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Liquid-phase synthesis method of semaglutide side chain

A liquid-phase synthesis and side-chain technology, which is applied in the field of liquid-phase synthesis of semaglutide side-chains, can solve the problem of not finding a pure liquid-phase synthesis method for the side-chain, and achieves easy control of the reaction process, simple production process, and easy process. workable effect

Active Publication Date: 2019-07-23
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] There are three patents on the synthesis of semaglutide side chains, namely: [WO 2009022013], [WO2009115469], [WO 2009083549], but all of them adopt the Fmoc strategy of solid-phase synthesis, and regard the side chains as four Reaction unit, within the scope of the inventor's understanding, there is no report on the pure liquid phase synthesis method of the side chain

Method used

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  • Liquid-phase synthesis method of semaglutide side chain
  • Liquid-phase synthesis method of semaglutide side chain
  • Liquid-phase synthesis method of semaglutide side chain

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Experimental program
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Effect test

Embodiment 1

[0058] according to figure 1 The synthetic route shown carries out the liquid phase synthesis of the side chain of semaglutide:

[0059] a. Preparation process of compound 3

[0060] Dissolve 1.05g of compound 2 (10mmol) in 50ml of DCM solution, place it in a nitrogen-protected flask, and carefully add (Boc) 2 O (2.62 g, 12 mmol). The mixture was stirred for 12 hours, then the crude material was concentrated in vacuo. Purification by flash column chromatography gave a colorless oil in 95% yield.

[0061] b. The preparation process of compound 4:

[0062] Add 3.08g (9.5mmol) of compound 3, 8.6g (4eq) of benzyl bromoacetate and 2.75g (2.1eq) of potassium carbonate into a round-bottomed flask. Relatively complete; washed with water, extracted 2-3 times with EA, washed with saturated brine, anhydrous Na 2 SO 4 After drying, P:E=6:1, the product was collected and the yield was 85%.

[0063] c. The preparation process of compound 5:

[0064] Dissolve 1.412g (4mmol) of compo...

Embodiment 2

[0081] a. Preparation process of compound 3

[0082]Dissolve 5mmol / ml compound 2 (1ml) in DCM solution, place it in a nitrogen-protected flask, and after the above mixture drops to 0°C, add 1eq of Et dropwise 3 N; After 20 minutes, slowly add 2mmol / ml Trt-Cl (2.5ml) mixture to the above mixture, and remove the ice bath after 10 minutes; stir at room temperature, observe on the plate after 1h, the reaction is complete . Wash with water, extract with DCM 2-3 times, wash with saturated brine, anhydrous Na 2 SO 4 After drying, P:E=5:1, the product was collected and the yield was 85%.

[0083] b. The preparation process of compound 4:

[0084] Add 694mg (2mmol) of compound 3, 1832mg (4eq) of benzyl bromoacetate and 580mg (2.1eq) of potassium carbonate into a round-bottomed flask, and raise the reaction temperature to 50°C. After reacting for 18 hours, spot the plate and observe that the reaction is relatively complete; wash with water , EA extracted 2-3 times, washed with satu...

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Abstract

The invention discloses a liquid-phase synthesis method of a semaglutide side chain. The liquid-phase synthesis method comprises the following steps: taking diglycolamine and an X radical to react, soas to protect an amino terminal of the diglycolamine through the X radical; then realizing hydroxyl protection through the amino terminal and a reaction carboxyl terminal of benzyl bromoacetate, so as to remove benzyl and the X radical; after coupling two products without the radical, removing the X radical; then coupling with an Fmoc-glutamic acid and removing Fmoc; finally coupling with 18-(tert-butoxy)-18oxooctadecanoic acid and then removing the benzyl to obtain the semaglutide side chain. The method disclosed by the invention has the advantages that a synthesis method process is feasible, controllable, low in cost and high in yield; the synthesis method is applicable to large-scale production; the semaglutide side chain is finally prepared and can be directly assembled to a semaglutide main chain in a liquid phase after being modified into OSu ester.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and in particular relates to a liquid-phase synthesis method of a semaglutide side chain. Background technique [0002] Diabetes mellitus is an endocrine and metabolic common and frequently-occurring disease characterized by the coexistence of hyperglycemia and other complications caused by absolute or relative insulin deficiency. China has the heaviest burden of diabetes, with more than 114 million people suffering from diabetes. Glucagon-like peptide-1 (GLP-1) is an important incretin. Compared with traditional diabetes drugs, it can solve the β-cell apoptosis that cannot be solved by conventional oral hypoglycemic drugs. this conundrum. Semaglutide is known as the best GLP-1 agonist in the world. It has 94% homology with human GLP-1. It has good performance in hypoglycemic, weight loss, cardiovascular system benefits and safety. a greater advantage. Semaglutide connects the 26th...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C235/08
CPCC07C269/06C07C231/12C07C271/16C07C235/08
Inventor 苏贤斌卞亚楠杨洋
Owner NANJING UNIV OF TECH
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