Preparation method of 2-amino-5-nitrophenol impurity
By cyclizing, nitrating and hydrolysis reactions of 2-amino-4-nitrophenol, high-purity 2-amino-4,5-dinitrobenol is prepared, which solves the problem that the impurity is difficult to be prepared efficiently and at low cost in the prior art, and improves the purity and preparation efficiency of the drug.
Patent Information
- Application Number
- CN202411863201.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-17
- Publication Date
- 2025-04-29
AI Technical Summary
In the prior art, the 2-amino-4,5-dinitrobenol impurities produced during the preparation of 2-amino-5-nitrophenol are difficult to be prepared efficiently and at low cost, which affects the purity of the lenatinib raw materials.
2-amino-4-nitrophenol is used as the starting material, and high-purity 2-amino-4,5-dinitrobenol is prepared by cyclization reaction, nitration reaction and hydrolysis reaction, as the standard product for quality control of 2-amino-5-nitrophenol.
The preparation of high-purity 2-amino-4,5-dinitrobenol was achieved, reducing the preparation cost and increasing the purity of the lenatinib raw material.
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Figure CN119899114A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and specifically relates to a method for preparing 2-amino-5-nitrophenol impurities. Background Art
[0002] 2-Amino-5-nitrophenol is an important organic intermediate with wide applications in the fields of medicine, dyes, tobacco, rubber, etc., especially as an important organic intermediate for the breast cancer drug neratinib. Neratinib was first developed by Wyeth in the United States. In July 2014, the results of the Phase III clinical trial of neratinib showed an increase in the survival rate of breast cancer patients. In September 2016, Puma biotechnology submitted a new drug application for neratinib to the US FDA. In July 2017, neratinib was approved for marketing by the US FDA. Neratinib is used as an adjuvant drug for patients who have completed standard trastuzumab treatment. It is the only product in the world approved for enhanced adjuvant treatment after receiving trastuzumab for HER2-positive breast cancer. Impurity synthesis and control is an important part of the quality control of chemical drugs, because most of the impurities in raw materials have potential biological activity, which will eventually affect the safety and efficacy of the drug and even cause toxicity. The impurities in APIs mainly come from process impurities and degradation impurities. The process impurities in APIs are mainly due to the impurities introduced by the starting materials and generated by side reactions. Therefore, quality control of organic intermediates is conducive to obtaining high-quality APIs. 2-amino-5-nitrophenol will produce 2-amino-4,5-dinitrophenol impurities during the preparation process, which will affect the purity of neratinib API. Therefore, it is necessary to prepare this impurity as a standard to control the quality of 2-amino-5-nitrophenol.
[0003] At present, 2-amino-4,5-dinitrophenol is mainly prepared by reacting 2-amino-5-nitrophenol with excess concentrated nitric acid to obtain a small amount of 2-amino-4,5-dinitrophenol, which is then separated by preparative liquid chromatography. This method is relatively expensive. Therefore, it is particularly necessary to develop an efficient and low-cost method for preparing 2-amino-5-nitrophenol impurities. Summary of the invention
[0004] In order to solve the defects in the prior art, the present invention provides a method for preparing 2-amino-5-nitrophenol impurities.
[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:
[0006] The present invention provides a method for preparing 2-amino-5-nitrophenol impurities, comprising the following steps:
[0007] Step 1: Add 2-amino-4-nitrophenol (1) and a small amount of water and stir, add w(H2SO4)=98% concentrated sulfuric acid dropwise to dissolve, add urea, heat to 120-125°C, and then slowly add w(H2SO4)=98% concentrated sulfuric acid dropwise to keep the pH of the mixture at 2-3; after adding the concentrated sulfuric acid, continue to keep warm and stir; finally, add water, cool to room temperature, needle-shaped crystals precipitate, wash, filter and dry to obtain a cyclocompound (2);
[0008] Step 2: dissolving the cyclocompound (2) prepared in step 1 in a solvent, adding a mixed acid composed of concentrated sulfuric acid and concentrated nitric acid dropwise, heating to carry out a nitration reaction, cooling to 20-30° C. after the reaction is completed, filtering and drying to obtain a nitrated product (3);
[0009] Step 3: dissolving the nitrate (3) prepared in step 2 in a solvent, first dropping a sodium hydroxide solution with a concentration of 10-15%, heating to 80-100° C. for reaction, cooling to 20-30° C. after the reaction, adjusting the pH of the mixture to 6-7 with hydrochloric acid, filtering, washing with water, and drying to obtain 2-amino-4,5-dinitrophenol (4);
[0010] The chemical formula for preparing 2-amino-5-nitrophenol impurity is as follows:
[0011]
[0012] Preferably, in step 1, the mass ratio of 2-amino-4-nitrophenol to concentrated sulfuric acid is 1:2-5, and the molar ratio of 2-amino-4-nitrophenol to urea is 1:1-2.
