CN110483270B - Preparation method for efficient green synthesis of fenofibric acid - Google Patents
Preparation method for efficient green synthesis of fenofibric acid Download PDFInfo
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- CN110483270B CN110483270B CN201910849737.3A CN201910849737A CN110483270B CN 110483270 B CN110483270 B CN 110483270B CN 201910849737 A CN201910849737 A CN 201910849737A CN 110483270 B CN110483270 B CN 110483270B
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- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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Abstract
The invention discloses a preparation method for efficiently and environmentally synthesizing fenofibric acid. The method comprises the following steps: putting 4-chloro-4' -hydroxybenzophenone, acetone and TEBA into a high-concentration alkali solution; and (3) dropwise adding chloroform at the temperature of below 40 ℃, refluxing for 1-2 hours after dropping, filtering salt at high temperature after liquid phase detection is qualified, distilling off acetone in mother liquor, adding water, extracting twice with an extracting agent, removing unreacted raw materials, and recycling the extracting agent twice for centralized treatment. Adding activated carbon into water, refluxing and decoloring, and adjusting acid to obtain fenofibric acid solid. The invention has the advantages of simple process, short production period, higher yield than relevant documents, low cost, small environmental pollution and the like.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of efficient green synthetic fenofibric acid
Background
Fenofibric acid is an important intermediate for synthesizing a blood fat reducing drug fenofibrate, has very wide application, and has increasingly strict requirements on appearance, content, known impurities and unknown impurities in the market at present. The traditional process is difficult to reach the market standard at one time. The traditional process is generally obtained by taking 4-chloro-4' -hydroxybenzophenone, acetone and chloroform as raw materials and carrying out condensation reaction under the conditions of strong alkali and a phase transfer catalyst. At present, inorganic base is reported to prepare fenofibric acid in China, but the defects of large using amount of acetone, inorganic base, chloroform and acid, 85 percent of crude product yield, high cost due to the fact that crystal needs to be converted by toluene, more three wastes, no effective treatment of solvent, more salt, difficulty in layering, influence on subsequent reaction, large difficulty in industrial implementation and the like exist. Gucaixian et al (synthesis of hypolipidemic drug Prulifen, pharmaceutical industry, 1983) use inorganic base as catalyst, 4-hydroxy-4' -chlorobenzophenone, chloroform and acetone as main raw materials, and obtain fenofibric acid through condensation, distillation, acidification, filtration, recrystallization and drying. The Ligan uses sodium hydroxide as a catalyst in a method application number 201410164268.9 for preparing fenofibric acid by using an inorganic base as a catalyst, but the problems of high salt content in a mother solution, large wastewater, complex post-treatment, introduction of a new easy-to-prepare toxic solvent toluene in subsequent material throwing, large peculiar smell, yellow material color and the like still exist.
The invention content is as follows:
in order to solve the problems in the background art, the invention provides a method for efficiently and environmentally synthesizing fenofibric acid, which reduces three wastes and directly achieves the market standard in appearance and content (the appearance is white in the current high-end market requirement, the content is not lower than 99.5%, the content of 4-chloro-4' -hydroxybenzophenone is not higher than 0.2%, and the content of unknown impurities is not higher than 0.2%) without refining.
The technical scheme adopted by the invention is as follows:
the invention comprises the following steps:
1) putting 4-chloro-4-hydroxybenzophenone, acetone and TEBA into a high-concentration alkali solution; TEBA is benzyltriethylammonium chloride C13H22ClN。
2) Controlling the temperature of the solution in the step 1) to be below 40 ℃, dropwise adding chloroform, refluxing for 1-2 hours after dropwise adding, and filtering salt (NaCl) while hot;
3) evaporating acetone in the mother liquor filtered in the step 2), adding water, adjusting the pH, extracting twice by using an extracting agent to remove unreacted raw materials, and taking a water layer;
4) adding activated carbon into the water layer extracted in the step 3), refluxing and decoloring, filtering, and adjusting the acid of the mother solution to separate out fenofibric acid solid.
The alkali solution in the step 1 is a sodium hydroxide solution, and the mass percentage concentration is 40-70%, and preferably 60%.
4-chloro-4-hydroxybenzophenone: alkali solution: acetone: TEBA: the molar ratio of chloroform is 1: 8-12: 16:0.1:2.3, preferably 1:10:16:0.1: 2.3.
In the step 2), after the chloroform reaction is qualified, one step of filtration is added for removing most of salt, so that the salt content in the mother liquor is greatly reduced, and the environmental protection pressure is reduced; the qualified condition of the chloroform reaction is that the mass percentage concentration of the 4-chloro-4' -hydroxybenzophenone in the solution is less than or equal to 1.0 percent.
