Preparation method of terlipressin through combination of solid and liquid

Abstract

The invention relates to the field of polypeptide synthesis, and specifically relates to a preparation method of terlipressin through combination of solid and liquid. According to the preparation method, Boc-Gly-OH and glycylglycine are subjected to liquid phase synthesis so as to obtain a peptide fragment (Boc-Gly-Gly-Gly-OH); at the same time, solid phase synthesis is performed to obtain a cyclic peptide segment (H-c[Cys-Tyr(OtBu)-Phe-Gln(Trt)-Asn(Trt)-Cys]-Pro-Lys(Boc)-Gly-amino resin); finally the peptide fragment and cyclic peptide segment are coupled to prepare terlipressin resin; and then the terlipressin resin is cracked, purified, and freeze-dried to obtain terlipressin. The provided technology reduces the generation of impurity peptides, improves the purity and yield of coarse peptide, simplifies the operation steps, further reduces the production cost, and can be easily applied to large scale enlarged production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing terlipressin by combining solid phase and liquid phase. technical background [0002] Terlipressin (Terlipressin) was first developed by Ferring Company. It was first listed in the Netherlands as a hemostatic drug in 1977 under the trade name Glypressin; later it was launched in France, Germany, and the United Kingdom under the trade name Glypressine for the treatment of gastrointestinal veins. Varicea hemorrhage; Ferring obtained the marketing authorization of this variety in China in 1999. [0003] Terlipressin is a derivative of lysine vasopressin, which itself is inactive. After the action of aminopeptidase in vivo, the three glycyl residues at its N-terminal are removed, and the active vasopressin is slowly "released". Lysine vasopressin. Its structure is as follows: Gly-Gly-Gly-c[Cys-Tyr-Phe-Gln-Asn-Cys]-Pro-Lys-Gly-NH 2 [0004] The patent SK...

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Problems solved by technology

Patent CN101693738A also uses Fmoc to protect amino acids to synthesize linear terlipressin peptide resin in solid phase, and then uses iodine oxidation solid phase cyclization process to form disulfide bonds, and then undergoes cleavage, purification, and freeze-drying to obtain refined peptides, which simplifies the operation process , which is convenient for scale-up; however, there are disadvantages such as difficult ring formation and low purity of crude peptides

Patent CN102408471A, in order to solve the impurity of terlipressin±Gly that is easy to be produced in the process, Fmoc-Gly-OH and CTC resin are used to synthesize Fmoc-Gly-Gly-Gly-CTC resin, and then the monomer Fmoc-Gly is obtained by cracking -Gly-Gly-OH, synthesize linear terlipressin peptide resin in the solid phase; although it effectively avoids the generation of impurities of terlipressin±Gly, it increases the production cost

Patent CN104371008A adopts the method of fragment synthesis to prepare terlipressin, and its announced liquid phase synthesis of Boc-Gly-Gly-Gly-OH or Fmoc-Gly-Gly-Gly-OH requires coupling, deprotection, Four steps including re-coupling and re-deprotection, and the selected raw materials H-Gly-OMe or H-Gly-OtBu are relatively expensive, and the whole preparation process is complicated to operate, which is not suitable for large-scale production