[0013] Preferably, the stirring time in step 1 is 3-5h.
[0014] Preferably, in step 2, the mass ratio of the cyclocompound (2) to the solvent is 1:2-5, the molar ratio of the cyclocompound (2) to concentrated nitric acid is 1:1-1.5; the concentration of the concentrated sulfuric acid is 98%, the concentration of the concentrated nitric acid is 68%, and the volume ratio of the concentrated sulfuric acid to the concentrated nitric acid is 1:1.
[0015] Preferably, in step 3, the mass ratio of the nitrate (3) to the solvent is 1:2-5, and the molar ratio of the nitrate (3) to sodium hydroxide is 1:1-2.
[0016] Preferably, the nitration reaction time in step 3 is 6-8h.
[0017] Preferably, the solvent in step 2 is any one of water, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methanol, ethanol, ethyl acetate, toluene, dichloromethane, chloroform, and dichloroethane, or any combination of several thereof.
[0018] Preferably, the solvent in step 3 is any one of water, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methanol, ethanol, ethyl acetate, toluene, dichloromethane, chloroform, and dichloroethane, or any combination of several thereof.
[0019] Compared with the prior art, the present invention has the following beneficial effects:
[0020] The invention uses 2-amino-4-nitrophenol as a starting material, and obtains high-purity 2-amino-4,5-dinitrophenol through cyclization reaction, nitration reaction and hydrolysis reaction. The high-purity 2-amino-4,5-dinitrophenol can be used as a standard product for quality control of synthesizing 2-amino-5-nitrophenol. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 It is the liquid chromatogram of 2-amino-5-nitrophenol in the present invention.
[0022] Figure 2 The liquid chromatogram of the impurities of 2-amino-5-nitrophenol prepared by the method of the present invention is shown. DETAILED DESCRIPTION
[0023] The preferred embodiments of the present invention are described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.
[0024] Example 1: Preparation of 2-amino-5-nitrophenol impurity.
[0025] Step 1: Add 2-amino-4-nitrophenol (0.50 mol, 77.0 g) and 50 mL of water into a 500 mL three-necked round-bottom flask, add dropwise 70 mL of concentrated sulfuric acid (w(H2SO4)=98%), stir until dissolved, add urea (0.8 mol, 48.0 g), stir and heat to 120-125° C., and at the same time, add dropwise 65 mL of concentrated sulfuric acid (w(H2SO4)=98%) into the flask within 5 h, keeping the pH of the mixture at 2-3; after adding the concentrated sulfuric acid, continue heating and stirring until the peak of the liquid raw material is <1% when sampled and detected, then add 400 mL of water, cool to room temperature, needle-shaped crystals precipitate, filter, wash and dry to obtain 81.9 g of cyclocompound (2), with a product yield of 91.0%.
[0026] Step 2: Add the cyclocompound (2) (0.35 mol, 63.0 g) and 200 g of dichloroethane into a 500 mL three-necked flask, and under nitrogen protection, dropwise add the pre-mixed acid (28 ml of 68% concentrated nitric acid and 28 ml of 98% concentrated sulfuric acid, the molar number of concentrated nitric acid is 0.42 mol). After 1 h of dropping, heat to 60°C and keep warm for 5 h until the liquid raw material peak is <1% after sampling. Then cool to room temperature, filter, wash and dry to obtain 68.1 g of brown-yellow nitrate (3) with a yield of 86.5%.
