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Synthesis method and purification method of semaglutide protected amino acid

A technology of semaglutide and a synthesis method, which is applied in the field of biomedicine, can solve the problems of poor protection effect of tert-butanol, difficult separation and purification of products, and difficulty in complete reaction, and achieves low cost, short operation time, and reaction speed. quick effect

Pending Publication Date: 2022-01-07
山东盛安贝新材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the protection effect of tert-butanol used in the reaction is not good, the reaction time is long, and it is difficult to complete the reaction, and the product is extremely difficult to separate and purify

Method used

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  • Synthesis method and purification method of semaglutide protected amino acid
  • Synthesis method and purification method of semaglutide protected amino acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] A synthetic method for semaglutide protected amino acids, comprising the steps of:

[0022] Step 1, the amino acid is under the condition of dioxane solvent, stirring and adding sulfuric acid solution and isobutylene, and completely reacting to obtain intermediate I;

[0023] Step 2. Cool the reaction solution in the previous step to below 0°C in an ice bath, add sodium hydroxide solution, adjust the pH to 9-10, and react completely after stirring to obtain intermediate II.

[0024] Step 3. Keep the reaction solution in the previous step under ice bath conditions, add the dioxane solution of Fmoc-osu, the reaction is complete, acidify the pH to 3-4 with dilute hydrochloric acid, extract the aqueous phase with an organic solvent, and dry the extracted organic phase. Spin dry to get the product.

[0025] In step one, the amino acid is aspartic acid or glutamic acid. Sulfuric acid is one of strong acids, in the present invention, adopt sulfuric acid as strong acid, mainl...

Embodiment 2

[0030] The purification method of the semaglutide protected amino acid of embodiment 1, comprises the steps:

[0031] Step 1, adding the semaglutide-protected amino acid obtained by the above preparation method into concentrated hydrochloric acid, stirring and dissolving at 70-100 degrees Celsius to obtain a hydrochloride solution; cooling and crystallizing at 15-25 degrees Celsius;

[0032] Step 2, add methanol or acetonitrile solvent, stir at 70-100 degrees Celsius, wash, and filter to obtain a high-purity hydrochloride solution,

[0033] Step 3, add methanol or acetonitrile solvent to dissolve, then add propylene oxide to remove hydrochloric acid, filter, and wash with ethyl acetate, petroleum ether or dichloromethane to obtain high-purity semaglutide-protected amino acids.

Embodiment 3

[0035] Determine its optimum synthesis condition by contrast experiment: in the synthesis of Fmoc-Asp(Otbu)-OH, investigate the influences such as different reaction temperature, molar ratio, reaction time etc. to reaction, improve product yield and purity, make process The conditions have reached the advanced level at home and abroad.

[0036] 1.1 Synthetic route

[0037]

[0038] 1.2 Specifications of main raw materials

[0039] raw material name content(%) Specification 1 Aspartic acid 98 industrial grade 2 Isobutylene 98 industrial grade 3 sodium hydroxide 99 industrial grade 4 sulfuric acid 99 industrial grade 5 Dioxane 98 industrial grade 6 Anhydrous Sodium Sulfate 96 industrial grade 7 ethyl acetate 98 industrial grade 8 Fmoc-osu 98 industrial grade

[0040] 1.3 Operation steps

[0041] (1)H 2 Synthesis of N-Asp(otbu)-Otbu

[0042] In a 500ML three-neck flask, add 26.6g of ...

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Abstract

The invention belongs to the technical field of biological medicines, and discloses a synthesis method of semaglutide protected amino acid, which comprises: 1, adding a sulfuric acid solution and isobutene into amino acid under a dioxane solvent condition while stirring, and completely conducting reacting to obtain an intermediate I; 2, cooling the reaction solution to 0 DEG C or below under an ice bath condition, adding a sodium hydroxide solution, adjusting the pH value to 9-10, conducting stirring, and completely conducting reacting to obtain an intermediate II; and 3, keeping the ice bath condition of the reaction solution in the previous step, adding a dioxane solution of Fmoc-osu, conducting reacting completely, conducting acidifying to enable the pH to 3-4 by using diluted hydrochloric acid, extracting a water phase by using an ethyl acetate solution, and drying and spin-drying the extracted organic phase to obtain the product. The invention also discloses a purification method of the semaglutide protected amino acid.

Description

technical field [0001] The invention relates to a method for synthesizing and purifying amino acids protected by semaglutide, belonging to the technical field of biomedicine. Background technique [0002] Semaglutide is the world's first and only oral glucagon-like peptide-1 (GLP-1) receptor agonist drug used as an adjunct to diet control and exercise to improve blood sugar in adults with type 2 diabetes control. In the case of the high incidence of diabetes in the world and the long-term dependence of patients on diabetes drugs, oral drugs are more acceptable to patients than injections in the route of administration, because they are convenient to take, and can also avoid the burden of injections. sore skin. Therefore, semaglutide not only has market value, but also has social significance. [0003] Fmoc-Asp(Otbu)-OH and Fmoc-Glu(Otbu)-OH are the basic protected amino acids for the production of semaglutide, and their synthetic methods usually use tert-butanol under the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C269/08C07C271/22C07C227/18C07C229/24
CPCC07C269/04C07C269/08C07C227/18C07C2603/18C07C229/24C07C271/22
Inventor 赵嘉姜珍华徐涛
Owner 山东盛安贝新材料有限公司
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