CN108383709A - A kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid - Google Patents
A kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid Download PDFInfo
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- CN108383709A CN108383709A CN201810217011.3A CN201810217011A CN108383709A CN 108383709 A CN108383709 A CN 108383709A CN 201810217011 A CN201810217011 A CN 201810217011A CN 108383709 A CN108383709 A CN 108383709A
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- chlorobenzophenone
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
Abstract
The invention discloses a kind of methods that phase transfer catalysis process prepares high-purity Fenofibric Acid, belong to Fenofibric Acid catalysis synthesizing technology field.It is raw material with 4 hydroxyl, 4 ' chlorobenzophenone, acetone and chloroform, 40% sodium hydroxide solution makees catalyst, and PEG 400 makees phase transfer catalyst, and toluene makees solvent, by condensation reaction, filtering, acidification, liquid separation heat up, washing, filtering, washing, absolute ethyl alcohol recrystallization are dried to obtain Fenofibric Acid.Using and consuming for precursor chemicals acetone is greatly decreased in this method, and solvent loss is remarkably decreased, and the three wastes are few, is a kind of method of green syt Fenofibric Acid, is suitble to industrialized production.
Description
Technical field
The present invention relates to the preparation methods of Fenofibric Acid, and in particular to a kind of phase transfer catalysis process prepares high-purity Fenofibric Acid
Method, belong to Fenofibric Acid catalytic synthetic techniques fields.
Background technology
Fenofibric Acid is the important intermediate for synthesizing blood lipid-lowering medicine fenofibrate, and purposes is very extensive, usually with 4-
Hydroxyl -4 '-chlorobenzophenone, acetone and chloroform are raw material, are obtained by condensation reaction.
At present about the synthesis of Fenofibric Acid, most of document report using 4'- chloro-4-hydroxyls benzophenone as raw material,
Condensation reaction occurs with chloroform or 2- bromo acids and acetone or butanone under alkaline condition and generates Fenofibric Acid.Existing synthesis
In technology, Fenofibric Acid crude yield is relatively low, and needs to can be only achieved the requirement of medicine material, crystallization loss by repeatedly crystallization
It is larger so that Fenofibric Acid bulk pharmaceutical chemicals it is of high cost, it is difficult to industrialized production.
Zhang Dengke etc. discloses a kind of preparation method of Fenofibric Acid, by 2 acid for adjusting pH, 3 filterings, and 2 dryings,
Complicated for operation, the reaction time is long, and using a large amount of bronsted lowry acids and bases bronsted lowry, yield is low.Li Zhaolin etc. discloses a kind of high purity fenofibric acid
The preparation method of bulk pharmaceutical chemicals, by 2 acid for adjusting pH, 5 filterings, 2 dryings, complicated for operation, the reaction time is long, using a large amount of
Acid be not easily recycled using low boiling point dichloromethane solvent, yield is relatively low.Chen Yangyang etc. discloses a kind of system of Fenofibric Acid
Preparation Method, the technological reaction time is long, and crystallization time is long, and yield is relatively low.Wang Jipeng etc. discloses a kind of high-purity chloro shellfish butyric acid
The process for purification of derivative species lipid regulating agent Fenofibric Acid, the technique by recrystallizing three times, although product purity is high, uses
A large amount of solvents recycle high energy consumption, and product yield is low, and production cost is high, is not suitable for industrialized production.Peng Chao discloses a kind of non-promise
The production technology of shellfish acid, the technique are repeatedly extracted with fat-soluble organic solvent and water, and fat-soluble organic solvent and water consumption are big, institute
It is had difficulties with mixed solvent recycling, it is of high cost.
Invention content
The present invention provides a kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid, for solving prior art acetone
Dosage is big and is difficult to recycle, and the reaction time is long, repeatedly adjusts pH with sour, is filtered for multiple times, and repeatedly dry, soda acid dosage is big, of high cost,
There is the problems such as impurity is higher, and yield is low, and three-protection design difficulty is big good product quality, high income, solvent easily to recycle, operation letter
It is single, industrialized advantage environmental-friendly, easy to implement.