Adjusting the pH value to 8-9 in the step 3).
The extracting agent in the step 3) is one of toluene, chlorobenzene, butyl acetate or methyl tert-butyl ether, and butyl acetate is preferred; the dosage of the extractant is 0.5 to 2 times of that of the 4-chloro-4-hydroxybenzophenone, preferably 1 time; the extractant can be circularly used for two times and is treated in a centralized way.
The invention has the beneficial effects that:
1) the invention uses high-concentration liquid alkali to ensure that the reaction is carried out at a liquid-liquid interface, and the reaction is milder and has shorter reaction time due to the existence of a phase transfer catalyst.
2) The method adds a salt throwing procedure to remove salt generated by the reaction, solves the problem of high salt content in the subsequent wastewater, and greatly reduces the use amount of the wastewater.
3) The invention increases the extraction of the extracting agent, and because of the difference of the solubility, the solubility of the raw material in the extracting agent is far greater than that of the product, thereby removing the unreacted raw material and ensuring that the product has higher purity.
4) The invention adds one-step active carbon decolorization, so that the appearance and the content of the product can reach the market standard at one time, one-time refining is reduced, the process flow is shortened, and the product yield is improved.
Detailed Description
The present invention will be further described with reference to the following examples.
Example one
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4 '-hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering salts while hot after refluxing for two hours after dropwise adding, evaporating acetone in a mother solution (filtrate), adding 400 g of water to adjust the pH to 8-9, extracting with 100 g of butyl acetate twice, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH of the mother solution (filtrate) to 1-2, filtering and drying to obtain 125.87 g of white solid, wherein the molar yield is 90%, the purity is 99.73%, the content is 99.93%, and the content of the raw material (4-chloro-4' -hydroxybenzophenone) is 0.11%.
Example two
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering the hot salt after refluxing for two hours after dropwise adding, steaming the acetone, adding 400 g of water, adjusting the pH to be 8-9, extracting twice with 100 g of butyl acetate in example 1, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH of mother liquor to be 1-2, filtering and drying to obtain 128.26 g of white solid, wherein the molar yield is 91%, the purity is 99.69%, the content is 99.89% and the raw material is 0.13%.
EXAMPLE III
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering the hot salt after refluxing for two hours after dropwise adding, steaming the acetone, adding 400 g of water, adjusting the pH to be 8-9, extracting twice with 100 g of butyl acetate in example 2, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH of mother liquor to be 1-2, filtering and drying to obtain 128.31 g of white solid, wherein the molar yield is 91%, the purity is 99.68%, the content is 99.91% and the content is 0.12% of the raw material.
Comparative example 1
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, refluxing for two hours after dropwise adding, steaming the acetone, adding 1000 g of water, adjusting the pH value to 8-9, extracting twice by using 100 g of butyl acetate, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH value of mother liquor to 1-2, filtering and drying to obtain 126.03 g of white solid, wherein the molar yield is 90%, the purity is 99.65%, the content is 99.87%, and the raw material is 0.13%.
Comparative example No. two
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, refluxing for two hours after dropwise adding, steaming the acetone, adding 1000 g of water, adjusting the pH value to 8-9, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH value of mother liquor to 1-2, filtering and drying to obtain 128.19 g of white solid, wherein the molar yield is 91%, the purity is 99.17%, the content is 99.33%, and the raw material is 0.45%.
Comparative example No. three
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering the hot salt after refluxing for two hours after dropwise adding, steaming the acetone, adding 400 g of water, adjusting the pH to be 8-9, adding 3 g of activated carbon, stirring at 80 ℃ for 30 minutes, filtering the activated carbon, adjusting the pH of mother liquor to be 1-2, filtering and drying to obtain 128.25 g of white solid, wherein the molar yield is 91%, the purity is 99.15%, the content is 99.31%, and the raw material is 0.49%.
Comparative example No. four
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering the hot salt after refluxing for two hours after dropwise adding, steaming the acetone, adding 400 g of water, adjusting the pH to be 8-9, extracting 100 g of butyl acetate twice, adjusting the pH of the mother liquor to be 1-2, filtering and drying to obtain 126.11 g of light yellow solid, wherein the molar yield is 91%, the purity is 99.66%, the content is 99.88%, and the raw material is 0.13%.
Comparative example five
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, refluxing for two hours after dropwise adding, steaming the acetone, adding 1000 g of water, adjusting the pH value to be 1-2, filtering and drying to obtain 128.05 g of light yellow solid, wherein the molar yield is 91%, the purity is 99.09%, the content is 99.24% and the raw material is 0.51%.
