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A kind of semi-synthetic preparation method of semaglutide

A semaglutide and compound technology, which is 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: 2022-07-01
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 it is easy to cause the problem of low product yield; in addition, there are reports The sequential coupling + fragment synthesis method of semaglutide, although the step of connecting the side chain of the fatty chain is simplified, but before the side chain of the fatty chain is connected, the 26-position Lys side chain of the semaglutide needs a special protecting agent group (Mmt , Alloc) for protection, and a special deprotection reagent (Pd(PPh 3 ) 4 ) or repeated deprotection treatment, resulting in greatly reduced yield and increased production cost

Method used

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  • A kind of semi-synthetic preparation method of semaglutide
  • A kind of semi-synthetic preparation method of semaglutide
  • A kind of semi-synthetic preparation method of semaglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 Preparation of the crude product of compound I

[0075] Weigh out Boc-His(Trt)-Aib-Glu(Otbu)-Gly-OH (commercially purchased: purchased from Jill Biochemical (Shanghai), 1 g, 1.213 mmol), salicylaldehyde dimethyl acetal (407.8 mg, , 2.426mmol), PyBOP (946.8mg, 1.8195mmol), dissolve with 50mL DMF, add 600uLDIEA (3.639mmol) under the condition of ice-water bath, 0 ℃ of magnetic stirring for 20 hours. Complete conversion of the reaction was checked by liquid phase. After the reaction, the reaction solution was concentrated under reduced pressure, redissolved by adding DCM, washed with saturated brine three times, the collected DCM solution was put into a certain amount of anhydrous sodium sulfate for drying, left standing for 0.5 hours, suction filtered, and the filtrate was collected. It was drained to obtain 1.89 g of compound 0 crude product, which was used.

[0076]

[0077] Take all the samples of above compound 0, add 50mL cleavage reagent (TFA / H 2 0 / T...

Embodiment 2

[0079] Example 2 Purification of the crude product of compound I

[0080] Weigh 500 mg of the crude product of 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, the column temperature is 37°C, the mobile phase is water (phase A) containing 0.1% TFA and acetonitrile (phase B) containing 0.1% TFA, the flow rate is 8ml / min, gradient: B%: 20%-60%, After 30 min, the target fraction was collected, and the collected solution was concentrated under reduced pressure.

[0081] MAIDI-TOFMS was used for detection, and 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 concentrated solution was lyophilized to obtain 195 mg of compound I in the form of a white solid powder ...

Embodiment 3

[0083] Example 3 Synthesis of Compound II

[0084] Weigh compound I (50mg, 0.094mmol), Arg34GLP-1 (11-37) (150mg, 0.05mmol) respectively, dissolve with 100ul pyridine acetate buffer solution (acetic acid:pyridine, mol:mol, 120:1), 35 The reaction was magnetically stirred for 20 hours. The solvent was removed by blow-drying, 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 blow-drying, and lyophilized to obtain 230 mg of the reaction mixture. Analytical liquid phase analysis was carried out on the reaction mixture (using liquid phase conditions: using Agilent 1260 system for liquid phase analysis, wavelength 214nm, the chromatographic column was a reversed-phase C18 column of 4.6×250mm, the column temperature was 35°C, and the mobile phase was 0.1% of water (phase A) and 0.1% acetonitrile (phase B), the flow rate is 1 mL / min, gradient: B%: 30%-45%...

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Abstract

The invention relates to a technology for polypeptide synthesis, belonging to the technical field of medicinal chemistry. The invention provides a preparation method of semaglutide, which is based on the natural chemical linking method (STL) of serine and threonine, so that semaglutide has high purity, high yield, few reaction steps, simple operation, and has It is beneficial to realize the large-scale preparation of semaglutide.

Description

technical field [0001] The invention relates to a technology for polypeptide synthesis, belonging to the technical field of medicinal chemistry. Background technique [0002] Compared with other marketed hypoglycemic drugs, semaglutide shows better clinical therapeutic effect 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. The economical synthesis process of semaglutide is particularly important. [0003] At present, the reported synthesis method of semaglutide mainly adopts the method of solid-phase synthesis (SPPS). All the reactions are carried out in the middle, which is convenient for automatic operation, and high yield products can be obtained by adding excess reactants, and the products can be easily separated at the same time. However, the use of protected amino acids combined with the continuous use of excess reactants and, additionally, the need...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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