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CN-122017056-A - HPLC quantitative detection method for o-methylbenzyl chloride and impurities thereof

CN122017056ACN 122017056 ACN122017056 ACN 122017056ACN-122017056-A

Abstract

The invention belongs to the technical field of analysis and detection, and particularly relates to an HPLC quantitative detection method for o-methylbenzyl chloride and impurities thereof. Preparing blank solution, test solution and reference solution, respectively injecting the blank solution, the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, calculating according to a peak area normalization method to obtain the content of o-methylbenzyl chloride in the test solution, calculating according to an external standard method to obtain the content of o-dichlorobenzyl and/or o-xylene in the test solution according to a peak area, and calculating according to a main component self-comparison method to obtain the content of other impurities in the test solution. The main peak and each impurity peak of the invention have good separation degree, and have excellent precision, accuracy, stability, durability and repeatability. Provides a detection technology for the quality control of o-methyl benzyl chloride.

Inventors

  • WANG FURONG
  • WANG YIYUN
  • WU HUI

Assignees

  • 山东新华制药股份有限公司

Dates

Publication Date
20260512
Application Date
20251210

Claims (9)

  1. 1. An HPLC quantitative detection method for o-methylbenzyl chloride and impurities thereof is characterized in that a blank solution, a test solution and a reference solution are prepared, the blank solution, the test solution and the reference solution are respectively injected into a liquid chromatograph, a chromatogram is recorded, the content of the o-methylbenzyl chloride in the test solution is calculated according to a peak area normalization method, the content of the impurities o-dichlorobenzyl and/or o-xylene in the test solution is calculated according to an external standard method and the content of other impurities in the test solution is calculated according to a main component self-contrast method; The structural formula of the o-methyl benzyl chloride is as follows: ; the structural formula of the o-dichlorobenzene is as follows: ; the structural formula of ortho-xylene is as follows: ; The chromatographic conditions in the HPLC method comprise a mobile phase, wherein the mobile phase takes phosphoric acid aqueous solution as a mobile phase A and methanol as a mobile phase B; the chromatographic conditions also comprise a gradient elution program, wherein the gradient elution program comprises 0-2 minutes, 35-45% of the total volume of the mobile phase, 55-65% of the total volume of the mobile phase, 25-35% of the total volume of the mobile phase, 65-75% of the total volume of the mobile phase, 15-20 minutes, 25-35% of the total volume of the mobile phase, 65-75% of the total volume of the mobile phase, 20-25 minutes, 35-45% of the total volume of the mobile phase, 55-65% of the total volume of the mobile phase, 25-30 minutes, 35-45% of the total volume of the mobile phase and 55-65% of the total volume of the mobile phase.
  2. 2. The quantitative HPLC detection method for o-methylbenzyl chloride and impurities thereof according to claim 1, wherein the preparation method of the sample solution is characterized in that an o-methylbenzyl chloride sample is weighed, dissolved and diluted by a solvent to prepare the sample solution, and the concentration of the o-methylbenzyl chloride in the sample solution is 0.4-0.6mg/mL.
  3. 3. The quantitative HPLC detection method for o-methylbenzyl chloride and impurities thereof according to claim 1, wherein the preparation method of the reference solution is characterized in that a stock solution of any one single component or mixed components of o-dichlorobenzyl chloride, o-xylene and o-methylbenzyl chloride is diluted by a solvent to prepare the reference solution, and the concentration of any one single component or mixed components of the o-dichlorobenzyl chloride, the o-xylene and the o-methylbenzyl chloride in the reference solution is 0.25-7.5 mug/mL.
  4. 4. The method for quantitatively detecting o-methylbenzyl chloride and impurities thereof by HPLC according to claim 3, wherein the stock solution is prepared by respectively weighing o-dichlorobenzyl chloride, o-xylene and o-methylbenzyl chloride reference substances, dissolving and diluting the reference substances by a solvent to prepare a stock solution containing any single component or mixed components of the o-dichlorobenzyl chloride, the o-xylene and the o-methylbenzyl chloride, wherein the concentration of any single component or mixed component of the solution of any single component of the o-dichlorobenzyl chloride, the o-xylene and the o-methylbenzyl chloride is 2.5-1200 mug/mL.
  5. 5. The method for quantitative HPLC detection of o-methylbenzyl chloride and its impurities according to any one of claims 2-4, wherein the solvent is acetonitrile.
  6. 6. The method for quantitative HPLC detection of o-methylbenzyl chloride and its impurities according to claim 1, wherein mobile phase a is 0.05wt.% to 0.2 wt wt.% phosphoric acid aqueous solution.
  7. 7. The quantitative HPLC detection method for o-methylbenzyl chloride and impurities thereof according to claim 1, wherein the parameter conditions of the liquid chromatography comprise that the chromatographic column is a C18 column with octadecylsilane chemically bonded silica as a filler, and the column temperature of the chromatographic column is 38-42 ℃.
  8. 8. The quantitative HPLC detection method for o-methylbenzyl chloride and impurities thereof according to claim 7, wherein the parameter conditions of the liquid chromatograph comprise that the detector is a DAD/PDA detector or an ultraviolet detector, and the detection wavelength is 218-222nm.
  9. 9. The method for quantitative detection of o-methylbenzyl chloride and impurities thereof by HPLC according to claim 1, wherein the total flow rate of mobile phase A and mobile phase B is 0.95-1.05mL/min.

