Preparation method of teduglutide

A teduglutide and gradient technology, applied in the field of drug synthesis, can solve the problems of insufficient selection of solid-phase fragments, low overall yield, low purity of crude products, etc., reduce material costs and purification costs, and improve single-batch production Scale, the effect of reducing the difficulty of purification

Pending Publication Date: 2021-10-08
CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The chemical synthesis method of teduglutide has been reported in the literature, but the reported preparation methods have various shortcomings and disadvantages
For example, in CN201310102159, a solid-phase step-by-step synthesis method is used to prepare teduglutide molecules. Due to the incomplete reaction of individual amino acids in the teduglutide sequence, a large number of missing peptide impurities are produced. The similarity of the nature of such missing peptide impurities leads to separation and purification. Difficult and low yield; in CN111018962A, the coupling method of larger fragment peptides (greater than 10 amino acids) is used to prepare target molecules, and the coupling condensation efficiency between larger polypeptide fragments is low, and the content of missing peptide impurities is high and the overall yield is low; CN11217506A , CN106749614A and CN109456404A use a large number of short peptide fragments (2-5 amino acids) as i

Method used

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  • Preparation method of teduglutide
  • Preparation method of teduglutide
  • Preparation method of teduglutide

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preparation example Construction

[0052] The invention discloses a preparation method of teduglutide, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. 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.

[0053] Some abbreviations used in the present invention have the following meanings:

[0054]

[0055]

[0056] The invention provides a method for preparing teduglutide, comprising the following ...

Embodiment 1

[0078] A synthetic method for teduglutide, such as figure 2 shown, including the following steps:

[0079] 1. Synthesis of the first peptide resin

[0080] Weigh 2-Cl CTC resin (1.500g, 1.5mmol) with a degree of substitution of 1.013mmol / g, add it to a solid-phase reaction vessel, add DCM (15mL) to swell for 10min, and wash the resin 3 times with DCM after swelling. 15 mL each time, the resin was vacuum-dried for later use.

[0081] Fmoc-Asp(tBu)-OH (0.191g, 0.45mmol) and DIEA (0.4mL, 2.25mmol) were dissolved in DCM (15mL), and added to the above 2-Cl CTC resin to start the reaction after the dissolution was clarified. The temperature was controlled between 25 and 30°C, and the reaction was carried out for 2.5 hours. After the reaction was completed, the resin was washed 3 times with DCM, 15 mL each time. Add methanol / DIEA / DCM=1 / 2 / 7 (volume ratio) (15mL) to the resin, and cap it at 25-30°C for 15 minutes. After the reaction, the resin is drained and the capping operation ...

Embodiment 2

[0113] A synthetic method for teduglutide, comprising the following steps:

[0114] 1. Synthesis of the first peptide resin

[0115] Weigh 2-Cl CTC resin (3.000g, 3.00mmol) with a degree of substitution of 1.013mmol / g, add it to a solid-phase reaction vessel, add DCM (30mL) to swell for 10min, and wash the resin 3 times with DCM after swelling. 30 mL each time, the resin was vacuum-dried for later use.

[0116] Fmoc-Asp(tBu)-OH (0.381g, 0.90mmol) and DIEA (0.8mL, 2.50mmol) were dissolved in DCM (30mL), and added to the above 2-Cl CTC resin to start the reaction after the dissolution was clarified. The temperature was controlled between 25 and 30°C, and the reaction was carried out for 2.5 hours. After the reaction was completed, the resin was washed 3 times with DCM, 30 mL each time. Add methanol / DIEA / DCM=1 / 2 / 7 (volume ratio) (30mL) to the resin, and cap it at 25-30°C for 15 minutes. After the reaction, the resin is drained and the capping operation is repeated once more. ...

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of teduglutide. The method comprises the following steps: preparing a Phe-Ile-Asn (trt)-Trp (Boc)-Leu pentapeptide fragment, an Asp (tBu)-Asn (trt)-Leu tripeptide fragment (I), a His (trt)-Gly-Asp (tBu) tripeptide fragment (II), and an Ile-Gln (trt)-Thr (tBu)-Lys (Boc)-Ile-Thr (tBu)-Asp (tBu) first peptide resin; and sequentially coupling amino acid and polypeptide fragments on the first peptide resin, and cracking and purifying the obtained teduglutide resin. The method successfully breaks through the control difficulty of racemization impurities of teduglutide 1His, avoids intramolecular autonomous cyclization of 24Asn, and improves the coupling efficiency of 16Asn.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of teduglutide. Background technique [0002] Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, reduces gastric emptying and secretion, and regulates the growth, proliferation, and repair of small intestinal lining cells, thereby increasing intestinal absorption , Reduce diarrhea. Developed by NPS Pharmaceuticals, it was approved for marketing by the European Union and FDA in 2012. The trade name is Gattex / Revestive. It is an orphan drug for the treatment of Short Bowel Syndrome. Its structural formula and peptide sequence are as follows figure 1 shown. [0003] At present, the most effective chemical synthesis method of polypeptide drugs is the solid-phase synthesis Fmoc method, that is, starting from the -COOH of the polypeptide, after the first amino acid is connected to the resin, the Fmoc protecting group at the N-terminal of the amino acid is remov...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/08C07K1/06C07K1/04C07K1/20
CPCC07K14/605Y02P20/55
Inventor 刘宏邬莉娜周琳赵春林胡沙李浩
Owner CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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