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Method for synthesizing Etelcalcetide

A synthesis method and compound technology, applied in the field of peptide synthesis, can solve problems such as coupling difficulties and reduce production costs

Active Publication Date: 2021-01-05
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It overcomes the defect of difficult coupling between fragments under the action of traditional coupling reagents, reduces production costs, and is suitable for large-scale production

Method used

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  • Method for synthesizing Etelcalcetide
  • Method for synthesizing Etelcalcetide
  • Method for synthesizing Etelcalcetide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1: Synthesis of Compound 1 (β-S(Trt)-D-Arg(Boc) 3 -SPh)

[0097] β-S(Trt)-D-Arg(Boc) 3 -OH (30.0g, 40mmol), PhSH (5.3g, 48mmol), EDC (13.8g, 72mmol) and HOBt (9.43g, 72mmol) were added into 300mL dichloromethane and stirred to dissolve, and cooled in an ice bath to below 5°C. Continue to add DIPEA (37.7 mL, 216 mmol) dropwise, controlling the temperature not to exceed 10°C. After the dropwise addition, stirring was continued at room temperature for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, add purified water (300mL) to the reaction solution, stir for 15 minutes, leave to separate the liquids, and collect the lower organic phase. The organic phase was concentrated under reduced pressure at 30°C, the residue was stirred and dissolved with ethyl acetate (300 mL), washed successively with purified water (300 mL), saturated sodium bicarbonate solution (300 mL), and saturated sodium chloride solution (300 mL), The organic pha...

Embodiment 2

[0098] Embodiment 2: the synthesis of compound 2 (Ac-D-Cys(Acm)-D-Ala-OH)

[0099] Dissolve Ac-D-Cys(Acm)-OH (3.5g, 15mmol), HONb (3.0g, 16.5mmol) in 35mL DCM and stir to dissolve, cool in an ice bath to below 5°C, slowly add DIC (2.8mL, 18 mmol), stirring was continued at room temperature for 3 hours, and the reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in 35 mL of acetonitrile, 17.5 mL of purified water was added, and H-Ala-OH (1.6 g, 18 mmol) was added to continue stirring. DIPEA (4.0 mL, 22.5 mmol) was added dropwise. ). Stir at room temperature for 2 hours and monitor the reaction with TCL. After the reaction, filter and concentrate. Add 35 mL of ethyl acetate to the residue and stir to dissolve, then add saturated citric acid solution to adjust the pH to 3-4, and let the mixture stand to separate layers. The organic phase was washed with saturated ...

Embodiment 3

[0100] Example 3: Synthesis of Compound 3 (Ac-D-Cys(Acm)-D-Ala-SPh)

[0101] Ac-D-Cys(Acm)-D-Ala-OH (4.35g, 14.2mmol), H-D-Arg(Pbf)-NH HCI (1.87g, 18mmol), EDC (4.2g, 21.3mmol) and HOBt (2.88g, 21.3mmol) were added to 50mL of dichloromethane and stirred to dissolve, cooled in an ice bath to below 5°C, and continued to add DIPEA (10.9mL, 63.9mmol) dropwise, controlling the temperature not to exceed 10°C. After the dropwise addition, stirring was continued at room temperature for 5 hours, and the reaction was monitored by TLC. After the reaction was complete, purified water (50 mL) was added to the reaction liquid, stirred for 15 minutes, left to separate the liquids, and the lower organic phase was collected. The organic phase was concentrated under reduced pressure at 40°C, the residue was stirred and dissolved with ethyl acetate (50 mL), washed successively with purified water (50 mL), saturated sodium bicarbonate solution (50 mL), and saturated sodium chloride solution (50 ...

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Abstract

The invention relates to the field of polypeptide synthesis and particularly relates to a method for synthesizing Etelcalcetide. According to the method, beta-S(Trt)-D-Arg(Boc)3-OH serves as a raw material, alanine of a peptide sequence is replaced with cysteine, and a coupling reaction is performed by employing an NCL (natural chemical linking) method. According to the method, improvement is carried out in view of shortage of the existing liquid-phase methods, and coupling is completed by employing an S-to-N intramolecular transport reaction according to unique characteristics of the peptidesequence, so that the efficiency of coupling among peptide fragments is increased, and the total yield of the method disclosed by the invention is 71.3%. Therefore, the defect that the coupling amongthe fragments is difficult in the presence of the traditional coupling reagent is overcome, the production cost is reduced, and the method is applicable to large-scale production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a synthesis method of Etelcalcetide. Background technique [0002] Etelcalcetide is a novel calcimimetic agent developed by AMGEN INC. It is mainly used as a polypeptide drug for secondary hyperparathyroidism in adult patients with chronic kidney disease undergoing hemodialysis. It was launched in the United States on February 07, 2017, under the product name Parsabiv. The main chain of Etelcalcetide consists of seven D-amino acids, and the side chain is connected to L-cysteine ​​through a disulfide bond. Its peptide sequence is shown in formula I: [0003] [0004] Etelcalcetide adopts solid-phase coupling and needs to use resin, and large-scale production is limited. And amino acid usually needs excess (3-5 equivalent) during coupling, and Etelcalcetide is based on expensive D-type amino acid again, therefore, adopts solid-phase synthesis method, and cost is too high,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/02
CPCC07K7/06C07K1/02C07K1/20C07K1/06
Inventor 陶志强姚志军宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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