Description

HPLC quantitative detection method for o-methylbenzyl chloride and impurities thereof Technical Field The invention belongs to the technical field of analysis and detection, and particularly relates to an HPLC quantitative detection method for o-methylbenzyl chloride and impurities thereof. Background O-methylbenzyl chloride with chemical name of 2-methylbenzyl chloride and molecular formula of C 8H9 Cl and molecular weight of 140.61. The structural formula is as follows: . The o-methyl benzyl chloride is colorless or faint yellow liquid, is an initial raw material of an innovative drug LXH-1211 for treating pulmonary arterial hypertension, and is also an important raw material or intermediate for synthesizing drugs such as non-steroidal anti-inflammatory drugs ibuprofen, antihistaminic drugs chlorpheniramine, antifungal drugs clotrimazole derivatives and the like. The o-methyl benzyl chloride is prepared with o-xylene as initial material and through reaction with chlorine gas, and may have o-xylene residue, o-dichlorobenzyl byproduct and other technological impurities. In the synthesis and preparation process of the o-methylbenzyl chloride, the content of the existing process impurities plays a key role in the quality of each drug end product prepared by taking the o-methylbenzyl chloride as a starting material or an intermediate, so that the quality control of the o-methylbenzyl chloride is particularly important. Patent CN119500024A discloses an o-methyl benzyl chloride production process and a production system thereof, and up to the present, the research literature data of the detection method of the o-methyl benzyl chloride is less. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide the HPLC quantitative detection method for the o-methylbenzyl chloride and the impurities thereof, and the method has the advantages of good separation degree between a main peak and each impurity peak, and excellent precision, accuracy, stability, durability and reproducibility, and provides an analysis means for the quality control of the o-methylbenzyl chloride, thereby more effectively controlling the quality of a medical final product obtained by taking the o-methylbenzyl chloride as a raw material or an intermediate. Preparing a blank solution, a test sample solution and a reference sample solution, respectively injecting the blank solution, the test sample solution and the reference sample solution into a liquid chromatograph, recording a chromatogram, calculating according to a peak area normalization method to obtain the content of the o-methylbenzyl chloride in the test sample solution, calculating according to an external standard method and a peak area to obtain the content of the o-dichlorobenzyl and/or o-xylene serving as impurities in the test sample solution, and calculating according to a main component self-comparison method to obtain the content of other impurities in the test sample solution; The structural formula of the o-methyl benzyl chloride is as follows: ; the structural formula of the o-dichlorobenzene is as follows: ; the structural formula of ortho-xylene is as follows: ; The chromatographic conditions in the HPLC method comprise a mobile phase, wherein the mobile phase takes phosphoric acid aqueous solution as a mobile phase A and methanol as a mobile phase B; the chromatographic conditions also comprise a gradient elution program, wherein the gradient elution program comprises 0-2 minutes, 35-45% of the total volume of the mobile phase, 55-65% of the total volume of the mobile phase, 25-35% of the total volume of the mobile phase, 65-75% of the total volume of the mobile phase, 15-20 minutes, 25-35% of the total volume of the mobile phase, 65-75% of the total volume of the mobile phase, 20-25 minutes, 35-45% of the total volume of the mobile phase, 55-65% of the total volume of the mobile phase, 25-30 minutes, 35-45% of the total volume of the mobile phase and 55-65% of the total volume of the mobile phase. The preparation method of the test solution comprises the steps of weighing an o-methylbenzyl chloride sample, dissolving the o-methylbenzyl chloride sample in a solvent, and diluting the o-methylbenzyl chloride sample to prepare the test solution, wherein the concentration of the o-methylbenzyl chloride in the test solution is 0.4-0.6mg/mL. The preparation method of the reference solution comprises the steps of diluting stock solution of any single component or mixed component of o-dichlorobenzyl, o-xylene and o-methylbenzyl chloride with a solvent to prepare the reference solution, wherein the concentration of any single component in the solution of any single component or mixed component of o-dichlorobenzyl, o-xylene and o-methylbenzyl chloride in the reference solution is 0.25-7.5 mug/mL. The preparation method of the stock solution comprises the steps of respectively weighing o-dichlorobenzyl chloride, o-xylene and o-methylbenzyl chloride re