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A related substance of trexagliptin succinate and its preparation method, analysis method and application

The technology of a trelagliptin succinate and an analysis method is applied in the field of related substances of succinate and its preparation, which can solve the problems of low detection and separation efficiency, long elution time, poor applicability and the like, and achieves improved safety. and controllability, the preparation method is simple and easy to implement, and the effect of improving quality standards

Active Publication Date: 2021-05-25
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A related substance of trexagliptin succinate and its preparation method, analysis method and application
  • A related substance of trexagliptin succinate and its preparation method, analysis method and application
  • A related substance of trexagliptin succinate and its preparation method, analysis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of Trilagliptin Succinate Related Substance L

[0064]

[0065] Trilagliptin (1.0 g, 2.8 mmol), 2-cyano-5-fluorobenzyl bromide (0.63 g, 2.9 mmol), potassium carbonate (0.39 g, 2.8 mmol) and DMF (20 mL) were added to 100 mL of three wells in turn After the addition was completed, the system was heated to 60° C. and stirred at this temperature for 4 h. TLC detection showed that the reaction was basically complete. Water (20 mL) was slowly added dropwise to the system at room temperature, the dropwise addition was completed, stirring was continued for 1 h, suction filtration, the filter cake was washed with water and methanol, respectively, and vacuum-dried to obtain 1.0 g of a white solid, which was related substance L. The yield is 73.0%, and the purity is 99.12%.

[0066] The structure of substance L was confirmed, and the results were as follows:

[0067] Related Substance L: m / z: 491.3 [M+H] + .

[0068] 1 H-NMR (DMSO-d 6 ,600MHz),δ:1.2...

Embodiment 2

[0069] Example 2: Analysis of Trolagliptin Succinate Related Substances - Influence of Mobile Phase

[0070] Preparation of blank solvent: water: methanol = 80%: 20% (volume ratio)

[0071] Preparation of mixed solution:

[0072] Weigh the appropriate amount of related substances I, Q, K, G, B, L, D, C, J, M and troglitatin succinate, respectively, and add the blank solvent to dissolve and quantitatively dilute them into about 0.5 mg per 1 ml. solution, as a positioning solution. Measure 20 μl of each of the above-mentioned related substances positioning solution and 1 ml of trilagliptin succinate positioning solution, respectively, and mix them evenly, as a mixed solution of each related substance and succinate succinate.

[0073] Chromatographic conditions:

[0074] Chromatographic column: Agilent Pursuit 3C18 (4.6×150mm, 3μm)

[0075] Detection wavelength: 220nm

[0076] Column temperature: 30℃

[0077] Flow rate: 1.0ml / min

[0078] Mobile phase: take 0.05% perchlori...

Embodiment 3

[0101] Example 3: Analysis method of Trolagliptin succinate related substances-influence experiment of flow rate

[0102] The chromatographic conditions were consistent with experiment 3 in Example 2, only the flow rate was changed, 20 μl of the mixed solution in Example 2 was taken, and 20 μl of the mixed solution was injected into a liquid chromatograph, and the chromatogram was recorded.

[0103] Table 9 Test results of separation degree of troglitatin and known related substances

[0104]

[0105] Note: " / " means no degree of separation, "--" means that the degree of separation cannot be calculated.

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Abstract

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

Description

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

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04G01N30/02
CPCC07D401/04G01N30/02
Inventor 刘春磊郭阳周付刚贾铭刘洋姚冰洁
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD