group after gradually coupling the main chain, and then couple the entire side chain , but the acquisition of the entire side chain is relatively difficult and the production cost is high

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  • Preparation method of somaglutide
  • Preparation method of somaglutide
  • Preparation method of somaglutide

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preparation example Construction

[0030] The invention provides a preparation method of semaglutide, comprising the following steps:

[0031] (1) Mix the starting resin, Fmoc-Gly-OH, pyridine catalyst, coupling reagent and solvent, and perform the first coupling reaction and capping resin in sequence to obtain Fomc-Gly-resin;

[0032] (2) Fmoc-Arg (pbf)-OH is connected on the Fomc-Gly-resin to obtain Fomc-Arg (pbf)-Gly-resin; the connection includes the removal of the Fomc protecting group reaction and the second coupling reaction;

[0033] (3) According to the method of step (2), connect Fmoc-Gly-OH, Fmoc-Arg(pbf)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH and R 1 -Lys(R 2 )-OH, to obtain the first peptide resin; the R 1 Including Fmoc, Mtt, Mmt, ivDde, Dde or Alloc; the R 2 Including Fmoc, Mtt, Mmt, ivDde, Dde or Alloc; the structural formula of the first peptide resin is R 1 -Lys 26 (R 2 )-Glu(OtBu) 27 -Phe 28 -Ile 29 -Ala 30 -Trp(Boc...

Embodiment 1

[0085] (1) Add 17.25g Wang resin with a substitution degree of 0.58mmol / g to the synthesis reactor, add 80mL DMF to swell the resin for 60min; dissolve 8.94g Fmoc-Gly-OH, 4.08g HOBT and 0.611g Dmap with 20mL DMF , placed in an ice-water bath and mixed for 20 minutes, added 4.62mL DIC and stirred at room temperature for 5 minutes to obtain a mixed solution; the obtained mixed solution was added to the above-mentioned synthesis reactor, and the first coupling reaction was performed at room temperature for 2.5 hours, filtered, and the obtained Wash the solid component with DMF 5 times, add 100mL acetic anhydride / NMM / DMF (the concentration of acetic anhydride is 20%, and the concentration of NMM is 12%) to cap the resin for 3 hours, wash with DMF twice, methanol twice, dichloromethane twice After washing with methanol for 2 times, it was sucked dry to obtain Fmoc-Gly-resin (19.95g, 9.78mmol, degree of substitution: 0.49mmol / g, yield: 99.70%).

[0086] (2) Add 10.21 g of the Fmoc-G...

Embodiment 2

[0107] (1) Add 34.5g Wang resin with a substitution degree of 0.58mmol / g to the synthesis reactor, add 300mL DMF to swell the resin for 60min; dissolve 5.96g Fmoc-Gly-OH, 2.72g HOBT and 1.22g Dmap with 80mL DMF , placed in an ice-water bath and mixed for 20 minutes, added 3.08mL DIC and stirred at room temperature for 5 minutes to obtain a mixed solution; the obtained mixed solution was added to the above synthesis reactor, the first coupling reaction was performed at room temperature for 2.5 hours, filtered, and the obtained The solid component was washed 5 times with DMF, 500 mL of acetic anhydride / NMM / DMF (wherein the concentration of acetic anhydride was 20%, and the concentration of NMM was 11%) was added to cap the resin for 3 hours, washed twice with DMF, washed twice with methanol, dichloromethane After washing twice and twice with methanol, it was sucked dry to obtain Fmoc-Gly-resin (36.42g, 5.90mmol, degree of substitution: 0.16mmol / g, yield: 91.03%).

[0108] (2) Ad...

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Abstract

The invention provides a preparation method of somaglutide, and relates to the technical field of polypeptide synthesis. Firstly, 37 amino acid Fmoc-Gly-OH is coupled on initial resin, then an Fmoc protecting group is removed, then 36 to 26 amino acids in a somaglutide sequence are sequentially coupled, and side chains Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu-OtBu and octadecanedioic acidmono-tert-butyl ester are sequentially coupled on obtained first peptide resin; and an Lys main chain protecting group in an obtained second peptide resin is removed, the 25 to 7 amino acids in the somaglutide sequence are sequentially coupled, and an obtained third peptide resin is cracked to obtain the somaglutide. According to the preparation method, the side chain of the somaglutide isfirstly coupled, and then the main chain of the somaglutide is coupled, so that racemization impurities can be effectively prevented from being generated, the synthesis difficulty of the side chain is reduced, the yield is high, and the cost is low; and the preparation method is simple 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. Background technique [0002] Semaglutide (Semaglutide CAS: 910463-68-2) is a long-acting GLP-1 analog developed by Novo Nordisk for subcutaneous injection once a week. The structure of Semaglutide is GLP-1(7-37) chain The 8-position Aib replaced Ala, the 34-position Arg replaced Lys, and the 26-position Lys was connected with octadecanedioic acid fatty chain, glutamic acid and 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-term effect. Its structure is as follows: [0003] [0004] At present, there are two main methods for the synthesis of semaglutide: one is to gradually couple the main chain, then remove the Lys side chain protecting group, and then...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/04C07K1/06C07K1/10
CPCC07K14/605Y02P20/55
Inventor 邱鹤罗瑞昌纪东亮
Owner 浙江肽昇生物医药有限公司
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