Preparation method and application of metoclopramide nitrosamine impurity

Abstract

The invention relates to a preparation method and application of metoclopramide nitrosamine impurities. The preparation method comprises the following steps: adding 4-amino-5-chloro-N-[2-(ethylamino) ethyl]-2-methoxybenzamide and a reaction solvent into a beaker, stirring while adding a nitrosation reagent, controlling the temperature at 20-30 DEG C, and reacting for 5-20 hours; after the reaction is finished, column chromatography silica gel is added, a sample is stirred, after concentration, the stirred sample is subjected to column chromatography purification, and 4-amino-5-chloro-N-(2-(ethyl (nitroso) amino) ethyl)-2-methoxybenzamide is obtained; the application blank of the impurity in a high-end quality control scene in metoclopramide is filled.

Description

Technical Field

[0001] This invention relates to the field of chemical engineering, specifically to a method for preparing nitrosamine impurities from metoclopramide and its application. Background Technology

[0002] Nitrosamine impurities in metoclopramide, simply put, are a class of harmful compounds that may be introduced during the production process. These compounds pose a carcinogenic risk and require strict control. These impurities are typically generated during the synthesis of the active pharmaceutical ingredient (API) from the reaction of amines with nitrosating agents, such as N-nitrosodimethylamine. They are potent carcinogens, and long-term exposure may increase the risk of liver and stomach cancer; even extremely low concentrations (ppm or ppb levels) can accumulate harmful effects. In drug production, nitrosamines may originate from side reactions during API synthesis, reagent residues, or cross-contamination due to incomplete equipment cleaning. Therefore, regulatory agencies exercise very strict control over these impurities, making nitrosamine impurities a key focus of drug safety monitoring due to their potential health risks. Currently, there is no existing technology demonstrating the preparation method or application of nitrosamine impurities in metoclopramide. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a method for preparing nitrosamine impurities in metoclopramide and its application, which overcomes the deficiencies in existing technologies and fills the application gap of this impurity in high-end quality control scenarios of metoclopramide.

[0004] The technical solution of this invention is achieved as follows: a method for preparing metoclopramide nitrosamine impurities, the method comprising the following steps: S1. Add 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide.

[0005] A method for preparing metoclopramide nitrosamine impurities, the method comprising the following steps S1. Add metoclopramide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain N-nitrosomethoxychlorpromazine.

[0006] The nitrosating agents include tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid.

[0007] The reaction solvents include ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0008] An application of the nitrosamine impurity in metoclopramide as described in claim 1 involves using 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide for quantitative analysis of genotoxic impurities in metoclopramide. The results show that the concentration of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide in metoclopramide is less than 3.720 ug / g.

[0009] An application of the nitrosamine impurity of metoclopramide as described in claim 2 involves using N-nitrosometoclopramide for quantitative analysis of genotoxic impurities in the metoclopramide drug. According to the detection results, the amount of N-nitrosometoclopramide in metoclopramide is less than 3.720 ug / g.

[0010] This invention offers the following advantages: It provides a simple method for preparing nitrosamine impurities in metoclopramide and directly uses the prepared products for quantitative analysis of genotoxic impurities in metoclopramide, filling a gap in the application of this impurity in high-end quality control scenarios. The 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide and N-nitrosometoclopramide prepared by this invention are nitrosamine impurities that may be present in metoclopramide. Their chemical and structural formulas are clearly defined, facilitating pathological research; simultaneously, they can be used as impurity monitoring in the metoclopramide synthesis process for establishing quality standards for metoclopramide. The limit requirement for the 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide impurity in metoclopramide is 662.5 ng / g, filling a gap in the application of this impurity in high-end quality control scenarios for metoclopramide. The limit requirement for N-nitrosomethoclopramide in metoclopramide is 37.5 ug / g, filling the gap in the application of this impurity in high-end quality control scenarios of metoclopramide. Attached Figure Description

[0011] Figure 1 This is the synthetic route for 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide of the present invention.

[0012] Figure 2 This is the mass spectrum of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide of the present invention.

[0013] Figure 3 The present invention relates to 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide. 1 H nuclear magnetic resonance spectrum.

[0014] Figure 4 This is a synthetic route diagram for N-nitrosomethoxychloramphenicolamine according to the present invention.

[0015] Figure 5 This is the mass spectrum of N-nitrosomethoxychlorpromazine of the present invention.

[0016] Figure 6 The present invention is N-nitrosomethoxychlorpromazine. 1 H nuclear magnetic resonance spectrum. Detailed Implementation

[0017] like Figure 1 , 2 As shown in Figures 3, 4, 5, and 6, a method for preparing a metoclopramide nitrosamine impurity includes the following steps: S1. Add 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide.

[0018] A method for preparing metoclopramide nitrosamine impurities, the method comprising the following steps S1. Add metoclopramide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain N-nitrosomethoxychlorpromazine.

[0019] The nitrosating agent includes tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid. The reaction solvent includes ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0020] An application of nitrosamine impurities in metoclopramide involves the quantitative analysis of genotoxic impurities in metoclopramide using 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide. The results show that the concentration of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide in metoclopramide is less than 3.720 ug / g.

[0021] An application of N-nitrosomethoprim to quantify genotoxic impurities in metoclopramide was disclosed. The results showed that the concentration of N-nitrosomethoprim in metoclopramide was less than 3.720 μg / g.

[0022] Example 1: 2.00 g of 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide and 20.00 g of reaction solvent were added to a 50 mL flask. 1.14 g of tert-butyl nitrite, a nitrosating agent, was added with stirring, and the mixture was reacted at 20°C to 30°C for 5 to 20 hours. After the reaction, 6.00 g of silica gel for column chromatography was added, the sample was stirred, concentrated, and then purified by column chromatography to obtain 0.6 g of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide. Yield: 27.11%, LC-MS: 301.2 [M+H] + .

