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Terlipressin synthesis method

A technology of terlipressin and condensation reagents, which is applied in the field of synthesizing terlipressin, and achieves the effects of low cost and increased total yield

Active Publication Date: 2018-03-09
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the patent does not record the final total yield, it can be calculated according to the dosage disclosed in its examples that the total yield after purification is about 55%, which is the same as the total yield of the current overall terlipressin. The rate is quite

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0054] Embodiment 1: the synthesis of Fmoc-Gly-MOBHA resin

[0055] Take 0.15mol Fmoc-Gly and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add them to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution ,spare.

[0056] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Fmoc-Gly solution, stir and react at room temperature for 3 hours, remove the reaction solution, wash with DMF for 3 times, DCM was washed 3 times, and the washing time was 3 minutes each time to obtain Fmoc-Gly-MOBHA resin, which was deprotected with 20% PIP / DMF solution for 25 minutes, washed and filtered to obtain Gly-MOBHA resin.

Embodiment 2

[0057] Embodiment 2: the synthesis of Boc-Gly-MOBHA resin

[0058] Take 0.15mol Boc-Gly and 0.15mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15mol DIC, slowly add it to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated protected amino acid solution ,spare.

[0059] Take 0.05mol of MOBHA resin (substitution value about 0.6mmol / g), swell with DMF for 25 minutes, wash and filter, add activated Boc-Gly solution, stir and react at room temperature for 3 hours, remove the reaction solution, wash with DMF for 3 times, DCM was washed 3 times, and the washing time was 3 minutes each time to obtain Boc-Gly-MOBHA resin, which was deprotected with 30% TFA / DCM solution for 30 minutes, neutralized by DIEA / DCM solution, washed and filtered with DMF and DCM to obtain Gly- MOBHA resin.

Embodiment 3

[0060] Example 3: Synthesis of Peptide Resin 1

[0061] Take 0.15 mol Fmoc-Lys (Boc) and 0.15 mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.15 mol DIC, slowly add them to the protected amino acid DMF solution under stirring, and stir and react at room temperature for 30 minutes to obtain the activated Protected amino acid solution.

[0062] Add the above-mentioned activated protected amino acid solution to the Gly-MOBHA resin prepared in Example 1, stir and react at room temperature for 3 hours, remove the reaction solution, wash 3 times with DMF, and wash 3 times with DCM, each washing time is 3min, Then use 20% PIP / DMF solution to deprotect for 25 minutes, wash and filter, and complete the access of Fmoc-Lys (Boc).

[0063] Connect Fmoc-Pro, Fmoc-Cys(Trt), Fmoc-Asn(Trt), Fmoc-Gln(Trt), Fmoc-Phe, Fmoc-Tyr(tBu) and Fmoc-Cys(Trt) in the same way, and then use 20 %PIP / DMF solution deprotected, washed and filtered to obtain peptide resin 1, Cys(T...

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Abstract

The invention relates to the field of synthesis of medicines and discloses a terlipressin synthesis method. A brand new MOBHA resin is used to synthesize the terlipressin, the time for the cyclizationin the molecule is adjusted, the cost is lower in comparison with the exiting Rink Amide series resin, the whole yield of an obtained pure product is remarkably increased, and the whole method is simple and easy to operate, is mild in conditions and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a method for synthesizing terlipressin. Background technique [0002] 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. [0003] In clinical application, a double-blind study showed that terlipressin acetate can significantly reduce the need for blood transfusion, compared with placebo, the need for blood transfusion was about 40% lower than that of the placebo group. The rate of hemostasis within 12 hours w...

Claims

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Application Information

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IPC IPC(8): C07K7/16C07K1/36C07K1/34C07K1/16C07K1/06C07K1/04
CPCC07K7/16
Inventor 黄璜郭德文曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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