Method for preparing terlipressin by fragment condensation

Abstract

The invention discloses a fragment condensation method of terlipressin. The fully protected first peptide fragment sequence resin of terlipressin is prepared in solid phase, cyclized to form a disulfide bond, and then the cyclized fully protected first peptide is cyclized. The peptide fragment sequence is cleaved from the resin; the cyclized fully protected first peptide fragment sequence is condensed with H-Gly-NH2 in the liquid phase to obtain the cyclized fully protected second peptide fragment sequence; liquid phase or solid phase preparation of terlipress The third peptide fragment sequence of the protein; the cyclized fully protected second peptide fragment sequence is de-protected at the amino terminal and condensed with the third peptide fragment sequence, and then removes all protecting groups to obtain the crude terlipressin, which is purified and converted to salt to obtain the product Terlipressin acetate; the first peptide fragment sequence is the 4-11th amino acid in the terlipressin sequence, the second peptide fragment sequence is the 4-12th amino acid in the terlipressin sequence, the The tripeptide fragment sequence is the 1-3 amino acid in the terlipressin sequence.

Description

technical field

[0001] The invention relates to the field of pharmacy, in particular to a preparation method of terlipressin acetate. Background technique

[0002] The chemical name of terlipressin is triglycyllysine vasopressin, and its structural formula is as follows:

[0003]

[0004] It is a new type of synthetic long-acting vasopressin preparation, mainly used for gastrointestinal and genitourinary system bleeding, such as esophageal varices, gastric and duodenal ulcers, functional and other causes Treatment of bleeding caused by uterine bleeding, labor and / or miscarriage, etc. It is long-lasting and does not cause dangerous complications compared with vasopressin.

[0005] At present, the preparation method of terlipressin is mainly based on solid-state condensation. For example, patents CN1865282B, CN101693738A and 201310214366.4 all use Rink Amide or Sieber resin as the starting material, Fmoc-protected amino acid as the monomer, HBTU / HOBt / DIEA, DIC / HOBt or PyB...

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