[0023] The nitrosating agent includes tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid. The reaction solvent includes ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0024] Example 2: 2.00 g of 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide and 20.00 g of reaction solvent were added to a 50 mL flask. 1.29 g of isoamyl nitrite, a nitrosating agent, was added with stirring, and the mixture was reacted at 20°C to 30°C for 5 to 20 hours. After the reaction was complete, 6.00 g of silica gel for column chromatography was added, the sample was stirred, concentrated, and then purified by column chromatography to obtain 0.9 g of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide. Yield: 40.66%.

[0025] The nitrosating agent includes tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid. The reaction solvent includes ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0026] In Examples 1 and 2 above, the reaction raw materials include, but are not limited to: 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide, 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide hydrochloride, or 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide acid salt. The 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide prepared in this invention is a nitrosamine impurity that may be present in metoclopramide. Its chemical formula and structural formula have been clarified, facilitating pathological research; it can also be used as an impurity monitoring agent in the synthesis process of metoclopramide, for the formulation of metoclopramide quality standards. The limit requirement for this impurity in metoclopramide is 662.5 ng / g, filling the application gap of this impurity in high-end quality control scenarios in metoclopramide.

[0027] Example 3: 2.00 g of metoclopramide and 20.00 g of reaction solvent were added to a 50 mL flask. 1.03 g of tert-butyl nitrite, a nitrosating agent, was added with stirring, and the mixture was reacted at 20°C to 30°C for 5 to 20 hours. After the reaction, 6.00 g of silica gel for column chromatography was added, the sample was stirred, concentrated, and then purified by column chromatography to obtain 0.51 g of N-nitrosometoclopramide. Yield: 23.25%, LC-MS: 329.18 [M+H] + .

[0028] The nitrosating agent includes tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid. The reaction solvent includes ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0029] Example 4: 2.00 g of metoclopramide and 20.00 g of reaction solvent were added to a 50 mL flask. 1.17 g of isoamyl nitrite, a nitrosating agent, was added with stirring. The mixture was then reacted at 20°C to 30°C for 5 to 20 hours. After the reaction was complete, 6.00 g of silica gel for column chromatography was added, the sample was stirred, concentrated, and then purified by column chromatography to obtain 0.80 g of N-nitrosometoclopramide. Yield: 36.47%.

[0030] The nitrosating agent includes tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid. The reaction solvent includes ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

[0031] In Examples 3 and 4 above, the reaction raw materials include, but are not limited to, metoclopramide, metoclopramide hydrochloride, or metoclopramide acid salt. Metoclopramide undergoes a nitrosation reaction with a nitrosating agent to obtain N-nitrosometoclopramide, which is then purified by column chromatography. The obtained N-nitrosometoclopramide was directly used for the quantitative analysis of genotoxic impurities in metoclopramide. Based on multiple batch tests, the results showed that the concentration of N-nitrosometoclopramide in metoclopramide was less than 3.720 μg / g, filling a gap in the application of this impurity in high-end quality control scenarios.

[0032] Example 5: 4-Amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide prepared in Example 1 or Example 2 was used for the quantitative analysis of genotoxic impurities in metoclopramide. The results showed that the concentration of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide in metoclopramide was less than 3.720 μg / g. This fills a gap in the application of this impurity in high-end quality control scenarios.

[0033] Example 6: The N-nitrosomethoclopramide prepared in Example 3 or Example 4 was used for quantitative analysis of genotoxic impurities in metoclopramide. The results showed that the concentration of N-nitrosomethoclopramide in metoclopramide was less than 3.720 μg / g. This fills a gap in the application of this impurity in high-end quality control scenarios.

[0034] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing metoclopramide nitrosamine impurities, characterized in that, The method includes the following steps: S1. Add 4-amino-5-chloro-N-[2-(ethylamino)ethyl]-2-methoxybenzamide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide.

2. A method for preparing metoclopramide nitrosamine impurities, characterized in that, The method includes the following steps S1. Add metoclopramide and the reaction solvent to a beaker, stir and add nitrosating agent, control the temperature to 20℃ to 30℃, and react for 5h to 20h. S2. After the reaction is complete, add silica gel for column chromatography and mix the sample. After concentration, purify the mixed sample by column chromatography to obtain N-nitrosomethoxychlorpromazine.

3. The method for preparing metoclopramide nitrosamine impurities according to claim 1 or 2, characterized in that: The nitrosating reagents include tert-butyl nitrite, isoamyl nitrite, or a combination of sodium nitrite with hydrochloric acid, sulfuric acid, acetic acid, or hydrobromic acid.

4. The method for preparing metoclopramide nitrosamine impurities according to claim 1 or 2, characterized in that: The reaction solvents include ethanol, methanol, acetone, dichloromethane, 1,4-dioxane, or water.

5. An application of the metoclopramide nitrosamine impurity as described in claim 1, characterized in that: 4-Amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide was used for the quantitative analysis of genotoxic impurities in metoclopramide. According to the detection results, the content of 4-amino-5-chloro-N-(2-(ethyl(nitroso)amino)ethyl)-2-methoxybenzamide in metoclopramide was less than 3.720 ug / g.

6. An application of the metoclopramide nitrosamine impurity as described in claim 2, characterized in that: N-nitrosomethoclopramide was used for the quantitative analysis of genotoxic impurities in metoclopramide. The results showed that the concentration of N-nitrosomethoclopramide in metoclopramide was less than 3.720 ug / g.

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