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Method for preparing polypeptide used for treating osteoporosis

A peptide fragment and peptide resin technology, applied in the field of medicinal chemistry, can solve the problems of difficulty, low product yield, difficult product purification, etc., and achieve the effects of less by-products, high product yield and low cost

Inactive Publication Date: 2012-10-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since teriparatide is composed of 34 amino acids, the solid-phase step-by-step synthesis method has a low product yield, and product purification is difficult, and it is difficult to obtain high-purity teriparatide

Method used

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  • Method for preparing polypeptide used for treating osteoporosis
  • Method for preparing polypeptide used for treating osteoporosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: Preparation of Teriparatide according to Strategy 1

[0083] 1. Peptide resin fragment 1 (amino acids 34-26 of the teriparatide sequence)

[0084] 1. Preparation of Fmoc-Phe-Wang Resin

[0085] Weigh 1.2g of Wang Resin with a degree of substitution of 0.8mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and after swelling the resin with DMF for 30 minutes, weigh 0.51g of Fmoc-Phe-OH, 0.13g of HOBT and 0.01g DMAP was dissolved in DMF, activated by adding 0.16mL DIC in an ice-water bath, and then added to the above-mentioned reaction column equipped with resin. After 2 hours of reaction, 5mL pyridine and 5.5ml acetic anhydride were added to block for 12 hours. Washed 6 times with DMF to obtain Fmoc-Phe-Wang Resin, the detection degree of substitution was 0.20mmol / g.

[0086] 2. Preparation of peptide resin fragments

[0087] Weigh 1.5g of Fmoc-Phe-Wang Resin with a substitution degree of 0.20mmol / g, add it to a solid-phase reaction co...

Embodiment 2

[0107] Example 2: Preparation of Teriparatide according to Strategy 2

[0108] 1. Preparation of side chain protection peptide fragment b (25-11 amino acids of teriparatide sequence)

[0109] 1. Preparation of side chain protected peptide fragment b-peptide resin

[0110] Weigh 5.35g of 2-CTC resin with a degree of substitution of 0.47mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 3.24g of Fmoc-Arg(pbf)-OH Dissolve in DMF, activate by adding 1.7mL DIPEA in an ice-water bath, add to the above-mentioned reaction column equipped with resin, react for 2 hours, add 10mL of anhydrous methanol to seal for 1 hour, and wash with DMF 6 times. Fmoc protection was removed with DBLK, followed by 6 washes with DMF.

[0111]Dissolve 1.77g Fmoc-Leu-OH, 0.74g HOBt, and 0.86ml DIC in a mixed solution of DCM and DMF with a volume ratio of 1:1, add it to a solid-phase reaction column, and react at room temperature ...

Embodiment 3

[0129] Teriparatide was prepared according to strategies 3, 4 and 5, respectively. The purity and total yield of the teriparatide crude peptide and the teriparatide acetate refined peptide prepared by each method were counted, and the results are shown in Table 1.

[0130] The teriparatide result that each method makes in table 1 embodiment 1~3

[0131]

[0132]

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Abstract

The invention belongs to the pharmacochemistry technical field, and discloses a method for preparing polypeptide used for treating osteoporosis, concretely relates to a teriparatide preparation method. The preparation method is characterized by comprising the following steps: preparing each peptide resin fragment for forming teriparatide, gradually coupling each peptide resin fragment to teriparatide on a solid phase, then pyrolysizing to obtain the teriparatide crude product, and purifying to obtain the product teriparatide. Compared with the prior art, the preparation method has the advantages of simple operation, short synthesis cycle, low cost, less environmental pollution and high yield of teriparatide, and the total yield is 30%. The method of the invention is suitable for large-scale industrial production of teriparatide, and the prepared teriparatide has the advantages of high purity and less by-products, and has considerable economical and practical value as well as wide application prospect.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a preparation method of a polypeptide for treating osteoporosis. In particular, it relates to a preparation method of teriparatide. Background technique [0002] Teriparatide, the English name is Teriparatide, is a 1-34 amino acid fragment of the biologically active N-terminal region of endogenous parathyroid hormone PTH containing 84 amino acids, with a molecular formula of C 181 H 291 N 55 O 51 S 2 , the molecular weight is 4177.77, and its peptide sequence is: [0003] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu -Asn-Ser-Met-Glu-Arg-21 22 23 24 25 26 27 28 29 30 31 32 33 34Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn- Phe-OH. [0004] Teriparatide was developed by Eli Lilly and Company of the United States. The U.S. Food and Drug Administration approved teriparatide on November 26, 2002...

Claims

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Application Information

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IPC IPC(8): C07K14/635C07K1/20C07K1/06C07K1/04
Inventor 肖庆刘建马亚平袁建成
Owner HYBIO PHARMA
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