[0027] Step 3: Add the nitrate (3) (0.30 mol, 67.5 g) and 150 g of methanol into a 500 mL three-necked flask, slowly drop 15% sodium hydroxide (0.45 mol, 120.0 g) under nitrogen protection, heat and reflux for 6 h after the dropwise addition, evaporate the methanol and recover it, add activated carbon for decolorization, filter, adjust the filtrate to pH = 5 with hydrochloric acid, precipitate the product, filter, wash and dry to obtain 50.4 g of yellow solid 2-amino-4,5-dinitrophenol, with a yield of 84.5%.
[0028] Example 2: Preparation of 2-amino-5-nitrophenol impurity.
[0029] Step 1: Add 2-amino-4-nitrophenol (0.50 mol, 77.0 g) and 50 mL of water into a 500 mL three-necked round-bottom flask, add dropwise 70 mL of concentrated sulfuric acid (w(H2SO4)=98%), stir until dissolved, add urea (0.7 mol, 42.0 g), stir and heat to 120-125° C., and at the same time, add dropwise 65 mL of concentrated sulfuric acid (w(H2SO4)=98%) into the flask within 5 h, keeping the pH of the mixture at 2-3; after adding the concentrated sulfuric acid, continue heating and stirring until the peak of the liquid raw material is <1% when sampled and detected, then add 400 mL of water, cool to room temperature, needle-shaped crystals precipitate, filter, wash and dry to obtain 76.5 g of cyclocompound (2), with a product yield of 85.0%.
[0030] Step 2: Add the cyclocompound (2) (0.35 mol, 63.0 g) and 200 g of toluene into a 500 mL three-necked flask, and under nitrogen protection, dropwise add the pre-mixed acid (28 ml of 68% concentrated nitric acid and 28 ml of 98% concentrated sulfuric acid, the molar number of concentrated nitric acid is 0.42 mol). After 1 h of dropping, heat to 60°C and keep warm for 5 h until the liquid raw material peak is <1% when sampled and detected. Then cool to room temperature, filter, wash and dry to obtain 62.4 g of brown-yellow nitrate (3) with a yield of 79.3%.
[0031] Step 3: Add the nitrate (3) (0.30 mol, 67.5 g) and 150 g of ethanol into a 500 mL three-necked flask, slowly drop 15% sodium hydroxide (0.45 mol, 120.0 g) under nitrogen protection, heat and reflux for 6 h after the dropwise addition, evaporate the ethanol and recover it, add activated carbon for decolorization, filter, adjust the filtrate to pH = 5 with hydrochloric acid, precipitate the product, filter, wash and dry to obtain 48.5 g of yellow solid 2-amino-4,5-dinitrophenol, with a yield of 81.3%.
[0032] Example 3: Preparation of 2-amino-5-nitrophenol impurity.
[0033] Step 1: Add 2-amino-4-nitrophenol (0.50 mol, 77.0 g) and 50 mL of water into a 500 mL three-necked round-bottom flask, add dropwise 70 mL of concentrated sulfuric acid (w(H2SO4)=98%), stir until dissolved, add urea (0.8 mol, 48.0 g), stir and heat to 120-125° C., and at the same time, add dropwise 65 mL of concentrated sulfuric acid (w(H2SO4)=98%) into the flask within 5 h, keeping the pH of the mixture at 2-3; after adding the concentrated sulfuric acid, continue heating and stirring until the peak of the liquid raw material is <1% when sampled and detected, then add 400 mL of water, cool to room temperature, needle-shaped crystals precipitate, filter, wash and dry to obtain 81.9 g of cyclocompound (2), with a product yield of 91.0%.
[0034] Step 2: Add the cyclocompound (2) (0.35 mol, 63.0 g) and 200 g of dichloroethane into a 500 mL three-necked flask, and under nitrogen protection, dropwise add the pre-mixed acid (31 ml of 68% concentrated nitric acid and 28 ml of 98% concentrated sulfuric acid, the molar number of concentrated nitric acid is 0.46 mol). After 1 h of dropping, heat to 60° C. and keep warm for 5 h until the liquid raw material peak is <1% when sampled and detected. Then cool to room temperature, filter, wash and dry to obtain 68.5 g of brown-yellow nitrate (3), with a yield of 87.0%.
