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Method for synthetizing aviptadil

A technology of solid-phase synthesis of alendidil, which is applied in the field of pharmaceutical synthesis, and can solve the problems of many impurities, the yield and purity cannot reach a high level, and the impurities are difficult to remove

Inactive Publication Date: 2015-03-18
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of preparing Altideil by the coupling method one by one, the synthesis period is long, the impurities are more, and the yield and purity cannot reach a higher level, especially for the synthesis of His 1 and Ser 2 At the same time, the one-by-one coupling method is very easy to produce racemic impurities, and the impurities are difficult to remove by purification methods, resulting in the reduction of the purity of alendidel products and the impurity D-His 1 -Altideil and D-Ser 2 - Excessive content of Altideil affects product quality

Method used

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  • Method for synthetizing aviptadil
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  • Method for synthetizing aviptadil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Synthesis of Polypeptide Fragment Resin I

[0054] Weigh 100 g (20 mmol) of Rink Amide resin with a degree of substitution of 0.2 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then add 20% piperidine / DMF (V: V) 100ml solution, deprotection for 5 and 10 minutes, after the reaction, wash the resin 6 times with DMF, and use ninhydrin to detect the color of the resin. Weigh 23.87g Fmoc-Asn(Trt)-OH (40mmol), HOBt5.94g (44mmol) and dissolve it with 80ml DMF / DCM (1:1, V:V), add 6.85ml DIPCDI (44mmol) to activate for 3 minutes under ice-water bath Finally, add it to the above-mentioned reaction column equipped with resin and react for 2 hours. The end point of the reaction is judged by ninhydrin detection (if the resin is colorless and transparent, the reaction is complete; if the resin develops color, continue to reflect for 1 hour. The same below), After the reaction, the resin was washed 3 ti...

Embodiment 2

[0057] Example 2: Synthesis of Polypeptide Fragment Resin I

[0058] Weigh 33.3g (20mmol) of Rink Amide resin with a substitution degree of 0.6mmol / g, add it to the solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then add 20% piperidine / DMF (V : V) 100ml solution, deprotection for 5 and 10 minutes, after the reaction, wash the resin 6 times with DMF, and use ninhydrin to detect the color of the resin. Weigh 23.87g Fmoc-Asn(Trt)-OH (40mmol), HOBt5.94g (44mmol) and dissolve it with 80ml DMF / DCM (1:1, V:V), add 6.85ml DIPCDI (44mmol) to activate for 3 minutes under ice-water bath Finally, add it to the above-mentioned reaction column equipped with resin and react for 2 hours. The end point of the reaction is judged by ninhydrin detection (if the resin is colorless and transparent, the reaction is complete; if the resin develops color, continue to reflect for 1 hour. The same below), After the reaction, the resin was washed 3 time...

Embodiment 3

[0061] Example 3: Synthesis of Polypeptide Fragment Resin I

[0062] Weigh 20 g (20 mmol) of Rink Amide resin with a substitution degree of 1.0 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then add 20% piperidine / DMF (V: V) 100ml solution, deprotection for 5 and 10 minutes, after the reaction, wash the resin 6 times with DMF, and use ninhydrin to detect the color of the resin. Weigh 23.87g Fmoc-Asn(Trt)-OH (40mmol), HOBt5.94g (44mmol) and dissolve it with 80ml DMF / DCM (1:1, V:V), add 6.85ml DIPCDI (44mmol) to activate for 3 minutes under ice-water bath Finally, add it to the above-mentioned reaction column equipped with resin and react for 2 hours. The end point of the reaction is judged by ninhydrin detection (if the resin is colorless and transparent, the reaction is complete; if the resin develops color, continue to reflect for 1 hour. The same below), After the reaction, the resin was washed 3 times ...

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Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthetizing aviptadil. The method comprises the steps of according to the amino acid sequence of aviptadil peptide chain from N terminal to C terminal, synthetizing a 1-9 fragment by using Boc-His(3-Bum)-Ser(Psi(Me, Me)pro)-OH, synthetizing 10-18 and 19-28 fragments simultaneously, coupling the three polypeptide fragments to obtain the aviptadil. By adopting the method, the problems that in the conventional synthetic methods, the content of racemic impurities D-Hisl- aviptadil and D-Ser2-aviptadil is higher and the aviptadil purity is lower due to the inappropriate synthetic materials and coupling methods are solved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing alendidil. Background technique [0002] Aviptadil (Aviptadil) is a neuropeptide, in addition to nerve conduction, it is also a vasoactive intestinal peptide agonist, and its peptide sequence is as follows: [0003] NH 2 -His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser -Ile-Leu-Asn-COONH 2 [0004] The use of alendidil in patients with pulmonary hypertension (PH) found that it can cause transient hyperselective pulmonary vasodilation, increased stroke volume and mixed venous oxygen saturation, and can improve oxygenation in patients with lung disease . The phase III clinical trial of alendidil for the treatment of pulmonary arterial hypertension has entered the preparation stage, the phase II clinical trial for pulmonary sarcoidosis has been completed, and the phase II clinical trial for acu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K1/20C07K1/06C07K1/04
Inventor 潘俊锋覃亮政刘建马亚平袁建成
Owner HYBIO PHARMA
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