Novel synthetic preparation method of medical intermediate 2-(4-nitrophenyl) butyric acid
By reacting nitrochlorobenzene with alkyl cyanoacetate and hydrolyzing diethyl sulfate, the problems of complex operation and high cost in the preparation of 2-(4-nitrophenyl)butyric acid in the prior art have been solved, and the preparation of products with high yield and high purity has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-10
- Publication Date
- 2026-03-27
AI Technical Summary
Existing methods for preparing 2-(4-nitrophenyl)butyric acid suffer from problems such as cumbersome operation steps, low yield, difficulty in separating isomer impurities, and high cost.
2-cyano-2-(4-nitrophenyl)acetoacetic acid alkyl ester was generated by reacting p-nitrochlorobenzene with alkyl cyanoacetate under alkaline conditions, then reacted with diethyl sulfate, and finally hydrolyzed in a mixed system of concentrated sulfuric acid and acetic acid to obtain 2-(4-nitrophenyl)butyric acid.
A high-yield and low-cost preparation process was achieved, with high product purity and no isomer impurities such as 2-(2-nitrophenyl)butyric acid. The process is simple and easy to operate.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of pharmaceutical fine chemicals, and particularly relates to a new preparation method of a pharmaceutical intermediate 2-(4-nitrophenyl) butyric acid. BACKGROUND
[0002] Indobufen is an anti-platelet aggregation drug, mainly used for treating ischemic cardiovascular diseases, ischemic cerebrovascular diseases and venous thrombosis caused by arteriosclerosis. The drug has a similar anti-platelet aggregation mechanism as aspirin, but has lower side effects, and is particularly suitable for the treatment of senile peripheral vascular diseases. 2-(4-nitrophenyl) butyric acid is an important starting material for preparing indobufen. At present, there are various preparation processes for 2-(4-nitrophenyl) butyric acid. For example, benzyl cyanide is reacted with bromoethane under alkaline conditions to generate 2-phenyl butyric acid, which is then nitrified to obtain; or 2-phenyl butyronitrile is nitrified and purified to obtain 2-(4-nitrophenyl) butyronitrile, which is then hydrolyzed under acidic conditions of sulfuric acid to obtain the target product 2-(4-nitrophenyl) butyric acid. A method for preparing 2-(4-nitrophenyl) butyric acid is disclosed in Chinese patent document (application number 20211145915.2), which comprises adding p-nitrohalobenzene and acetoacetic acid alkyl ester into a solvent, and reacting under the action of sodium alcoholate or sodium hydride to obtain 2-(4-nitrophenyl) acetoacetic acid alkyl ester; then reducing under alkaline conditions with hydrazine hydrate, and then adjusting the pH to 4-6 to obtain 2-(4-nitrophenyl) butyric acid by crystallization. However, the existing preparation methods all have technical defects, such as complicated operation steps, low yield, or difficulty in separation and purification of isomer impurities. The reduction of 2-(4-nitrophenyl) acetoacetic acid alkyl ester requires high temperature, and the cost is high. Therefore, there is an urgent need for a method to prepare high-quality 2-(4-nitrophenyl) butyric acid with high yield, low cost and green environmental protection. SUMMARY
[0003] The application aims to provide a preparation method of a pharmaceutical intermediate 2-(4-nitrophenyl) butyric acid. P-nitrochlorobenzene and cyanoacetic acid alkyl ester are used as raw materials to prepare the intermediate 2-cyano-2-(4-nitrophenyl) acetoacetic acid alkyl ester, which is then reacted with diethyl sulfate under alkaline conditions to obtain 2-cyano-2-(4-nitrophenyl) butyric acid alkyl ester. Finally, 2-cyano-2-(4-nitrophenyl) butyric acid is obtained by hydrolysis in a concentrated sulfuric acid and acetic acid mixed system. The raw materials and reagents used in the application are cheap and easy to obtain, the process is simple and easy to implement, and has a significant cost advantage. At the same time, the reaction route adopted by the application does not generate 2-(2-nitrophenyl) butyric acid and other isomer impurities, and has high yield and good product quality.
[0004] In order to achieve the purpose of the application, the technical scheme adopted is: A method for preparing a pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid, comprising the following steps: Step one, adding p-nitrochlorobenzene and acetoacetic acid alkyl ester into a solvent, heating and stirring under the action of a base until the raw material is reacted completely, adding 20% sulfuric acid to adjust the pH value to 1.5-2, and filtering to obtain 2-cyano-2-(4-nitrophenyl)acetoacetic acid alkyl ester.
