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Method for preparing semaglutide side chain by liquid phase method

A side chain and aliphatic chain technology, applied in the field of liquid phase synthesis of side chains, can solve problems such as reducing renal clearance rate, and achieve the effect of low cost and wide selection.

Inactive Publication Date: 2020-06-12
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The presence of this side chain allows semaglutide to bind more tightly to the protein, thereby reducing the renal clearance rate

Method used

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  • Method for preparing semaglutide side chain by liquid phase method
  • Method for preparing semaglutide side chain by liquid phase method
  • Method for preparing semaglutide side chain by liquid phase method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0078] One Pot Preparation

[0079] Dissolve 150mL of ethanol solution with 2-(2-aminoethoxy)ethanol 2 as the starting material (100mmol, 10.5g), add di-tert-butyl dicarbonate (100mmol, 23mL) dropwise under ice bath conditions, and remove the ice bath, react at room temperature for 2 hours, remove the ethanol solvent by distillation under reduced pressure; THF redissolved, add NaH (1.2-1.5eq) at 0~-10°C, keep stirring at this temperature for half an hour, and distill ethyl bromoacetate 3 (1.2-1.5eq ) slowly drop into the reaction solution, remove the ice bath after the dropwise addition, and stir overnight at room temperature. Add MeOH to the reaction system so that MeOH:THF=1:1, the reaction solution is yellow and clear, weigh solid NaOH (1-2.2eq) into the reaction solution, heat to reflux, and react for 2h. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was redissolved in water, extracted twice with ethyl acetate, the a...

Embodiment 1-2

[0081] preparation.

[0082] (1) Dissolve 150mL of ethanol solution with 2-(2-aminoethoxy)ethanol 2 as the starting material (100mmol, 10.5g), and add di-tert-butyl dicarbonate (100mmol, 23mL) dropwise under ice bath conditions , removed the ice bath, reacted at room temperature for 2h, distilled off the ethanol solvent under reduced pressure; THF redissolved, added NaH (1.2-1.5eq) at 0~-10°C, kept stirring at this temperature for half an hour, and distilled benzyl bromoacetate 3'( 1.2-1.5eq) slowly drop into the reaction solution, remove the ice bath after the dropwise addition, transfer to a 50°C oil bath and stir overnight. TLC monitoring reaction (CH 2 Cl 2 :EA=10:1). After the reaction was complete, the solvent was distilled off under reduced pressure, and the residue was redissolved in ethyl acetate, followed by extraction with 10% citric acid (75mL×2), saturated sodium bicarbonate solution (75mL×2), and washing with saturated brine (100mL). , the organic layer was...

Embodiment 1-3

[0085] preparation.

[0086] Weigh the above intermediate 4 (10mmol, 2.63g) and dissolve it in 25mL of dichloromethane, add N,N-diisopropylethylamine (3eq), EDCI (1.2eq), HOBT (1.2eq) in sequence, and stir After 30 min compound 6 (1.2 eq) was added and stirred overnight. After the reaction was complete, the solvent was distilled off under reduced pressure, and the residue was redissolved with ethyl acetate, extracted with 1M hydrochloric acid solution (50mL×2), saturated sodium bicarbonate solution (50mL×2), washed with saturated brine (75mL), The organic layer was collected and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 7 as a yellow oil. Yield 79%.

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Abstract

The invention discloses a method for preparing a semaglutide side chain. The preparation method comprises the following steps: protecting amino of an initial raw material 2-(2-aminoethoxy) ethanol byusing R1; then carrying out nucleophilic substitution reaction with alpha halogenated ester to prolong a carbon chain; preparing an aliphatic chain with two protected ends by a one-pot method; removing a protecting group at one end of each aliphatic chain and condensing to obtain a compound 7; removing the R1 protecting group to obtain a compound 8, performing condensation reaction on the compound8 and fluorenylmethoxycarbonyl-L-glutamic acid 1-tert-butyl ester to obtain a compound 10, removing the fluorenylmethoxycarbonyl, performing amidation condensation reaction on the compound 10 and 18-(tert-butoxy)-18-oxooctadecanoic acid to obtain a compound 13, and removing the R2 protecting group to obtain a target product chain 1. Compared with solid-phase synthesis, the method disclosed by theinvention is lower in cost and wider in selection of protecting groups, and has industrial production and application prospects.

Description

technical field [0001] The invention belongs to the field of polypeptide synthesis, and in particular relates to a liquid-phase synthesis method of a side chain of a polypeptide drug semaglutide for treating type 2 diabetes. Background technique [0002] Semaglutide is a new generation of glucagon-like peptide-1 (GLP-1) analogue developed by Novo Nordisk, Denmark, with the molecular formula C1 87 h 291 N 45 o 59 , the molecular weight is 4113.58, and the CAS number is 910463-68-2. GLP-1 is a hormone that induces insulin secretion and has beneficial effects on various vital organs including pancreas, heart and liver. The advantage of semaglutide drugs is that they can control blood sugar, while significantly reducing the probability of hypoglycemic events, and can also significantly reduce weight and reduce the risk of cardiovascular events. [0003] Semaglutide was approved by the US FDA in 2017 (0.5mg or 1mg injection), and is clinically used for the treatment of type ...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C231/14
CPCC07C231/12C07C231/14C07C269/06C07C269/04C07C2603/18C07C237/22C07C271/22C07C235/08C07C271/16Y02P20/55
Inventor 张逢质杨彬
Owner ZHEJIANG UNIV OF TECH
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