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Solid synthetic method of semaglutide

A solid-phase synthesis, Samolu technology, applied in the preparation methods of peptides, chemical instruments and methods, animal/human proteins, etc., can solve the problems of strong steric hindrance effect, low product yield, difficult coupling reaction, etc. Achieve the effect of short synthesis cycle, high product yield and low cost

Active Publication Date: 2014-06-11
HYBIO PHARMA
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  • Application Information

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Problems solved by technology

[0007] However, there is no relevant report on the solid-phase synthesis method of samoglutide, and samoglutide needs to be coupled with 2-(2-(2-aminoethoxy)ethoxy)acetic acid, 2- (2-(2-aminoethoxy) ethoxy) acetic acid, Glu and octadecanedioic acid, because the side chain is longer, cause the steric hindrance effect to be strong, the coupling reaction is difficult to carry out, easily causes low product yield The problem

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preparation example Construction

[0066] The invention provides a solid-phase synthesis method of samoglutide, comprising the following steps:

[0067] Step A: coupling Gly with resin to obtain Gly-resin;

[0068] Step B: Gly-resin undergoes the first stepwise coupling of amino acids or amino acid derivatives to obtain the first peptide resin whose sequence is shown in SEQ ID No.1;

[0069] Step C: removing the side chain protecting group of Lys in the first peptide resin whose sequence is shown in SEQ ID No.1, and coupling 2-(2-(2-aminoethoxy)ethoxy) through the second stepwise coupling ) acetic acid, 2-(2-(2-aminoethoxy) ethoxy) acetic acid, Glu and octadecanedioic acid to obtain a second peptide resin;

[0070] Step D: The second peptide resin is obtained by cleavage, purification and freeze-drying.

[0071] In some embodiments provided by the present invention, the resin in step A is 2-CTC resin, and the activator used for the coupling of 2-CTC resin and N-terminal Fmoc-protected Gly is selected from DIE...

Embodiment 1

[0084] Embodiment 1 degree of substitution is the synthesis of the Fmoc-Gly-CTC resin of 0.1mmol / g

[0085] Weigh 20 g of 2-CTC resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 3.27 g of Fmoc-Gly-OH and dissolve it in DMF. Add 4.78mL DIEA to activate under ice-water bath, add to the above-mentioned reaction column filled with resin, react for 2 hours, add 8mL of anhydrous methanol to block for 1 hour. Wash 3 times with DMF and 3 times with DCM, block with anhydrous methanol for 30 minutes, shrink and dry with methanol to obtain Fmoc-Gly-CTC resin, and the detected substitution degree is 0.104mmol / g.

Embodiment 2

[0086] Embodiment 2 degree of substitution is the synthesis of the Fmoc-Gly-CTC resin of 0.25mmol / g

[0087] Weigh 20 g of 2-CTC resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and use DMF to swell the resin for 30 minutes, then take 8.18 g of Fmoc-Gly-OH and dissolve it in DMF. Add 11.95mL DIEA to activate under ice-water bath, then add to the above-mentioned reaction column filled with resin, react for 2 hours, add 8mL of anhydrous methanol to block for 1 hour. Washed 3 times with DMF and 3 times with DCM, blocked with anhydrous methanol for 30 minutes, shrank and dried with methanol to obtain Fmoc-Gly-CTC resin, and the detected substitution degree was 0.255mmol / g.

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Abstract

The invention relates to the technical field of polypeptide synthesis, and particularly relates to a solid synthetic method of semaglutide. The solid synthetic method includes coupling Gly and a resin to obtain a Gly-resin; coupling step by step for the first time an ammonia acid or an amino acid derivative to obtain a first peptide resin the sequence of which is shown as SEQ ID No.1; removing a side chain protective group of Lys; coupling step by step for a second time 2-(2-(2-aminoethoxy)ethoxy) acetic acid, 2-(2-(2-aminoethoxy)ethoxy) acetic acid, Glu and octadecanedioic acid to obtain a second peptide resin; performing pyrolysis; and purifying. The solid synthetic method is simplified in operation step, short in synthetic period, low in cost, reduced in production of waste liquid, low in side products and high in product yield, and is suitable for large-scale production of the semaglutide.

Description

technical field [0001] The invention relates to the technical field of polypeptide synthesis, in particular to a solid-phase synthesis method of samoglutide. Background technique [0002] Diabetes (diabetes) is a sugar, protein, A series of metabolic disorder syndromes such as fat, water and electrolytes are clinically characterized by hyperglycemia. Typical cases may present with symptoms such as polyuria, polydipsia, polyphagia, and weight loss. If it is not good, it will cause complications, leading to failure and lesions in the kidneys, eyes, feet and other parts, and it cannot be cured. Diabetes is divided into gestational diabetes, specific diabetes, type 1 diabetes and type 2 diabetes. According to data from the International Diabetes Federation, there were about 246 million diabetics in the world in 2007, and it is expected to reach 380 million in 2025, or 7.1% of the adult population, of which type 2 diabetics account for about 90%. [0003] Type 2 diabetes, also...

Claims

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Application Information

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IPC IPC(8): C07K14/435C07K1/06C07K1/04
CPCY02P20/55C07K14/605
Inventor 宓鹏程潘俊锋马亚平袁建成
Owner HYBIO PHARMA
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