[0005] Step two, adding 2-cyano-2-(4-nitrophenyl)acetoacetic acid alkyl ester obtained in step one and diethyl sulfate into a solvent, heating and stirring under the action of a base until the raw material is reacted completely, and filtering to obtain 2-(4-nitrophenyl)butyric acid alkyl ester.
[0006] Step three, adding 2-cyano-2-(4-nitrophenyl)butyric acid alkyl ester obtained in step two into water, adding acetic acid and concentrated sulfuric acid, refluxing until the raw material is consumed, cooling, and filtering to obtain 2-(4-nitrophenyl)butyric acid.
[0007] The reaction formula is as follows:
[0008] In the reaction formula, R is methyl or ethyl.
[0009] In the above method for preparing 2-(4-nitrophenyl)butyric acid, the acetoacetic acid alkyl ester in step one is acetoacetic acid methyl ester and / or acetoacetic acid ethyl ester. Preferably, the acetoacetic acid alkyl ester is acetoacetic acid methyl ester.
[0010] In the above method for preparing 2-(4-nitrophenyl)butyric acid, preferably, the solvent in step one is tetrahydrofuran, N , N dimethylformamide, and dimethyl sulfoxide. More preferably, the solvent is N , N dimethylformamide.
[0011] In the above method for preparing 2-(4-nitrophenyl)butyric acid, preferably, the base in step one is anhydrous potassium carbonate, anhydrous sodium carbonate, sodium methoxide, or sodium ethoxide. More preferably, the base is anhydrous potassium carbonate.
[0012] In the above method for preparing 2-(4-nitrophenyl)butyric acid, preferably, the solvent in step two is petroleum ether, ethyl acetate, and dichloromethane. More preferably, the solvent is petroleum ether.
[0013] In the above method for preparing 2-(4-nitrophenyl)butyric acid, preferably, the base in step two is triethylamine, anhydrous potassium carbonate, and anhydrous sodium carbonate. More preferably, the base is triethylamine.
[0014] Preferably, the concentrated sulfuric acid / acetic acid mixed acid system in step three is concentrated sulfuric acid / acetic acid with a mass ratio of 1:2-2:1. More preferably, the concentrated sulfuric acid / acetic acid mixed acid system is concentrated sulfuric acid / acetic acid with a mass ratio of 1:1.
[0015] Compared with the prior art, the present application has the following beneficial effects: the raw materials and reagents used in the present application are cheap and easy to obtain, the process is simple and easy to implement, and has a significant cost advantage. At the same time, the reaction route used in the present application does not generate 2-(2-nitrophenyl) butyric acid isomer impurities, has high yield, and the obtained product has good quality. DETAILED DESCRIPTION
[0016] In order to further understand the purpose, content and advantages of the present application, the specific embodiments of the present application are described in detail as follows, but they cannot be limited to the following examples, and should be freely combined according to the actual situation. The endpoints and any values of the range disclosed herein are not limited to the exact range and values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
[0017] The present application is further described in detail below in combination with examples: The present application provides a preparation method of a pharmaceutical intermediate 2-(4-nitrophenyl) butyric acid, comprising the following steps: Step one, p-nitrochlorobenzene and acetoacetic acid alkyl ester are added to a solvent, heated and stirred under the action of a base until the raw material is completely reacted, 20% sulfuric acid is added to adjust the pH value to 1.5-2, and then filtered to obtain 2-cyano-2-(4-nitrophenyl) acetoacetic acid alkyl ester; Step two, 2-cyano-2-(4-nitrophenyl) acetoacetic acid alkyl ester obtained in step one and diethyl sulfate are added to a solvent, heated and stirred under the action of a base until the raw material is completely reacted, and then filtered to obtain 2-(4-nitrophenyl) butyric acid alkyl ester; Step three, 2-cyano-2-(4-nitrophenyl) butyric acid alkyl ester obtained in step two is added to water, acetic acid and concentrated sulfuric acid are added, refluxed until the raw material is completely consumed, cooled, and then filtered to obtain 2-(4-nitrophenyl) butyric acid; The acetoacetic acid alkyl ester in step one is acetoacetic acid methyl ester and / or acetoacetic acid ethyl ester; The concentrated sulfuric acid / acetic acid mixed acid system in step three is concentrated sulfuric acid: acetic acid = 1:2-2:1 (mass ratio). The raw materials and reagents used in the above method are cheap and easy to obtain, the process is simple and easy to implement, and has a significant cost advantage. At the same time, there is no 2-(2-nitrophenyl) butyric acid isomer impurity generated, which is easy to purify, and has the characteristics of high yield (the yield can reach the existing technology level) and high product purity.
