Preparation method of teduglutide

A technology of teduglutide and degree of substitution, which is applied in the field of medicinal chemistry, can solve problems such as ineffective degradation and other side reactions, reduced yield of teduglutide, difficulty in purification of teduglutide, etc., to facilitate large-scale production , high product yield, and the effect of improving the purity of crude peptide

Inactive Publication Date: 2015-03-18
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the researchers found that whether the conventional step-by-step coupling method in the patent publication number CN101824087A or the solid-phase fragment condensation method in the patent publication number WO2012028602A1 is used to prepare teduglutide, there is a problem that His1 is easy to racemize
Due to the racemization of His, the prepared teduglutide is difficult to purify, resulting in a decrease in the yield of teduglutide
In addition, the patent publication number WO2012028602A1 uses the method of solid-phase coupling of fragment 1-4 and fragment peptide resin 5-33 to prepare teduglutide, which still cannot effectively solve the degradation caused by the Asp-Gly structure at the 3-4 position Such side reactions will also make it difficult to purify the prepared teduglutide, further leading to a decrease in the yield of teduglutide

Method used

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preparation example Construction

[0025] The embodiment of the invention discloses a preparation method of teduglutide. Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. 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 of the present invention has been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention .

[0026] For realizing the purpose of the present invention, the present invention adopts following technical scheme:

[0027] A preparation method of teduglutide, comprising:

[0028] Step 1: coupling Fmoc-Asp(OtBu)-OH with a sol...

Embodiment 1

[0094] Embodiment 1: the degree of substitution is the synthesis of Fmoc-Asp(OtBu)-Wang resin of 0.5mmol / g

[0095] Weigh 40 g of Wang 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 24.72g Fmoc-Asp(OtBu)-OH (60mmol), 9.73g HOBt (72mmol) and 0.73g DMAP (6mmol) and dissolve them in a mixed solution of DCM and DMF with a volume ratio of 1:1, and add 11.26mL of DIC (72mmol) 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 70mL of blocking solution (pyridine / acetic anhydride = 1:1, 400mmol: 400mmol) 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-Asp(OtBu)-Wang resin. The detected substitution degree was 0.503mmol / g.

Embodiment 2

[0096] Embodiment 2: the degree of substitution is the synthesis of Fmoc-Asp(OtBu)-Wang resin of 0.2mmol / g

[0097] Weigh 40 g of Wang 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 9.89g Fmoc-Asp(OtBu)-OH (24mmol), 3.90g HOBt (28.8mmol) and 0.29g DMAP (0.24mmol) and dissolve in the mixed solution of DCM and DMF with a volume ratio of 1:1, and add 4.50mL DIC (28.8mmol) was activated for 3min and added to the solid-phase reaction column, and reacted at room temperature for 2 hours. Wash 3 times with DMF, add 70mL of blocking solution (pyridine / acetic anhydride = 1:1, 400mmol: 400mmol) 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-Asp(OtBu)-Wang resin. The detected substitution degree was 0.198mmol / g.

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of teduglutide. The preparation method of the invention is as below: respectively synthesizing a teduglutide sequence site No.4-33 peptide resin fragment and a teduglutide sequence No.1-3 peptide resin fragment through solid phase synthesis; then coupling the teduglutide sequence site No.4-33 peptide resin fragment and the teduglutide sequence No.1-3 peptide resin fragment by an appropriate resin vector to obtain a teduglutide resin; and finally cracking to obtain crude teduglutide, and purifying to obtain the pure teduglutide. The preparation method provided by the invention can effectively avoid side reaction such as degradation caused by an Asp-Gly structure of the No. 3-4 site, also can reduce the His1 racemization, thus effectively improving the purity of crude peptide and improve the purification yield. Compared with the prior art, the preparation method of the invention has the advanategs of high purity of the prepared teduglutide product, less by-product and high product yield, and is beneficial for mass production of teduglutide.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation method of teduglutide. Background technique [0002] Short bowel syndrome (short bowel syndrome, SBS) refers to a series of syndromes caused by the body's inability to absorb nutrients normally due to severe small intestinal disease or surgical removal of most of the small intestine. SBS reduces the patient's ability to absorb fluids and nutrients. Due to the short residual intestine, nutrient absorption and digestion disorders can manifest as diarrhea, steatorrhea, and weight loss, leading to dehydration and malnutrition, and even life-threatening in severe cases. Most patients with short bowel syndrome cannot eat normally. Some can resume oral diet after active and appropriate intestinal rehabilitation treatment, but some need to rely on parenteral nutrition for life. Parenteral nutrition support will increase the risk of systemic infection and other long-term ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04C07K1/20
CPCC07K14/605
Inventor 张文治潘俊锋马亚平袁建成
Owner HYBIO PHARMA
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