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Method for synthesizing Etelcalcetide

A d-cys and fragment technology, applied in the field of synthesis of Etelcalcetide, can solve the problems of low total yield, high production cost, cumbersome reaction steps, etc., and achieve the improvement of total yield, high purity and yield, crude peptide yield and The effect of high purity

Active Publication Date: 2017-07-07
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reaction steps of this method are relatively cumbersome, and multi-step purification preparation is required, the production cost is correspondingly high, and the final total yield is low

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0043] Example 1: N-Ac-D-Cys(Mmt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf) -Synthesis of Rink-Amide Resin

[0044] Weigh 25.00 g of Rink-Amide resin with a substitution degree of 0.20 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, add 20% piperidine / DMF (V / V) Remove Fmoc from the solution for 5+10 minutes, wash the resin 6 times with DMF after removal, and detect the color of the resin with ninhydrin. Weigh 16.30g (25mmol) Fmoc-D-Arg(Pbf)-OH, 4.05g (30mmol) HOBt, 9.51g (25mmol) HBTU, dissolve with 75ml DMF and 75ml DCM, add 6.5ml (37.5mmol) under ice water bath DIPEA was activated for 5 minutes, and the mixture was added to the reaction column, and reacted at room temperature for 2 hours, and the end of the reaction was detected with ninhydrin (if the resin is colorless and transparent, stop the reaction; if the resin develops color, prolong the reaction for 1 hour, the same below).

[0045] Af...

Embodiment 2

[0047] Example 2: N-Ac-D-Cys(Mmt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf) -Synthesis of Rink-Amide Resin

[0048] Weigh 11.10 grams of Rink-Amide resin with a substitution degree of 0.45 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, add 20% piperidine / DMF (V / V) Remove Fmoc from the solution for 5+10 minutes, wash the resin 6 times with DMF after removal, and detect the color of the resin with ninhydrin. Weigh 16.30g (25mmol) Fmoc-D-Arg(Pbf)-OH, 4.05g (30mmol) HOBt, 9.51g (25mmol) HBTU, dissolve with 75ml DMF and 75ml DCM, add 6.5ml (37.5mmol) under ice water bath DIPEA was activated for 5 minutes, the mixture was added to the reaction column, and reacted at room temperature for 2 hours, and the end of the reaction was detected by ninhydrin.

[0049] After the reaction is finished, wash the resin 3 times with DMF, add 20% piperidine / DMF (V / V) solution for 5+10 minutes to remove Fmoc, wash the ...

Embodiment 3

[0051] Example 3: N-Ac-D-Cys(Mmt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf) -Synthesis of Rink-Amide Resin

[0052] Weigh 8.33 grams of Rink-Amide resin with a substitution degree of 0.60 mmol / g, add it to the solid phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, add 20% piperidine / DMF (V / V) Remove Fmoc from the solution for 5+10 minutes, wash the resin 6 times with DMF after removal, and detect the color of the resin with ninhydrin. Weigh 16.30g (25mmol) Fmoc-D-Arg(Pbf)-OH, 4.05g (30mmol) HOBt, 9.51g (25mmol) HBTU, dissolve with 75ml DMF and 75ml DCM, add 6.5ml (37.5mmol) under ice water bath DIPEA was activated for 5 minutes, the mixture was added to the reaction column, and reacted at room temperature for 2 hours, and the end of the reaction was detected by ninhydrin.

[0053] After the reaction is finished, wash the resin 3 times with DMF, add 20% piperidine / DMF (V / V) solution for 5+10 minutes to remove Fmoc, wash the...

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Abstract

The invention relates to the field of medicine synthesis, and discloses a method for synthesizing Etelcalcetide. The method disclosed by the invention comprises the following steps: by adopting a strategy of solid-phase synthesis, firstly, synthesizing Etelcalcetide main chain peptide resin, secondly, removing a side chain protecting group of Cys in a peptide chain, further activating sulfydryl on a Cys side chain of the peptide resin by using 2,2'-dithio bipyridine, constructing a disulfide bond with L-Cys, and performing splitting decomposition, thereby obtaining crude peptide of Etelcalcetide. Multiple steps of purification are avoided in the whole process, the obtained crude peptide is relatively high in yield and purity, and the total yield of purified fine peptide is greatly increased.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a method for synthesizing Etelcalcetide. Background technique [0002] 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. [0003] Etelcalcetide is a novel calcimimetic agent developed by Kai Pharmaceuticals, Inc., which can inhibit the secretion of parathyroid hormone (PTH). Seconda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/08C07K1/06C07K1/04
CPCC07K7/06Y02P20/55C07K7/02C07K1/061A61K38/08C07K1/04C07K1/003C07K1/006
Inventor 陈永汉宓鹏程陶安进袁建成
Owner HYBIO PHARMA