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CN-121721197-B - Method for detecting substances related to (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride

CN121721197BCN 121721197 BCN121721197 BCN 121721197BCN-121721197-B

Abstract

The invention relates to the technical field of medicine analysis and detection, in particular to a detection method of substances related to (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride. The detection method comprises the steps of detecting by adopting a high performance liquid chromatography, wherein chromatographic conditions comprise a chromatographic column which is octadecylsilane chemically bonded silica, and gradient elution by taking an aqueous solution of alkali as a mobile phase A and acetonitrile and/or methanol as a mobile phase B. The detection method can accurately, stably and reliably analyze and detect impurities existing in a process route based on (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride with high sensitivity, and has very important significance for quality research and control of INR101 injection.

Inventors

  • ZHANG NING
  • LEI YONGSHENG
  • SUN JIYUN
  • WAN WUZHOU
  • CHEN JIAN

Assignees

  • 云核医药(天津)有限公司
  • 云南白药集团股份有限公司

Dates

Publication Date
20260512
Application Date
20260213

Claims (9)

  1. 1. The detection method of the (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride related substances is characterized by comprising the following steps of detecting by adopting a high performance liquid chromatography; wherein the chromatographic conditions include: the chromatographic column is octadecylsilane chemically bonded silica chromatographic column; The method comprises the steps of taking an aqueous solution of alkali as a mobile phase A and acetonitrile and/or methanol as a mobile phase B, and performing gradient elution, wherein the gradient elution conditions comprise that the volume ratio of the mobile phase A is 95% -97% in 0-2 min, the volume ratio of the mobile phase A is changed from 95% -97% to 9% -11% in 2-15 min, the volume ratio of the mobile phase A is 9% -11% in 15-20 min, the volume ratio of the mobile phase A is changed from 9% -11% to 95% -97% in 20-20.1 min, and the volume ratio of the mobile phase A is 95% -97% in 20.1-25 min; the related substances comprise structures shown in the following formulas I-III: 、 、 。
  2. 2. The method according to claim 1, wherein the chromatographic column is selected from at least one of Inertsil ODS-4, inertsil ODS-3, AGILENT ECLIPSE XDB C18, waters Xbridge C18, and Shim-PACK GIST C-AQ.
  3. 3. The detection method according to claim 1, wherein the column temperature of the chromatographic column is 20-35 ℃.
  4. 4. The method according to claim 1, wherein the mobile phase a includes at least one of ammonia, triethylamine, diethylamine and ethylenediamine as a base; and/or, in the mobile phase A, the volume fraction of the alkali is 0.01% -0.2%.
  5. 5. The method according to claim 1, wherein the flow rate of the mobile phase is 0.5 to 1.5ml/min.
  6. 6. The method of detection of claim 1, wherein the detector comprises at least one of an ultraviolet detector, a differential detector, an evaporative light scattering detector, an electrospray detector, and a diode array detector.
  7. 7. The method according to claim 1, wherein the detector is a diode array detector with a detection wavelength of 215-225 nm.
  8. 8. The method according to claim 1, wherein the preparation of the test solution comprises dissolving a proper amount of (S) -2-amino-3- [2- (tert-butoxy) -2-oxoacetamido ] propionic acid tert-butyl ester hydrochloride in acetonitrile aqueous solution to a certain volume to obtain the test solution.
  9. 9. The method of claim 1, wherein the chromatographic conditions comprise: the column was Waters Xbridge C18,4.6 mm. Times.150 mm,3.5 μm; The mobile phase A is aqueous ammonia solution with the volume fraction of 0.05%, and the mobile phase B is acetonitrile; the flow rate is 1.0mL/min, and the column temperature is 25 ℃; The detector is a diode array detector, and the detection wavelength is 220nm; the gradient elution procedure was as follows: 。

