Preparation method of teduglutide

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...

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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 intermediates to prepare target molecules, and the process is cumbersome and not suitable for production process development; CN201310102450, CN201310369843 and CN201510274924 all use solid-phase fragment condensation to prepare target molecules, and all around control 1 His racemization research was carried out, but the selection of solid-phase fragments was not rational enough, resulting in low purity of the crude product and poor overall yield

[0005] In the research and development of the synthesis method of teduglutide, we found that the target molecule cannot be effectively obtained by sequentially coupling the amino acids of teduglutide according to the step-by-step synthesis method. 24 Asn and 16 Subsequent amino acids of teduglutide cannot continue to be coupled at Asn

Finish 1 A large number of racemized impurities of this amino acid appear in His, and the separation and purification of this impurity is very difficult, resulting in a low overall yield

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