[0018] In some preferred embodiments, the solvent in step one is any one or several of tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide.
[0019] In some preferred embodiments, the base in step one is any one or several of anhydrous potassium carbonate, anhydrous sodium carbonate, sodium methoxide, sodium ethoxide.
[0020] In some preferred embodiments, the solvent in step two is any one or several of petroleum ether, ethyl acetate, dichloromethane.
[0021] In some preferred embodiments, the base in step two is any one or several of triethylamine, anhydrous potassium carbonate, anhydrous sodium carbonate.
[0022] In some preferred embodiments, the reaction temperature in step one is 120-123℃, the molar ratio of p-nitrochlorobenzene to acetyl alkyl ester is 3:5-6, and the mass ratio of p-nitrochlorobenzene to base is 1:0.6-1.56. Under these conditions, the yield of 2-cyano-2-(4-nitrophenyl) acetoacetic acid methyl ester can reach more than 90%.
[0023] In some more preferred embodiments, the base in step one is anhydrous potassium carbonate, and the mass ratio of p-nitrochlorobenzene to anhydrous potassium carbonate is 1:1.5-1.56, so that the yield is more than 91%.
[0024] In some preferred embodiments, in step two, heating is carried out to reflux, the mass ratio of 2-cyano-2-(4-nitrophenyl) acetoacetic acid methyl ester to diethyl sulfate is 110:92-93, and the solvent is petroleum ether, so that the yield of methyl 2-(4-nitrophenyl) butyrate is more than 90%.
[0025] The application will be further described below in conjunction with more specific embodiments: Example 1 This embodiment includes the following steps: Step one, 50 g of p-nitrochlorobenzene and 77.4 g of anhydrous potassium carbonate are dissolved in 222 g of N , N- dimethylformamide (DMF) in a three-necked flask, equipped with a thermometer, a distillation head and a condenser, was heated to 120-123°C with stirring and maintained for 30 minutes. 55.2 g of methyl cyanoacetate was added dropwise and the reaction was continued for 12 hours until no starting material was detected. The temperature was lowered to 20°C, 160 g of water was added, and 222.5 g of 20% sulfuric acid was added dropwise. The temperature was maintained at about 20°C and the reaction was continued for 3 hours. The solid was filtered, washed with 200 g of water twice, and dried at 50°C to give 63.9 g of methyl 2-cyano-2-(4-nitrophenyl)acetoacetate (yield 91.2%).
[0026] Step two, 110 g of methyl 2-cyano-2-(4-nitrophenyl)acetoacetate and 92.5 g of diethyl sulfate were dissolved in 330 g of petroleum ether 90-120°C. The stirring was started and the temperature was slowly increased to reflux. 83 g of anhydrous potassium carbonate was added portionwise and the reaction solution turned red. The reaction was continued for 5 hours until no starting material was detected. The temperature was lowered to 50°C, the stirring was stopped and the solid was allowed to settle for 30 minutes. The solid was filtered, 19 g of water was added, the temperature was increased to 70-75°C and the reaction was continued for 1 hour until the unreacted diethyl sulfate was decomposed. The temperature was lowered to 50°C, 256 g of methanol was added, the temperature was increased to reflux and the solid was dissolved. The temperature was maintained for 1 hour, the temperature was lowered to 0°C and the solid was filtered to give 112.6 g of methyl 2-(4-nitrophenyl)butanoate (yield 90.8%).
[0027] Step three, 90 g of methyl 2-(4-nitrophenyl)butanoate was added to 90 g of water, 90 g of acetic acid and 90 g of concentrated sulfuric acid were added with stirring. The temperature was increased to reflux and low boiling point substances and gases were produced during the reaction. The reaction was continued until no gas bubbles were produced. The temperature was lowered to about 20°C and the solid was filtered. The solid was washed with 50 g of water twice and filtered again. The solid was dried at 50°C to give 70.6 g of 2-(4-nitrophenyl)butanoic acid (yield 93.1%) with a melting point (mp) of not less than 121°C, and an average of 122°C.
