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A teduglutide preparing method

A technology for teduglutide and polypeptide fragments, which is applied in the field of polypeptide drug preparation, can solve problems such as degradation, and achieve the effects of avoiding the formation of a five-membered ring structure and improving the purity and yield.

Active Publication Date: 2014-10-01
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In view of this, the technical problem to be solved by the present invention is to provide a preparation method of teduglutide, using Fmoc-Asp(OtBu)-(Hmb)Gly-OH or Fmoc-Asp(OtBu)-(Dmb)Gly- OH is used as the coupling raw material to solve the problem of Asp-Gly degradation during the synthesis process

Method used

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  • A teduglutide preparing method
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  • A teduglutide preparing method

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preparation example Construction

[0074] The invention provides a method for preparing teduglutide, which can be realized by appropriately improving the process parameters for reference by those skilled in the art. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0075] The invention provides a method for preparing teduglutide, comprising the following steps:

[0076] Step 1: using Asp-Gly dipeptide and amino acid as raw materials to prepare the first polypeptide fragment;

[0077] S...

Embodiment 1

[0176] Embodiment 1: the synthesis of Fmoc-Glu (OtBu)-HMPB resin

[0177] Weigh 100 g of HMPB resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 127.7g Fmoc-Glu(OtBu)-OH (300mmol), 48.6g HOBt (360mmol) and 3.7g DMAP (30mmol) and dissolve in the mixed solution of DCM and DMF with a volume ratio of 1:1, add 56.3mL DIC (360mmol) was activated for 3 minutes and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 350.1mL blocking solution (pyridine / acetic anhydride = 1:1, 2000mmol: 2000mmol) to block for 8 hours (if the resin is not fully diffused, add DCM as a solvent). Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Glu(OtBu)-HMPB resin. The detected substitution degree was 0.679mmol / g.

Embodiment 2

[0178] Embodiment 2: the synthesis of Fmoc-Glu (OtBu)-HAL resin

[0179] Weigh 100 g of HAL resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes. Weigh 127.7g Fmoc-Glu(OtBu)-OH (300mmol), 48.6g HOBt (360mmol) and 3.7g DMAP (30mmol) and dissolve in the mixed solution of DCM and DMF with a volume ratio of 1:1, and add 56.3ml DIC (360mmol) was activated for 3 minutes and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 350.1ml of blocking solution (pyridine / acetic anhydride = 1:1, 2000mmol: 2000mmol) to block for 8 hours (if the resin is not fully diffused, add DCM as a solvent). Wash 4 times with DMF, 4 times with DCM, shrink and dry with methanol to obtain Fmoc-Glu(OtBu)-HAL resin. The detected substitution degree was 0.683mmol / g.

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Abstract

The invention relates to the field of polypeptide medicine preparing methods and particularly relates to a teduglutide preparing method. The preparing method includes: preparing a first polypeptide fragment by adopting Asp-Gly dipeptide and amino acids as raw materials; synthesizing C-end polypeptide fragment-resin and a middle polypeptide fragment; coupling the middle polypeptide fragment and the first polypeptide fragment in sequence onto the C-end polypeptide fragment-resin according to the peptide sequence of the teduglutide to obtain teduglutide resin; and splitting the teduglutide resin and purifying. A Gly side chain protective group in the Asp-Gly dipeptide is Dmb or Hmb. The first polypeptide fragment has an amino acid sequence shown as SEQ ID NO:1 or SEQ ID NO:2. The C-end polypeptide fragment has an amino acid sequence shown as SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5. The number of the middle polypeptide fragment is 1-3. The method avoids formation of a five-membered ring and increases the purity.

Description

technical field [0001] The invention relates to the field of preparation methods of polypeptide drugs, in particular to a preparation method of teduglutide. Background technique [0002] Short bowel syndrome (SBS) refers to a series of syndromes caused by the body's inability to absorb nutrients normally due to severe small bowel disease or surgical removal of a large part of the small intestine. SBS reduces patients' ability to take in fluids and nutrients, causing them to become dehydrated and malnourished. Parenteral nutrition support will increase the risk of systemic infection and other long-term complications. So far, there is no drug to treat short bowel syndrome. [0003] Teduglutide (teduglutide) is a glucagon-like peptide 2 (GLP-2) analogue. The amino acid sequence of teduglutide contains 33 amino acids, and its structure is shown in SEQ ID NO:11. Is a naturally occurring hormone that reduces gastric emptying and secretion and regulates the growth, proliferation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06
CPCY02P20/55C07K14/605
Inventor 宓鹏程刘建马亚平袁建成
Owner HYBIO PHARMA
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