Unlock instant, AI-driven research and patent intelligence for your innovation.

Method for preparing etelcalcetide through solid-liquid phase combination

A technology of veracatide and solid-liquid phase, which is applied in the field of solid-liquid phase preparation of veracatide, can solve the problems of unfavorable large-scale industrial production, expensive amino acid materials, high synthesis cost, etc., and achieve the goal of being suitable for large-scale production, The effect of less synthetic impurities and low synthesis cost

Pending Publication Date: 2021-03-19
深圳市健翔生物制药有限公司
View PDF7 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, when the main chain Cys and Arg side chain protecting groups are cracked at the same time, more impurities are produced and the yield is low
[0008] Based on the above literature, the existing preparation method of veracatide has many impurities, the price of amino acid materials is expensive, and the synthesis cost is high, which is not conducive to large-scale industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for preparing etelcalcetide through solid-liquid phase combination
  • Method for preparing etelcalcetide through solid-liquid phase combination
  • Method for preparing etelcalcetide through solid-liquid phase combination

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The synthesis of embodiment 1 Fmoc-D-Arg (Pbf)-Rink Amide resin

[0029] Weigh the Rink Amide resin (5.95g, 5mmol) with a substitution degree of 0.84mmol / g, add it to the polypeptide solid-phase reactor, wash it with DMF (30ml) three times, drain it, and add DMF (60ml) to swell for 30min. After filtering, add 20% piperidine / DMF solution to remove the Fmoc protecting group, detect the reaction with ninhydrin, the resin turns blue, the deprotection is complete, drain the solvent, add DMF to wash the resin 6 times.

[0030] Fmoc-D-Arg(Pbf)-OH (8.12g, 12.5mmol) and HOBt (2.54g, 18.75mmol) were weighed and dissolved in 40ml of DMF, DIC (2.86g, 22.50mmol) was added for activation for 5min, and the activated The amino acid solution was added to the above solid-phase reactor, and stirred at room temperature for 2 hours. The reaction was detected with ninhydrin, the resin was colorless, the condensation reaction was complete, the solvent was drained, and DMF was added to wash t...

Embodiment 2

[0031] The synthesis of embodiment 2 Fmoc-D-Arg (Pbf)-Sieber resin

[0032] Sieber resin (7.04 g, 5 mmol) with a substitution degree of 0.71 mmol / g was weighed and added to a polypeptide solid-phase reactor, washed three times with DMF (35 ml), drained, and swelled by adding DMF (75 ml) for 30 min. After filtering, add 20% piperidine / DMF solution to remove the Fmoc protecting group, detect the reaction with ninhydrin, the resin turns blue, the deprotection is complete, drain the solvent, add DMF to wash the resin 6 times.

[0033] Fmoc-D-Arg(Pbf)-OH (8.12g, 12.5mmol) and HOBt (2.54g, 18.75mmol) were weighed and dissolved in 45ml of DMF, DIC (2.86g, 22.50mmol) was added to activate for 5min, and then the activated The amino acid solution was added to the above solid-phase reactor, and stirred at room temperature for 2 hours. The reaction was detected with ninhydrin, the resin was colorless, the condensation reaction was complete, the solvent was drained, and DMF was added to w...

Embodiment 3

[0034] Example 3 Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-Rink Amide Synthesis of resin

[0035] Get the Fmoc-D-Arg(Pbf)-Rink Amide resin obtained in Example 1, according to the coupling method in Example 1, sequentially couple Fmoc-D-Ala-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)-OH.

[0036]After the coupling is completed, the Fmoc protecting group is removed. Weigh acetic anhydride (1.55g, 10mmol), add 40ml of DMF and DIEA (1.96g, 10mmol), add the mixed solution to the resin for reaction, detect ninhydrin, the resin is colorless, wash the resin 6 times with DMF. Then wash 3 times with DCM, 40ml / time, after washing, take out the peptide resin and dry it to obtain 15.54g peptide resin.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for preparing etelcalcetide through solid-liquid phase combination. A solid-liquid phase combination mode is adopted, cheap side chain protective amino acid and acid-sensitive solid phase carrier resin are selected to synthesize main chain peptide resin, a protective group of a Cys side chain and resin are selectively removed, the main chain Cys sulfydryl is activated, direct reacting with cheap L-Cys-OH is achieved, and finally, pyrolysis is conducted to remove an Arg protective group to obtain the etelcalcetide. Synthesis impurities are few, the yield is high, purification is easy, raw materials are cheap and easily available, the synthesis cost is low, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing veracatide through solid-liquid phase combination. [0002] technical background [0003] Secondary hyperparathyroidism (SHPT, referred to as secondary hyperparathyroidism), refers to chronic renal insufficiency, intestinal malabsorption syndrome, Fanconi syndrome and renal tubular acidosis, vitamin D deficiency or resistance, and pregnancy , breast-feeding, etc., the parathyroid glands are stimulated by hypocalcemia, hypomagnesemia or hyperphosphatemia for a long time to secrete excessive parathyroid hormone (PTH) to increase blood calcium, blood magnesium and reduce blood phosphorus. Chronic compensatory clinical presentation, long-standing parathyroid hyperplasia eventually leads to the formation of functionally autonomous adenomas. [0004] Veracatide, English name Etelcalcetide, is a calcium-sensing receptor agonist developed by Kai Pharmaceuticals...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/04C07K1/06C07K1/02
CPCC07K7/06Y02P20/55
Inventor 胡鹏刘自成付玉清李文静龙娓芳
Owner 深圳市健翔生物制药有限公司