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Preparation method of semaglutide dipeptide side chain

A side chain and dimethylformamide technology, which is applied in the field of preparation of semaglutide dipeptide side chains, can solve the problems of difficult product separation, long synthesis period, many synthesis steps, etc., and achieves simplified operation steps and reaction rate. Fast, high-yield effects

Pending Publication Date: 2021-11-19
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problems of many synthetic steps in the semaglutide process in the prior art, long synthesis period, and difficult product separation, the present invention provides a method for preparing the basic dipeptide side chain of semaglutide, which has a short reaction route , easy to operate, more mild reaction, economical and environmental protection and high yield, suitable for industrial production

Method used

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  • Preparation method of semaglutide dipeptide side chain
  • Preparation method of semaglutide dipeptide side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add N-protected-L-histidine (6.20g, 0.01mol) in the reaction flask, thionyl chloride (9.52g, 0.08mmol) and heat to reflux, add DMF (30mL), control temperature and reflux, reduce The unisolated intermediate III (according to 100% yield) was distilled under high pressure with solvent.

[0032] Add 2-aminoisobutyric acid (1.24g, 12.0mmol), triethylamine (1.21g, 12.0mmol), dichloromethane (20mL) into the reaction flask, lower to 0°C, add the above compound III (4.32g, 10.0 mmol) was incubated for reaction, and after TLC detected that the reaction was complete, water (20 mL) was added to the reaction system and stirred for 10 minutes, the organic phase was collected, and concentrated under reduced pressure until no liquid flowed out. Add dichloromethane / methyl tert-butyl ether (30mL, V 二氯甲烷 :V 甲基叔丁基醚 =1:1) mixed solution, stirred and crystallized at room temperature, and filtered to obtain a white solid, compound I, with a yield of 98.2% and a purity of 99.87% by HPLC.

Embodiment 2

[0034] N-protected-L-histidine (6.20g, 0.01mol) was added to the reaction flask, thionyl chloride (7.14g, 0.06mmol) was heated to reflux, N,N-dimethylacetamide (30mL) was added, Control the temperature and reflux. After the reaction is completed, the unisolated intermediate III (according to the yield of 100%) is distilled under reduced pressure.

[0035] Add 2-aminoisobutyric acid (1.24g, 12.0mmol), triethylamine (1.21g, 12.0mmol), dichloromethane (20mL) into the reaction flask, lower to 0°C, add the above compound III (4.32g, 10.0 mmol) was incubated for reaction, and after TLC detected that the reaction was complete, water (20 mL) was added to the reaction system and stirred for 10 minutes, the organic phase was collected, and concentrated under reduced pressure until no liquid flowed out. Add dichloromethane / methyl tert-butyl ether (30mL, V 二氯甲烷 :V 甲基叔丁基醚 =1:1) mixed solution, stirred and crystallized at room temperature, and filtered to obtain a white solid, compound I,...

Embodiment 3

[0037] N-protected-L-histidine (6.20g, 0.01mol) was added to the reaction flask, thionyl chloride (11.9g, 0.1mmol) was heated to reflux, N,N-dimethylformamide (30mL) was added, Control the temperature and reflux. After the reaction is completed, the unisolated intermediate III (according to 100% yield) is distilled under reduced pressure.

[0038] Add 2-aminoisobutyric acid (1.24g, 12.0mmol), triethylamine (1.21g, 12.0mmol), chloroform (20mL) into the reaction flask, lower to 0°C, add the above compound III (4.32g, 10.0 mmol) was incubated for reaction, and after TLC detected that the reaction was complete, water (20 mL) was added to the reaction system and stirred for 10 minutes, the organic phase was collected, and concentrated under reduced pressure until no liquid flowed out. Add dichloromethane / methyl tert-butyl ether (30mL, V 二氯甲烷 :V 甲基叔丁基醚 =1:1) mixed solution, stirred and crystallized at room temperature, and filtered to obtain a white solid, compound I, with a yield...

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a semaglutide dipeptide side chain. According to the preparation method, Fmoc-His(Trt)-OH and thionyl chloride are subjected to heating reflux, and a obtained product further reacts with 2-aminoisobutyric acid to obtain the important semaglutide side chain Fmoc-His-Aib-OH; the semaglutide dipeptide side chain synthesis method provided by the invention simplifies the operation steps,that is, in the first step, Trt can be removed, carboxylic acid can be made into acyl chloride, the target product can be obtained only through two-step reaction, the cost is low, and byproducts are few; and meanwhile, the next acylation reaction speed is high, the yield is high, large-scale production of semaglutide is facilitated, and the requirements of industrial production are met.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a semaglutide dipeptide side chain. Background technique [0002] Sermaglutide is a new long-acting glucagon-like peptide-1 (GLP-1) analog developed by Novo Nordisk, which not only has a significant hypoglycemic effect, but also has a significant weight loss effect , the drug is also the second GLP-1 hypoglycemic drug (the other is liraglutide) in Novo Nordisk's diabetes pipeline that has both hypoglycemic and weight loss effects. Compared with liraglutide, semaglutide has a longer fatty chain and strong hydrophobicity, but semaglutide is modified by short-chain PEG, and its hydrophilicity is greatly enhanced. 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 the effect of long circulation. Sem...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/10C07K1/02C07K1/06
CPCC07K14/605Y02P20/55
Inventor 翟立海王全龙汪慧岩王少林
Owner LUNAN PHARMA GROUP CORPORATION
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