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Preparation method of terlipressin

A terlipressin and deprotection technology, applied in the field of preparation of polypeptide drugs, can solve problems such as coupling difficulties, and achieve the effects of high coupling efficiency, good coupling effect and reducing side reaction products

Inactive Publication Date: 2013-08-21
QINGDAO GUODA BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is that the existing terlipressin preparation method couples amino acids, and as the peptide chain grows, the coupling becomes more and more difficult

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1 prepares deprotection reagent

[0024] The preparation method of the deprotection reagent is: dissolve piperidine in the DCM / DMF / NMP solution, and add Triton-100 to prepare the deprotection reagent, wherein the volume ratio of DCM / DMF / NMP=1:1:1 , piperidine accounts for 20% by volume of the deprotection reagent, and Triton-100 accounts for 1% by volume of the deprotection reagent.

Embodiment 2

[0025] The pretreatment of embodiment 2Rink AmideAM resin

[0026] Put the Rink AmideAM resin into the reactor, wash it once with DMF, and drain it. Then use appropriate amount of DMF to swell at room temperature, N 2 Blow and stir for about 30 minutes until the resin is fully swelled, and the liquid is drained. Wash again with DMF and drain. The Rink AmideAM resin was deprotected at 15°C for 20 minutes to remove the Fmoc protecting group. The deprotection reagent is 600ml. The weight concentration of Rink AmideAM resin is 5-10ml / g. The deprotection temperature can effectively protect the peptide chain from being damaged by the heat released by the deprotection reaction, thereby effectively improving product quality. Then the deprotection reaction was carried out at room temperature for 20 min and drained. Finally, it was washed successively with DMF, methanol and DMF, and drained. After deprotection, use a glass rod to pick a little resin, indene inspection, deep purpl...

Embodiment 3

[0027] Example 3 Amino Acid Coupling Reaction to Obtain Terlipressin Peptide Resin

[0028] (1) Coupling of the first amino acid

[0029] The feeding ratio of the coupling reaction of the first amino acid is shown in Table 1, and the first amino acid is Fmoc-Gly-OH.

[0030] Table 1 The coupling reaction feeding ratio of the first amino acid

[0031] Raw materials / solvents

Feeding amount

The molar ratio of

Rink AmideAM Resin

100g (100mmol, 1mmol / g)

1

[0032] Fmoc-Gly-OH

89.2g

3

HOB

40.5g

3

DIC

46.5ml

3

DMF

500ml

[0033] Weigh 89.2g Fmoc-Pro-OH and 40.5g HOBt into a beaker, add 210ml refined DMF to dissolve the above reagents in the beaker. After complete dissolution, put the beaker in an ice bath to cool for 2 minutes, and then add 46.5ml DIC to activate the solution for about 8 minutes. If white flocculent foam appears, it indicates that the activation is comp...

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Abstract

The invention discloses a preparation method of terlipressin. The preparation method comprises the following steps of: deprotecting RinkAmideAM resin by using a deprotection reagent so as to remove a Fmoc protection group; coupling amino acids orderly with the deprotected RinkAmideAM resin as the starting raw material, the Fmoc protected amino acids as monomers and HOBt / DIC as a condensating agent, thus obtaining terlipressin peptide resin; before coupling the second to twelfth amino acids, depriving the Fmoc protection group of the last coupled product by using the deprotection reagent orderly; cracking the terlipressin peptide resin and then adding diethyl ether for settling the terlipressin peptide resin, thereby obtaining reduced terlipressin crude peptide; cyclizing the reduced terlipressin crude peptide to obtain oxidized terlipressin crude peptide; purifying the oxidized terlipressin crude peptide, converting the crude peptide into a salt, and then condensating and freeze-drying the oxidized terlipressin crude peptide, thus obtaining the terlipressin. The yield of the terlipressin prepared by the preparation method provided by the invention is 50% or above.

Description

technical field [0001] The present invention relates to a preparation method of polypeptide medicine, in particular to a preparation method of terlipressin. Background technique [0002] The chemical name of terlipressin is triglycyl lysine vasopressin, which is a new type of synthetic long-acting vasopressin preparation. It is a prodrug, which itself is inactive. After the action of aminopeptidase in the body, the three glycyl residues at its N-terminus are removed, and the active lysine vasopressin is slowly "released". Terlipressin thus acts as a depot from which lysine-vasopressin is released at a steady rate. The main function of terlipressin is to contract visceral vascular smooth muscle and reduce visceral blood flow (such as reducing the blood flow of mesentery, spleen, uterus, etc.), thereby reducing portal vein blood flow and reducing portal pressure. It can also act on the esophagus and uterus and other smooth muscles. On the other hand, in the research on the ...

Claims

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Application Information

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IPC IPC(8): C07K7/16C07K1/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 路兵徐伟张鸿雁
Owner QINGDAO GUODA BIOLOGICAL PHARMA
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