[0035] Step 3: Add the nitrate (3) (0.30 mol, 67.5 g) and 150 g of methanol into a 500 mL three-necked flask, slowly drop 15% sodium hydroxide (0.42 mol, 112.0 g) under nitrogen protection, heat and reflux for 6 h after the dropwise addition, evaporate the methanol and recover it, add activated carbon for decolorization, filter, adjust the filtrate to pH = 5 with hydrochloric acid, precipitate the product, filter, wash and dry to obtain 59.0 g of yellow solid 2-amino-4,5-dinitrophenol, with a yield of 82.1%.
[0036] The following liquid chromatography was used to analyze 2-amino-5-nitrophenol (results are shown in Figure 1 ) and the prepared 2-amino-5-nitrophenol impurity (results see Figure 2) for liquid chromatography detection.
[0037] Liquid chromatograph: Shimadzu LC-20AD, SPD-20A UV detector;
[0038] Chromatographic workstation: Zheda Zhida N2000;
[0039] Mobile phase: Volume ratio: methanol: water = 50:50, add 1 ml of formic acid for every 100 L of mobile phase;
[0040] Flow rate: 0.5 mL / min;
[0041] Wavelength: 254nm;
[0042] Column temperature: room temperature;
[0043] Chromatographic column model: C18, 4.6*150mm.
[0044] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing 2-amino-5-nitrophenol impurities, characterized in that: The following steps are involved: Step 1: Add 2-amino-4-nitrophenol (1) and a small amount of water and stir, add w(H2SO4)=98% concentrated sulfuric acid dropwise to dissolve, add urea, heat to 120-125°C, and then slowly add w(H2SO4)=98% concentrated sulfuric acid dropwise to keep the pH of the mixture at 2-3; after adding the concentrated sulfuric acid, continue to keep warm and stir; finally, add water, cool to room temperature, needle-shaped crystals precipitate, wash, filter and dry to obtain a cyclocompound (2); Step 2: dissolving the cyclocompound (2) prepared in step 1 in a solvent, adding a mixed acid composed of concentrated sulfuric acid and concentrated nitric acid dropwise, heating to carry out a nitration reaction, cooling to 20-30° C. after the reaction is completed, filtering and drying to obtain a nitrated product (3); Step 3: dissolving the nitrate (3) prepared in step 2 in a solvent, first dropping a sodium hydroxide solution with a concentration of 10-15%, heating to 80-100° C. for reaction, cooling to 20-30° C. after the reaction, adjusting the pH of the mixture to 6-7 with hydrochloric acid, filtering, washing with water, and drying to obtain 2-amino-4,5-dinitrophenol (4); The chemical formula for preparing 2-amino-5-nitrophenol impurity is as follows:
2. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: In the step 1, the mass ratio of 2-amino-4-nitrophenol to concentrated sulfuric acid is 1:2-5, and the molar ratio of 2-amino-4-nitrophenol to urea is 1:1-2.
3. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: The stirring time in step 1 is 3-5h.
4. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: In step 2, the mass ratio of the cyclocompound (2) to the solvent is 1:2-5, the molar ratio of the cyclocompound (2) to concentrated nitric acid is 1:1-1.5; the concentration of the concentrated sulfuric acid is 98%, the concentration of the concentrated nitric acid is 68%, and the volume ratio of the concentrated sulfuric acid to the concentrated nitric acid is 1:
1.
5. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: In the step 3, the mass ratio of the nitrate (3) to the solvent is 1:2-5, and the molar ratio of the nitrate (3) to sodium hydroxide is 1:1-2.
6. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: The nitration reaction time in step 3 is 6-8h.
7. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: The solvent in step 2 is any one of water, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methanol, ethanol, ethyl acetate, toluene, dichloromethane, chloroform, and dichloroethane, or any combination of several thereof.
8. The method for preparing 2-amino-5-nitrophenol impurities according to claim 1, characterized in that: The solvent in step 3 is any one of water, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, methanol, ethanol, ethyl acetate, toluene, dichloromethane, chloroform, and dichloroethane, or any combination thereof.