[0028] Example 2
[0029] This example includes the following steps: Step one, 50 g of p-nitrochlorobenzene and 77.4 g of anhydrous potassium carbonate were dissolved in 222 g of dimethylformamide (DMF) in a three-necked flask, equipped with a thermometer, a distillation head and a condenser. The temperature was increased to 120-123°C with stirring and maintained for 30 minutes. 55.2 g of methyl cyanoacetate was added dropwise and the reaction was continued for 12 hours until no starting material was detected. The temperature was lowered to 20°C, 160 g of water was added, and 222.5 g of 20% sulfuric acid was added dropwise. The temperature was maintained at about 20°C and the reaction was continued for 3 hours. The solid was filtered, washed with 200 g of water twice, and dried at 50°C to give 63.9 g of methyl 2-cyano-2-(4-nitrophenyl)acetoacetate (yield 91.2%). N , N- dimethylformamide (DMF) in a three-necked flask, equipped with a thermometer, a distillation head and a condenser, was heated to 120-123°C with stirring for 30 minutes. 58.6 g of ethyl cyanoacetate was added dropwise and the reaction was continued for 12 hours until no starting material was present. The temperature was lowered to 20°C and 160 g of water was added. Then 222.5 g of 20% sulfuric acid was added dropwise. The temperature was controlled at about 20°C and the reaction was continued for 3 hours. The solid was filtered and washed with 200 g of water twice to remove the residual sulfuric acid. The solid was dried at 50°C to obtain 65.2 g of ethyl 2-cyano-2-(4-nitrophenyl)acetoacetate (yield 87.5%).
[0030] Step two, 110 g of ethyl 2-cyano-2-(4-nitrophenyl)acetoacetate and 90.6 g of diethyl sulfate were dissolved in 330 g of petroleum ether 90-120°C. The stirring was started and the temperature was slowly increased to reflux. 61 g of triethylamine was added dropwise and the reaction solution turned red. The reflux was continued for 5 hours until no starting material was present. The temperature was lowered to 50°C and the stirring was stopped for 30 minutes. The solid was filtered and 19 g of water was added. The temperature was increased to 70-75°C and the reaction was continued for 1 hour until the diethyl sulfate was completely decomposed. The temperature was lowered to 50°C and 256 g of methanol was added. The temperature was increased to reflux and the solid was dissolved. The temperature was lowered to 0°C and the solid was filtered. Ethyl 2-(4-nitrophenyl)butyrate (101.2 g) was obtained (yield 82.2%).
[0031] Step three, 90 g of ethyl 2-(4-nitrophenyl)butyrate was added to 90 g of water and stirred. Then 70 g of acetic acid and 90 g of concentrated sulfuric acid were added. The temperature was increased to reflux and low boiling point materials and gas were produced during the reaction. The reaction was continued until no gas was produced. The temperature was lowered to about 20°C and the solid was filtered. The solid was washed with 50 g of water twice and then filtered. The solid was dried at 50°C to obtain 2-(4-nitrophenyl)butyric acid (59.1 g) (yield 82.3%) with a melting point (mp) not less than 121°C (average 121.6°C).
[0032] Example 3
[0033] This example includes the following steps: Step one, 50 g of p-nitrochlorobenzene and 30.3 g of sodium methoxide were dissolved in 210 g of tetrahydrofuran, placed in a three-necked flask, equipped with a thermometer, a distillation head and a condenser, and heated to 70-72°C under stirring for 30 minutes. 55.2 g of methyl cyanoacetate was added dropwise, and the reaction was continued for 12 hours until no raw material was detected. The temperature was lowered to 20°C, 160 g of water was added, and 222.5 g of 20% sulfuric acid was added dropwise. The pH was adjusted to 1.5-2, and the temperature was controlled at about 20°C. The reaction was continued for 3 hours, and the solid was filtered. The solid was washed with 200 g of water twice to remove the residual sulfuric acid. The solid was filtered again, and dried at 50°C to obtain 60.7 g of methyl 2-cyano-2-(4-nitrophenyl)acetoacetate (yield 86.6%).