Description

Method for detecting substances related to (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride Technical Field The invention relates to the technical field of medicine analysis and detection, in particular to a detection method of substances related to (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride. Background INR101 injection belongs to a chemical 1 radioactive diagnosis medicament and is suitable for PET imaging of PSMA positive lesions of prostate cancer patients. The active molecular structure of the PSMA-expressed positive cancer cell comprises a targeting ligand and a radioisotope fluorine F-18, wherein the targeting ligand can be specifically combined with the PSMA-expressed positive cancer cell, the carried fluorine F-18 emits positrons in the decay process, gamma rays are generated through annihilation, and related signals are detected by PET and reconstructed into a quantifiable three-dimensional image, so that the diagnosis of the PSMA-expressed positive focus is realized. (S) -2-amino-3- [2- (tert-butoxy) -2-oxoacetamido ] propionic acid tert-butyl ester hydrochloride is a key starting material for the production of INR101 injection precursors, and has the following structural formula: In the synthesis process of the key starting materials, the following three impurities exist: 、、 Impurity I and impurity II are the remainder of the raw materials in the synthesis process, and impurity III and the key starting materials are isomers. According to ICH M7 impurity toxicity classification principle, impurity I and impurity II are 5 class impurities, and impurity III is 3 class impurities, all need to be controlled. Research of impurities is an important item of medicine development, and includes selecting proper analysis method, accurately distinguishing and measuring impurity content and combining results of pharmaceutical, toxicological and clinical research to determine reasonable limit of impurities. This study extends throughout the process of drug development. Adverse reactions generated in clinical use of the drug are related to the pharmacological activity of the drug itself, and also have a great relationship with impurities existing in the drug. Therefore, research and development of a separation and detection method for the impurities of the key starting materials is particularly important for optimizing the synthesis process and controlling the purity of the key starting materials, so that a foundation is laid for controlling the content of the impurities in the final product of the radioactive diagnosis medicine INR101 injection, and medication safety is ensured. Currently, there is no method in the prior art for analytical detection of substances of interest in (S) -tert-butyl 2-amino-3- [2- (tert-butoxy) -2-oxoacetamido ] propanoate hydrochloride. In view of this, the present invention has been made. Disclosure of Invention The invention aims to provide a detection method of substances related to (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride, which has the characteristics of strong practicability, rapidness, high efficiency, strong specificity, high sensitivity and the like, and can be used for effectively researching impurities of the (S) -2-amino-3- [2- (tert-butoxy) -2-oxo-acetamido ] propionic acid tert-butyl ester hydrochloride. In order to achieve the above object, the first aspect of the present invention provides a method for detecting a substance related to tert-butyl (S) -2-amino-3- [2- (tert-butoxy) -2-oxoacetamido ] propanoate hydrochloride, comprising the steps of detecting by high performance liquid chromatography; wherein the chromatographic conditions include: the chromatographic column is octadecylsilane chemically bonded silica chromatographic column; taking an aqueous solution of alkali as a mobile phase A, and acetonitrile and/or methanol as a mobile phase B, and performing gradient elution; The related substances comprise at least one of structures shown in the following formulas I-III: 、、。 Further, the chromatographic column is selected from at least one of Inertsil ODS-4, inertsil ODS-3, AGILENT ECLIPSE XDB C18, waters Xbridge C18 and Shim-PACK GIST C18-AQ. Further, the column temperature of the chromatographic column is 20-35 ℃. Further, in the mobile phase a, the base includes at least one of ammonia, triethylamine, diethylamine, and ethylenediamine. Further, in the mobile phase A, the volume fraction of the alkali is 0.01% -0.2%. Further, the gradient elution condition comprises the following steps that the volume ratio of the mobile phase A is 95% -97% within 0-2 min, the volume ratio of the mobile phase A is changed from 95% -97% to 9% -11% within 2-15 min, the volume ratio of the mobile phase A is 9% -11% within 15-20 min, the volume ratio of the mobile phase A is changed from 9% -11% to 95% -97% within 20-20