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Preparation method for pure solid-phase synthesis of salmon calcitonin

A salmon calcitonin and solid-phase synthesis technology, which is applied to the preparation method of peptides, calcitonin, chemical instruments and methods, etc., can solve the problems of long process synthesis cycle, increased production cost, increased raw material input, etc.

Active Publication Date: 2020-10-20
湖南甲骨文生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the existing synthetic methods, in order to improve the synthetic efficiency, some specifically protected amino acids or specific coupling fragments are used. The coupling time of each amino acid is about 2 hours or 4 hours, which must be added during the production process. The input of large raw materials and the long synthesis cycle of the process will eventually increase the production cost

Method used

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  • Preparation method for pure solid-phase synthesis of salmon calcitonin
  • Preparation method for pure solid-phase synthesis of salmon calcitonin
  • Preparation method for pure solid-phase synthesis of salmon calcitonin

Examples

Experimental program
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Embodiment 1

[0037] The abbreviated meanings of the reagents involved in the present invention are as follows:

[0038]

[0039] The corresponding protected amino acid comparison table and the manufacturer of the amino acid used in the present invention are as follows:

[0040]

[0041]

Embodiment 2

[0043] A preparation method for solid-phase synthesis of salmon calcitonin, comprising the steps of:

[0044] (1) preparation of calcitonin deprotected docosopeptide resin

[0045]Using amino resin as the starting material, Fmoc-protected amino acids as monomers, and HOBT / HATU as condensation reagents, the Fmoc protection groups are sequentially removed in the peptide synthesis column, and the corresponding amino acids are coupled one by one to obtain the deprotected three Dodecapeptide resin; wherein, in the amino acid coupling step, different coupling times are designed according to the difficulty of synthesis of each amino acid;

[0046] (2) Preparation of crude reduced salmon calcitonin

[0047] Add a cleavage reagent to the deprotected docosopeptide resin to cut the peptide, then add ether to precipitate, and collect the precipitate to obtain the crude reduced salmon calcitonin;

[0048] (3) Refolding

[0049] Firstly, the crude product of reduced salmon calcitonin is ...

Embodiment 3

[0053] Taking the synthesis of 0.1mM salmon calcitonin as an example, this example elaborates the specific steps for preparing the deprotected docosopeptide resin, as follows:

[0054] (1) Weigh 0.1mM, 0.32mmol / g Rink Amide Resin, 4-fold excess amino acid and 5-fold excess HOBT / HATU condensation reagent as the subsequent reaction system of a couple of coupled amino acids, and configure 20% of Piperidine and 5% N-methylmorpholine (both by volume with DMF).

[0055] (2) Weigh 0.32g of Rink Amide Resin with a degree of substitution of 0.32mmol / g and soak in 2-3mL of DMF in the synthesis column for 30min to make it fully expanded, and then use a vacuum pump to filter out the DMF.

[0056] (3) Add 2-3 mL of 20% piperidine to the puffed resin to deprotect it for 7 minutes, shake it on a rotary mixer every 2 seconds, filter out the piperidine, and then add an appropriate amount of 20% piperidine for the second step. The second deprotection was carried out for 8 minutes, during which...

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Abstract

The invention discloses a preparation method for solid-phase synthesis of salmon calcitonin. The method comprises the following steps of (1) preparing calcitonin-deprotected 32 peptide resin, (2) preparing a reduced salmon calcitonin crude product, (3) performing renaturation, and (4) performing separation and purification. The preparation method is characterized in that the step of preparing thecalcitonin deprotected 32 peptide resin specifically comprises the following sub-steps of taking amino resin as an initial raw material, taking Fmoc protected amino acid as a monomer, taking HOBT / HATUas a condensation reagent, sequentially removing Fmoc protecting groups in a polypeptide synthesis column, and coupling corresponding amino acids one by one, so as to obtain the deprotected 32 peptide resin, wherein in the amino acid coupling step, different coupling time is designed according to the synthesis difficulty degrees of the amino acids. By analyzing the amino acid synthesis difficultyand changing the coupling time, the synthesis efficiency can be improved, the product purity is increased, and the production cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical solid-phase polypeptide synthesis, and in particular relates to a preparation method of pure solid-phase synthetic salmon calcitonin. Background technique [0002] At present, the synthesis methods of salmon calcitonin are mostly synthesized by Fmoc-strategy solid-phase method, deprotected on Fmoc-RinkAmide MBHA resin and coupled with corresponding amino acids, and the obtained reduced crude product is obtained by weak base air oxidation method to obtain salmon calcitonin. Calcium. However, due to the large steric hindrance of this peptide, the synthesis efficiency has been very low. In the existing published Chinese patents, such as the Chinese patent (publication number CN104672320A), a variety of amino acid fragments and specific protected amino acids are connected to the carrier resin by coupling one by one, and oxidized on the resin by iodine to obtain pure Products salmon calcitonin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/585C07K1/04C07K1/06C07K1/20C07K1/113
CPCC07K14/585Y02P20/55
Inventor 霍林巨罗玉娇张常昕陈松刘国芳王紫珺张文龙陈虹佳司品法刘一佑金伟
Owner 湖南甲骨文生物医药有限公司
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