Comparative example six
Adding 280 g of 60% sodium hydroxide solution into a 2L three-necked bottle, cooling to room temperature, adding 100 g of 4-chloro-4' -hydroxybenzophenone, 400 g of acetone and 9 g of TEBA, dropwise adding 120 g of chloroform, filtering the hot salt after refluxing for two hours after dropwise adding, steaming the acetone, adding 400 g of water, adjusting the pH to 1-2, filtering and drying to obtain 128.21 g of light yellow solid, wherein the molar yield is 91%, the purity is 99.11%, the content is 99.33%, and the raw material is 0.45%.
From the experimental data in the above table it can be seen that:
1) when the salt is not thrown off, the amount of water needs to be increased in order to dissolve the excess salt, and the amount of wastewater is increased.
2) When the extraction agent is not used for extraction, the product purity is low, the requirement of the current market is difficult to meet, the product needs to be refined once again, the yield is inevitably lost, and the energy consumption is inevitably increased.
3) Active carbon is not used for decoloring, the material is yellow, and the prepared product is difficult to meet the market requirement.
To sum up, the conclusion can be drawn that the salt throwing and the extraction are carried out in one step in the early stage, and the activated carbon is used for decoloring in the later stage, so that the purity can be improved, the wastewater is reduced, the appearance is improved, and the energy consumption is reduced and the market requirement is met.
The above examples are only preferred embodiments of the present invention, which is not intended to be limiting in any way, and any person skilled in the art may, using the teachings of the present invention, modify or adapt the same for various equivalent embodiments. However, any simple modification of the above embodiments according to the technical essence of the present invention will still fall within the scope of the technical solution of the present invention.
Claims (5)
1. The preparation method for efficiently and environmentally synthesizing fenofibric acid is characterized by comprising the following steps:
1) putting 4-chloro-4-hydroxybenzophenone, acetone and TEBA into a high-concentration alkali solution;
2) controlling the temperature of the solution in the step 1) to be below 40 ℃, dropwise adding chloroform, refluxing for 1-2 hours after dropwise adding, and filtering salt while the solution is hot;
3) evaporating acetone in the filtered mother liquor in the step 2), adding water, adjusting the pH, extracting twice by using an extracting agent, and taking a water layer;
4) adding activated carbon into the water layer extracted in the step 3), refluxing and decoloring, filtering, and adjusting the acid of the mother solution to separate out fenofibric acid solid;
adjusting the pH value to 8-9 in the step 3);
the extractant in the step 3) adopts butyl acetate.
2. The method for preparing fenofibric acid with high efficiency and green color as claimed in claim 1, wherein the alkali solution in step 1 is sodium hydroxide solution with a concentration of 40-70% by weight.
3. The method for preparing fenofibric acid with high efficiency and green color as claimed in claim 1, wherein the ratio of 4-chloro-4-hydroxybenzophenone: alkali solution: acetone: TEBA: the molar ratio of chloroform is 1: 8-12: 16:0.1:2.3.
4. The method for preparing fenofibric acid with high efficiency and green color as claimed in claim 1, wherein the extractant used in step 3) is butyl acetate; the dosage of the extractant is 0.5 to 2 times of that of the 4-chloro-4-hydroxybenzophenone.
5. The method for preparing fenofibric acid with high efficiency and green color according to claim 1, wherein the fenofibric acid solid obtained in step 4) has a purity of 99.5% or more and is white.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4058552A (en) * | 1969-01-31 | 1977-11-15 | Orchimed Sa | Esters of p-carbonylphenoxy-isobutyric acids |
| CN103360240A (en) * | 2013-07-23 | 2013-10-23 | 西安新通药物研究有限公司 | Preparation method of high purity fenofibric acid |
| CN108383709A (en) * | 2018-03-16 | 2018-08-10 | 徐州工业职业技术学院 | A kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4058552A (en) * | 1969-01-31 | 1977-11-15 | Orchimed Sa | Esters of p-carbonylphenoxy-isobutyric acids |
| CN103360240A (en) * | 2013-07-23 | 2013-10-23 | 西安新通药物研究有限公司 | Preparation method of high purity fenofibric acid |
| CN108383709A (en) * | 2018-03-16 | 2018-08-10 | 徐州工业职业技术学院 | A kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid |
Non-Patent Citations (1)
| Title |
|---|
| 非诺贝特酸的相转移催化合成;李敢等;《广州化工》;20141130;第42卷(第21期);第102-104页 * |
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