Semi-synthetic preparation method of semaglutide

A semaglutide and compound technology, applied in the field of peptide synthesis, can solve the problems of strong steric hindrance effect, increased production cost, low product yield, etc., and achieves the effects of rapid transformation, easy operation and high purity

Active Publication Date: 2020-05-15
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the similar polarity of these impurities to the target peptide, it may be difficult to achieve a good separation with the target peptide, resulting in the contamination of the product by the missing peptide
[0004] The currently reported method for synthesizing semaglutide requires stepwise coupling of 2-(2-(2-aminoethoxy)ethoxy)acetic acid, 2-(2-(2-amino Ethoxy) ethoxy) acetic acid, Glu and octadecanedioic acid, because the side chains are longer, cause the steric hindrance effect to be strong, the coupling reaction is difficult to carry out, and ...

Method used

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  • Semi-synthetic preparation method of semaglutide
  • Semi-synthetic preparation method of semaglutide
  • Semi-synthetic preparation method of semaglutide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] The preparation of embodiment 1 compound I crude product

[0075] Weigh respectively Boc-His(Trt)-Aib-Glu(Otbu)-Gly-OH (commercial purchase: purchased from Jill Biochemical (Shanghai), 1g, 1.213mmol), salicylaldehyde dimethyl acetal (407.8mg, , 2.426mmol), PyBOP (946.8mg, 1.8195mmol), dissolved in 50mL DMF, added 600uLDIEA (3.639mmol) in ice-water bath, stirred magnetically at 0°C for 20 hours. The reaction was checked for complete conversion by liquid phase. After the reaction, concentrate the reaction solution under reduced pressure, add DCM to redissolve, wash with saturated brine three times, put the collected DCM solution into a certain amount of anhydrous sodium sulfate for drying, let it stand for 0.5 hours, suction filter, and collect the filtrate After pumping to dryness, 1.89 g of crude compound 0 was obtained, which was set aside.

[0076]

[0077] Take all the samples of the above compound 0, add 50mL cutting reagent (TFA / H 2 0 / TIPS, 95:2.5:2.5, v / v / v)...

Embodiment 2

[0079] Embodiment 2 Purification of compound I crude product

[0080] Weigh 500 mg of the crude compound I prepared in Example 1, add 15 mL of distilled water to dissolve, use Water1525 system for semi-preparative purification, the wavelength is 214 nm, and the chromatographic column is 20 × 250 mm reverse phase C 18 Column, column temperature is 37 ℃, mobile phase is the water (A phase) that contains 0.1% TFA and the acetonitrile (B phase) that contains 0.1% TFA, flow velocity is 8ml / min, gradient: B%: 20%-60%, After 30 min, the target components were collected, and the collected solution was concentrated under reduced pressure.

[0081] Using MAIDI-TOFMS for detection, the results are shown in figure 2 , MAIDI-TOFMS calculates C 24 h 30 N 6 o 8 Theoretical molecular weight [M+H] + m / z=531.220,[M+Na] + = 553.202, observed: 531.098, 553.081. The above concentrate was lyophilized to obtain 195 mg of compound I in the form of white solid powder with a yield of 80%. Ana...

Embodiment 3

[0083] The synthesis of embodiment 3 compound II

[0084] Weigh compound Ⅰ (50mg, 0.094mmol), Arg34GLP-1 (11-37) (150mg, 0.05mmol), and dissolve them in 100ul pyridine acetate buffer solution (acetic acid:pyridine, mol:mol, 120:1), 35 ℃ magnetic stirring reaction for 20 hours. The solvent was removed by drying, and then the residue was acidolyzed with 10 mL of acid hydrolysis solution (TFA / water, 75 / 25, v / v), and magnetically stirred at room temperature for 2 hours. The solvent was removed by drying, and lyophilized to obtain 230 mg of the reaction mixture. Analytical liquid phase analysis was carried out to the reaction mixture (using liquid phase conditions: adopt Agilent 1260 system to carry out liquid phase analysis, wavelength 214nm, chromatographic column is the reverse phase C18 column of 4.6 * 250mm, column temperature is 35 ℃, mobile phase is 0.1% Water (phase A) and 0.1% acetonitrile (phase B), the flow rate is 1mL / min, gradient: B%: 30%-45%, 0-20min.), the results...

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Abstract

The invention relates to a technology of polypeptide synthesis, and belongs to the technical field of pharmaceutical chemistry. A preparation method of semaglutide is provided. Based on a method (STL)of natural chemical connection of serine and threonine, the semaglutide can be high in purity, high in yield, less in reaction step and simple in operation, so that large-scale preparation of the semaglutide can be realized.

Description

technical field [0001] The invention relates to a technique for polypeptide synthesis and belongs to the technical field of medicinal chemistry. Background technique [0002] Compared with other hypoglycemic drugs on the market, semaglutide has shown better clinical therapeutic effects in controlling and maintaining blood sugar levels, and is expected to become a new generation of long-acting hypoglycemic drugs that dominate the diabetes drug market. Therefore, finding a high-efficiency, The synthetic technique of economical semaglutide is especially important. [0003] At present, the synthesis method of semaglutide mainly adopts the method of solid phase synthesis (SPPS). The advantage of solid phase synthesis is that the initial reactants and products are all connected to the solid phase carrier, so it can All the reactions are carried out in the medium, which is convenient for automatic operation, and high yield products can be obtained by adding excess reactants, and t...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/30C07K1/06
CPCC07K14/605
Inventor 吴志猛戴士杰周志昉
Owner JIANGNAN UNIV
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