Method for preparing teriparatide

A technology of teriparatide and crude peptide, which is applied in the field of medicinal chemistry, can solve the problems of low yield, high price and cost, and cumbersome steps, and achieve the effect of facilitating industrial production, high total yield, and easy price

Inactive Publication Date: 2013-12-25
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the method is novel, 2-CTC resin is highly sensitive to acid, and the peptide is easy to fall off during coupling, resulting in low yield and high price of the resin
The purity of teriparatide is between 65.8-80.5%, and the total yield is between 20.5-32.2%. Generally speaking, the method has high cost and complicated steps, and the overall yield is not high
In addition, there are also a number of patents related to obtaining teriparatide through gene expression, such as US6590081. However, gene expression has the disadvantages of heavy workload, serious waste, and inability to produce on a large scale.

Method used

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  • Method for preparing teriparatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Preparation of Fmoc-Phe-Wang Resin with a degree of substitution of 0.3 mmol / g

[0058] Weigh 625 g (500 mmol) of Wang Resin with a substitution degree of 0.8 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, take 387.5 g (1000 mmol) of Fmoc-Phe -OH, 162 g (1200 mmol) HOBt, 151.5 g (1200 mmol) DIC, and 12.2 g (100 mmol) DMAP were dissolved in a mixed solution of DCM and DMF with a volume ratio of 1:1, added to a solid-phase reaction column, and reacted at room temperature for 2 Hour. After the reaction, wash 4 times with DMF and 2 times with DCM. Then add 791 g (10000 mmol) pyridine and 1021 g (10000 mmol) acetic anhydride mixed solution to seal the resin for 6 hours. After washing 4 times with DMF and 2 times with DCM, methanol was shrunk and drained to obtain 813.7 g Fmoc-Phe-Wang Resin, and the detection degree of substitution was 0.302 mmol / g (for the method of detection of resin substi...

Embodiment 2

[0059] Embodiment two: the preparation of peptide resin A

[0060] Weigh Fmoc-Phe-Wang Resin331.1g (100mmol) with a substitution degree of 0.302mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, and remove the Fmoc protection with DBLK ( Reaction time 5+7 minutes), followed by 4 washes with DMF and 2 washes with DCM. Take 179.0g (300mmol) Fmoc-Asn(Trt)-OH, 48.6g (360mmol) HOBt dissolved in a mixed solution of DCM and DMF with a volume ratio of 1:1, ice bath for 10 minutes, add 45.4g (360mmol) DIC to activate 5 Add it to the solid-phase reaction column after 10 minutes, and react at room temperature for 2 hours (the end point of the reaction is determined by the ninhydrin method. If the resin is colorless and transparent, the reaction is complete, and the color of the resin indicates that the reaction is incomplete, and another coupling reaction is required. 1 h), followed by three washes with DMF.

[0061] Repeat...

Embodiment 3

[0062] Embodiment three: the preparation of peptide resin B

[0063] Take 712.5g of peptide resin A (100.0mmol) prepared in Example 2 and put it into the solid phase reaction column. Take 358.2g (600mmol) Fmoc-Asn(Trt)-OH, 81g (600mmol) HOBt, 7.32g (60mmol) DMAP dissolved in a mixed solution of DCM and DMF with a volume ratio of 1:1, and drop into 75.7 g (600 mmol) DIC, activated for 5 minutes, added to the solid-phase reaction column, and reacted at room temperature for 1 hour. After the reaction, the Fmoc protection was removed with DBLK (reaction time 5+7 minutes), and then washed 4 times with DMF and 2 times with DCM to obtain 778.5 g of peptide resin B.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, relates to a peptide preparation method and particularly relates to a method for preparing teriparatide. The method comprises the steps of (1) sequentially coupling amino acids on a solid-phase carrier, starting from a carbon terminal, according to the amino acid sequence of teriparatide by adopting a solid-phase synthesis method, adopting Boc-Ser-OH as a raw material when 17-th serine is coupled, enabling free hydroxyl of the 17-th serine and carboxyl of 16-th asparagine to be subjected to ester condensation, and then, sequentially coupling the other amino acids; (2) carrying out pyrolysis to obtain crude peptide, and then, converting an ester bond between the 17-th serine and the 16-th asparagine into an amide bond, thereby obtaining a crude peptide solution of teriparatide. The method for preparing teriparatide, provided by the invention, is novel, the purity of teriparatide is improved, the operation is simple, convenient and practical, the total yield is high, the purity is high, the cost is low, and the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a preparation method of peptides, in particular to a preparation method of teriparatide. Background technique [0002] Teriparatide is a long-chain polypeptide drug whose peptide sequence is: [0003] Teriparatide is a synthetic polypeptide hormone developed by Eli Lilly and Company of the United States. It is a 1-34 amino acid fragment of human parathyroid hormone (PTH), which is a biologically active endogenous PTH containing 84 amino acids. the N-terminal region. [0004] PTH is secreted by the parathyroid glands and is an important regulator of blood calcium concentration. Decreased blood calcium concentration can stimulate the synthesis and secretion of PTH. PTH has 3 actions: increases the release of bone calcium; reduces the amount of calcium cleared from the kidneys; and stimulates the production of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which increases cal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/635C07K1/06C07K1/04
CPCY02P20/55
Inventor 朱日成宓鹏程马亚平袁建成
Owner HYBIO PHARMA
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