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Preparation method of Terlipressin

A technology of terlipressin and vasopressin, which is applied in the field of polypeptide drug preparation, can solve the problems of long air oxidation time, low total product yield, and reduced purity of crude products, etc., achieves extensive practical value and application prospects, and improves product quality. The effect of shortening the yield and production cycle

Inactive Publication Date: 2012-04-11
CHENGDU SHENGNUO BIOTEC CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This preparation method has the following disadvantages, [+1Gly]-terlipressin, [-1Gly]-terlipressin [+2Gly]-terlipressin and [-2Gly]-Terlipressin impurities reduce the purity of the crude product; at the same time, terlipressin is unstable under alkaline conditions and is easily decomposed into triglycerides and vasopressin. The air oxidation time is longer, and generally requires 24 hours, so the product is easy to degrade, so the above-mentioned deficiencies seriously affect the total yield of the product is low

Method used

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  • Preparation method of Terlipressin
  • Preparation method of Terlipressin
  • Preparation method of Terlipressin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The synthesis of embodiment 1Fmoc-Gly-Gly-Gly-OH

[0055] Take 3.0mol Fmoc-Gly and 3.0mol HOBt and dissolve them with appropriate amount of DMF; another 3.0mol DIC is slowly added to the protected amino acid DMF solution under stirring, and stirred and reacted at room temperature for 30 minutes to obtain the activated protected amino acid solution .

[0056] Take 1Kg of Fmoc-Gly-2-Cl-Trt-resin (substitution value is 1.0mmol / g), use 5L 20% PIP / DMF solution to remove Fmoc protection for 25 minutes, filter and wash the resin 3 times with MDF and DCM respectively, add The above-mentioned protected amino acid solution was stirred and reacted at room temperature for 3 hours. After the reaction was completed, the filtered resin was washed three times with MDF and DCM respectively.

[0057] The above two-step reaction was repeated, and another 2 Glys were added to obtain Fmoc-Gly-Gly-Gly-2-Cl-Trt-resin.

[0058] Take Fmoc-Gly-Gly-Gly-2-Cl-Trt-resin, add 20L 30% hexafluoroisop...

Embodiment 2

[0059] Example 2 Synthesis of Terlipressin Linear Peptide Resin

[0060] The terlipressin dendrimer is:

[0061] H-X-Cys(Trt)-Tyr(tBu)-Phe-Gln(Trt)-Asn(Trt)-Cys(Trt)-Pro-Lys(Boc)-Gly-resin wherein, X is Gly-Gly-Gly.

[0062] The Rink Amide AM resin was taken, and the terlipressin resin was obtained by sequentially coupling with the protected amino acids shown in Table 1 through de-Fmoc protection and coupling reactions. The protected amino acids used in this example correspond to the 1st to 10th amino acids from the resin as follows:

[0063] Table 1

[0064] The peptide sequence n=

Protected Amino Acids

molecular weight

1

Fmoc-Gly

297

2

Fmoc-Lys(Boc)

468

3

Fmoc-Pro

337

4

Fmoc-Cys(Trt)

586

5

Fmoc-Asn(Trt)

597

6

Fmoc-Gln(Trt)

611

7

Fmoc-Phe

387

8

Fmoc-Tyr(tBu)

460

9

Fmoc-Cys(Trt)

586

...

Embodiment 3

[0071] Example 3 Preparation of Crude Terlipressin Linear Peptide

[0072] Take the terlipressin linear peptide resin prepared in Example 2, add a cleavage reagent [TFA / water / EDT=95:5:5 (V / V) (10ml of cleavage reagent / g resin), stir evenly, and stir at room temperature React for 3 hours, filter the reaction mixture with a sand core funnel, collect the filtrate, wash the resin 3 times with a small amount of TFA, combine the filtrates, concentrate under reduced pressure, add anhydrous ether to precipitate, then wash the precipitate 3 times with anhydrous ether, and drain to obtain The white powder is the crude terlipressin linear peptide.

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Abstract

The invention belongs to the technical field of preparation methods of polypeptide drugs and particularly relates to a preparation method of Terlipressin. The method uses protected amino acid fragment Gly-Gly-Gly as a raw material to avoid the generation of impurities. The method comprises the following steps: preparing Terlipressin linear peptide resin by adopting a solid phase polypeptide method, performing acidolysis to obtain crude Terlipressin linear peptide, oxidizing to obtain crude Terlipressin and purifying to obtain pure Terlipressin, wherein the solid phase polypeptide method is as follows: amino resin is connected in the Fmoc-protected amino acid of the corresponding fragments in the following sequence in turn through a solid phase coupling synthesis method to prepare the Terlipressin linear peptide resin, the sequence is R1-X-Cys(R2)-Tyr(tBu)-Phe-Gln(R3)-Asn(R3)-Cys(R2)-Pro-Lys(Boc)-Gly-resin, the fragment X is Gly-Gly-Gly, R1 is R4 or H, R2 is Trt or Acm, R3 is Trt or H, R4 is Fmoc or Boc, and the fragment X is grafted only by performing the solid phase coupling synthesis reaction once. The method uses the new raw material, thus the product yield can be increased and the production cycle is greatly shortened.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a preparation method of terlipressin. Background technique [0002] Terlipressin has the following structure: [0003] [0004] Terlipressin (Terlipressin) is a derivative of lypressin, which has the effect of increasing gastrointestinal vasoconstriction, which is manifested by reducing splanchnic blood flow, while blood pressure and heart rate have only slight changes. Compared with lypressin, this product is more focused on reducing splanchnic blood flow and has a longer duration of action. After intravenous administration, the decrease in portal venous pressure indicates that this product has a contraction effect on the intestinal capillary bed. [0005] In clinical application, in a double-blind study, terlipressin acetate can significantly reduce the need for blood transfusion, compared with placebo, the need for blood transfusion was about 4...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/16C07K1/06C07K1/04
CPCY02P20/55
Inventor 文永均王晓莉郭德文
Owner CHENGDU SHENGNUO BIOTEC CO LTD
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