[0034] Step two, 110 g of methyl 2-cyano-2-(4-nitrophenyl)acetoacetate and 92.5 g of diethyl sulfate were dissolved in 420 g of dichloromethane. The stirring was started, and the temperature was slowly raised to reflux. 83 g of anhydrous potassium carbonate was added in portions, and the reaction solution turned red. The reaction was continued for 5 hours until no raw material was detected. The temperature was lowered to 50°C, and the stirring was stopped for 30 minutes. The solid was filtered, and 19 g of water was added. The temperature was raised to 70-75°C, and the reaction was continued for 1 hour until the unreacted diethyl sulfate was completely decomposed. The temperature was lowered to 50°C, 256 g of methanol was added, and the temperature was raised to reflux. The solid was dissolved completely. The temperature was lowered to 0°C, and the solid was filtered to obtain 101.8 g of methyl 2-(4-nitrophenyl)butyrate (yield 82.1%).
[0035] Step three, 90 g of methyl 2-(4-nitrophenyl)butyrate was added to 90 g of water under stirring, and 90 g of acetic acid and 60 g of concentrated sulfuric acid were added. The temperature was raised to reflux, and low-boiling substances and gas were generated during the reaction. The reaction was continued until no gas bubbles were generated. The temperature was lowered to about 20°C, and the solid was filtered. The solid was washed with 50 g of water twice, and filtered again to obtain 62.3 g of 2-(4-nitrophenyl)butyric acid (yield 82.2%), which had a melting point (mp) of not less than 121°C, and an average melting point of 122.2°C.
[0036] The above is only a preferred specific embodiment of the present application, but the protection scope of the present application is not limited thereto. Any person skilled in the art can make equivalent replacements or changes according to the technical solution and concept of the present application within the technical range disclosed by the present application, which should be covered by the protection scope of the present application. It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict.
Claims
1. A method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid, characterized in that, The steps include the following: Step 1: Add p-nitrochlorobenzene and alkyl acetoacetate to a solvent, heat and stir under the action of alkali until the reaction of the raw materials is completed, add 20% sulfuric acid to adjust the pH value to 1.5-2, filter, and 2-cyano-2-(4-nitrophenyl)alkyl acetoacetate is obtained. Step 2: Add the 2-cyano-2-(4-nitrophenyl)acetoacetic acid alkyl ester obtained in Step 1 and diethyl sulfate to the solvent, heat and stir under the action of alkali until the reaction of the raw materials is completed, and filter to obtain 2-(4-nitrophenyl)butyric acid alkyl ester. Step 3: Add the alkyl 2-cyano-2-(4-nitrophenyl)butyric acid obtained in Step 2 to water, add acetic acid and concentrated sulfuric acid, reflux until the raw materials are consumed, cool down, and filter to obtain 2-(4-nitrophenyl)butyric acid; The alkyl acetoacetate mentioned in step one is methyl acetoacetate and / or ethyl acetoacetate; The concentrated sulfuric acid / acetic acid mixed acid system mentioned in step three is a concentrated sulfuric acid:acetic acid ratio of 1:2-2:1 (mass ratio).
2. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, The solvent mentioned in step one is any one or more of tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.
3. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, The alkali mentioned in step one is any one or more of anhydrous potassium carbonate, anhydrous sodium carbonate, sodium methoxide, and sodium ethoxide.
4. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, The solvent mentioned in step two is any one or more of petroleum ether, ethyl acetate, and dichloromethane.
5. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, The alkali mentioned in step two is any one or more of triethylamine, anhydrous potassium carbonate, and anhydrous sodium carbonate.
6. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, In step one, the reaction temperature is 120-123℃, the molar ratio of p-nitrochlorobenzene to alkyl acetoacetate is 3:5~6, and the mass ratio of p-nitrochlorobenzene to alkali is 1:0.6~1.
56.
7. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 6, characterized in that, In step one, the alkali is anhydrous potassium carbonate, and the mass ratio of p-nitrochlorobenzene to anhydrous potassium carbonate is 1:1.5~1.
56.
8. The method for preparing the pharmaceutical intermediate 2-(4-nitrophenyl)butyric acid according to claim 1, characterized in that, In step two, the mixture is heated to reflux. The mass ratio of 2-cyano-2-(4-nitrophenyl)acetoacetic acid methyl ester to diethyl sulfate is 110:92~93, and the solvent is petroleum ether.