Trelagliptin succinate-related substance, preparation method, analysis method and application of substance

Abstract

The invention relates to a Trelagliptin succinate-related substance L which has not been reported in literature, a preparation, analysis and detection method and an application of the substance L. Theanalysis and detection method can detect 10 related substances including related substance L, and has good separation degree and high sensitivity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a related substance of trexagliptin succinate and its preparation method, analysis method and application. Background technique [0002] Trelagliptin succinate structural formula: [0003] [0004] Trexagliptin succinate (trade name Zafatek) is an ultra-long-acting dipeptidyl peptidase IV (DPP-4) inhibitor for the treatment of type 2 diabetes and is taken once a week. A new drug application was filed by Takeda in March 2014, and it was approved for marketing in Japan on March 26, 2015. [0005] The drug itself usually includes the active ingredients of the drug and related substances. The existence of related substances has an important impact on the quality and curative effect of the product. Therefore, it is necessary to detect and effectively control the related substances in the raw materials. [0006] The related substances are mainly the starting materials, intermed...

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Problems solved by technology

[0010] CN104237421B discloses a kind of related substance detection method of trexagliptin succinate and its preparation, its mobile phase A is a phosphate buffer, mobile phase B is acetonitrile, and the detection wavelength is 278nm, but the method has the following problems: (1 ) The patent does not give any known impurities, and the applicability of the method cannot be judged; (2) The wavelength parameter of the analysis method is set to 278nm, which cannot cover all impurities. After analyzing the spectrum of each known impurity, a certain Some impurities have no UV absorption at this wavelength

[0011] CN106290596A discloses the method for separating and analyzing trexagliptin succinate and its preparation related substances, its mobile phase A is a phosphate buffer (wherein 0.3 volume % triethylamine is also added), and the mobile phase B is acetonitrile or methanol, The preparation of its mobile phase A is relatively complicated, and only three kinds of impurities are detected, so the applicability of the detection system for multiple impurities is poor

[0012] CN106526010A discloses a related substance detection method of troxagliptin succinate and its preparation, its mobile phase A is ammonium chloride buffer, mobile phase B is methanol-acetonitrile (15:85), and the sample preparation solvent is formic acid water , the method is specially developed for "impurity III", which is not applicable to the detection and separation of various impurities, and there is also the problem of complicated mobile phase preparation

The disadvantages of this method are: (1) mobile phase A and B are binary systems of aqueous solvent and organic solvent, the preparation is relatively complicated, and the organic solvent is difficult to reuse; (2) the elution time is too long, and the detection and separation efficiency is relatively low. Low and excessive solvent consumption

[0014] CN108680678A is called the method for measuring related substances of trexagliptin, and discloses the separation of 8 kinds of related substances. Its mobile phase A is phosphoric acid aqueous solution, and mobile phase B is acetonitrile. The method is actually a two-stage isocratic elution, which is not suitable for The elution and separation of impurities with large differences in structure and polarity, and this method does not give the corresponding situation of each impurity and the HPLC elution peak, and correspondingly cannot confirm the retention time of each impurity, so it is very important for the research curve The reference significance of the analysis method for other impurities of Gliptin is not very great

[0015] CN105738517B discloses a method for determining related substances in trexagliptin tablets. In the 3 examples of this patent, mobile phase A is phosphoric acid aqueous solution, mobile phase B is acetonitrile, and the ratio of mobile phase B reaches 70% at most. figure 2 It can be seen from the figure that it tested the separation of 8 known impurities and trexagliptin, and all impurities were eluted within 23 minutes. The elution speed is very fast, but it can be seen from the figure that there are at least five known impurities. The retention time is concentrated around 20 minutes, and there are some small peaks between the peaks of these known impurities. It is not confirmed whether the peaks of unknown impurities will be covered or overlapped by the peaks of these known impurities.

[0018] On the other hand, the related substance L found to affect the purity of trexagliptin succinate, as shown below, has not been reported in the literature

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