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

A technology for trelagliptin succinate and related substances, which is applied in the field of related substances of succinate and preparation thereof, 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: 2019-10-08
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

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: Preparation of related substance L of trexagliptin succinate

[0064]

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

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

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

[0068] 1 H-NMR (DMSO-d 6 ,...

Embodiment 2

[0069] Embodiment 2: The impact of the analysis method of related substances of trexagliptin succinate-mobile phase

[0070] The 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 trexagliptin succinate respectively, add blank solvent to dissolve and quantitatively dilute to obtain about 0.5mg per 1ml solution, as a positioning solution. Measure 20 μl each of the above-mentioned related substance positioning solutions and 1 ml of the succinate trexagliptin succinate localization solution, and mix them uniformly to form a mixed solution of each related substance and succinate trexagliptin succinate.

[0073] Chromatographic conditions:

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

[0075] Detection wavelength: 220nm

[0076] Column temperature: 30°C

[0077] Flow rate: 1.0ml / min

[0078] Mobile p...

Embodiment 3

[0101] Example 3: Analysis method of related substances of trexagliptin succinate-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, injected into a liquid chromatograph, and the chromatogram was recorded, and the results of investigating the resolution of related substances were shown in Table 9 below.

[0103] Table 9 The results of investigation on the degree of separation between Trexagliptin and known related substances

[0104]

[0105] Note: " / " means no resolution, "--" means the resolution cannot be calculated.

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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...

Claims

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Application Information

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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
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