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Method for preparing terlipressin by fragment condensation

A technology of terlipressin and fragments, which is applied in the field of preparation of terlipressin acetate, and can solve problems such as not easy terlipressin, low yield, difficult product purification, etc.

Active Publication Date: 2017-10-24
海南建邦制药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide a method for preparing terlipressin by fragment condensation in view of the disadvantages of low yield of the existing preparation method, difficulty in product purification, and difficulty in obtaining high-purity terlipressin. Improved yield and purity; cost reduction due to 2-chloro-trityl chloride resin and solid-phase cyclization, which is conducive to large-scale production

Method used

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  • Method for preparing terlipressin by fragment condensation
  • Method for preparing terlipressin by fragment condensation
  • Method for preparing terlipressin by fragment condensation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: Preparation of terlipressin acetate by three fragments.

[0080] 1. Resin Preparation

[0081] 1.1 Preparation of Fmoc-Lys(Boc)-2-chloro-trityl resin: Add 2-chloro-trityl chloride resin (5g, substitution value 0.84mmol / g resin, 1eq) into a 150mL polypeptide synthesizer, and use 60 mL DCM washed the resin. The solvent was drained and a solution of Fmoc-Lys(Boc)-OH (1.3 eq) and DIEA (2.5 eq) in 30 mL of DCM was added. The mixture was mechanically stirred under an argon atmosphere for 1 hour. Add 10 mL of chromatographic methanol (2 ml / g resin) to block the active part on the resin for 30 minutes. The solvent was sucked dry, washed with 3×50mL DMF, 3×50mL DCM, 3×50mL MeOH, and vacuum-dried to constant weight to obtain 6.08g of Fmoc-Lys(Boc)-2-chloro-trityl resin. The amount of Fmoc in the piperidine deprotection solution was measured by ultraviolet spectrophotometry, and the loading amount of the resin was 0.5 mmol / g.

[0082] 1.2 Preparation of Fmoc-Gly-2-...

Embodiment 2

[0142] Example 2: Preparation of terlipressin from two fragments.

[0143] 1. Resin Preparation

[0144] The preparation of Fmoc-Lys(Boc)-2-chloro-trityl resin is the same as in Example 1.

[0145] 2. Fragment Preparation

[0146] Preparation of Peptide Fragment Boc-AA(1-11)-OH(cyclized)

[0147] Add 5 g of Fmoc-Lys(Boc)-2-chloro-trityl resin to the 150 mL peptide reaction chamber. Add 60mL DCM to stir and swell the resin, and drain it. Fmoc was removed by treating the resin with 2 x 50 mL of 20% piperidine / DMF solution for 5 and 15 minutes respectively. The resin was washed 4 times with 50 mL of DMF to remove Fmoc by-products (dibenzofulvene and its piperidine adduct) and residual piperidine, as determined by ninhydrin test.

[0148] Simultaneously activates the subsequent amino acid Fmoc-Pro-OH in the sequence to react at its carboxyl terminus. Fmoc-protected amino acids (2eq), HOBT (2eq) and DIEA (4eq) were dissolved in 25 mL DMF at room temperature. Under the protec...

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PUM

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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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/16C07K1/20C07K1/06C07K1/04
CPCY02P20/55
Inventor 常民王锐彭雅丽薛宏祥
Owner 海南建邦制药科技有限公司
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