The present invention is achieved through the following technical solutions, and a kind of phase transfer catalysis process prepares the side of high-purity Fenofibric Acid
Method, primary raw material include 4- hydroxyls -4 '-chlorobenzophenone, acetone and chloroform, and phase transfer catalyst PEG-400, solvent is first
Benzene；Specific preparation method carries out as follows：
Step 1）I and of water is added in the four-hole boiling flask for having electric stirring, thermometer, reflux condensing tube, constant pressure funnel
Sodium hydroxide opens stirring, and rotating speed 400-450r/min is cooled to 40 DEG C, and toluene I, acetone, 4- hydroxyls -4 '-chlorine two is added
Benzophenone and PEG-400；
Step 2）Chloroform is added dropwise under the conditions of 46-50 DEG C, keeps the temperature 0.5h after being added dropwise at 46-50 DEG C, then reheats in 58-
60 DEG C of heat preservation 2-2.5h；
Step 3）Water II is added into reaction solution, toluene II is added into filtrate for filtering, is acidified to pH=2-3 with hydrochloric acid, then add
Enter water III, salt is promoted to be completely dissolved（React the sodium chloride generated）, stand and sub-cloud water layer, upper layer feed liquid divided to be heated to
65-70 DEG C, water IV is added to be cooled to 30-35 DEG C, standing divides sub-cloud water layer, the filtering of upper layer feed liquid, filter cake be washed with water to filtrate pH=
6-7 obtains wet product Fenofibric Acid；
Step 4）By step 3）Gained wet product Fenofibric Acid and absolute ethyl alcohol sequentially add to have electric stirring, thermometer, return
It in the four-hole boiling flask for flowing condenser pipe, is warming up to Fenofibric Acid and is completely dissolved, activated carbon is added, 5-10 min are kept the temperature at 70-75 DEG C,
Heat filter, is cooled to 0-5 DEG C, dry Fenofibric Acid.
The prioritization scheme of the method for high-purity Fenofibric Acid is prepared as a kind of phase transfer catalysis process of the present invention：
The acetone dosage is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Sodium hydroxide concentration is 1.0~1.2 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Chloroform dosage is 0.7~0.8 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
PEG-400 dosages are 0.07~0.13 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
I dosage of toluene is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
II dosage of toluene is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Hydrochloric acid dosage is 1.1~1.4 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
I dosage of water is 1.3~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
II dosage of water is 1.0~1.3 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Water III, IV dosage of water are respectively 1.3~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Absolute ethyl alcohol dosage is 4.0~4.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Activated carbon dosage is 0.01~0.02 times of 4- hydroxyls -4 '-chlorobenzophenone weight.
The optimisation technique scheme of the method for high-purity Fenofibric Acid is prepared as a kind of phase transfer catalysis process of the present invention：
4- hydroxyls-the 4 '-chlorobenzophenone, sodium hydroxide, chloroform, acetone, toluene are content 95.0%；PEG-400, anhydrous second
Alcohol is content 99.0%；Hydrochloric acid is mass concentration 36.0%；Activated carbon is medicinal.
Beneficial effects of the present invention：This method 4- hydroxyls -4 '-chlorobenzophenone, acetone and chloroform are raw material, 40% hydrogen
Sodium hydroxide solution makees catalyst, and PEG-400 makees phase transfer catalyst, and toluene replaces acetone as solvent, by condensation reaction, mistake
Filter, acidification, liquid separation heat up, and wash, and filter, washing, and absolute ethyl alcohol recrystallization is dried to obtain Fenofibric Acid.This method substantially subtracts
Few precursor chemicals acetone using and consuming, and solvent loss is remarkably decreased, and the three wastes are few, avoids acetone rectifying recycling, first
Benzene is easily recycled, even if the toluene of recycling still will not have any influence containing moisture to reaction, using in Fenofibric Acid wet product
Existing water inhibits the generation of esterification, is a kind of method of the high-purity Fenofibric Acid of green syt, is suitble to industrialized production.
Description of the drawings
Fig. 1 is flow chart of the method for the present invention.
Specific implementation mode
To make to have further understanding to the purpose of the present invention, feature and its function, in conjunction with Fig. 1, raw material use is provided
Measure the result of implementation in the case of different three kinds.
Embodiment 1
I 60g of water, hydrogen-oxygen are added in the four-hole boiling flask for having electric stirring, thermometer, reflux condensing tube, constant pressure funnel
Change sodium 40g, rotating speed 400r/min, be cooled to 40 DEG C, I 50g of toluene, acetone 55g, 4- hydroxyl -4 '-chlorobenzophenone is added
40g, PEG-400,4g；Chloroform 28g is added dropwise at 47 ± 1 DEG C, keeps the temperature 0.5 h after being added dropwise at 47 ± 1 DEG C, then reheats
59-60 DEG C of 2 h of heat preservation；II 40g of water is added into reaction solution, II 55g of toluene is added into filtrate, uses hydrochloric acid for filtering（53g）Acid
Change to pH=2, add III 55g of water, salt is promoted to be completely dissolved, standing divides sub-cloud water layer, upper layer feed liquid to be heated to 66
± 1 DEG C, IV 60g of water is added to be cooled to 33 DEG C, standing divides sub-cloud water layer, the filtering of upper layer feed liquid, filter cake to be washed with water to filtrate pH=6,
Obtain wet product Fenofibric Acid；Gained wet product Fenofibric Acid, absolute ethyl alcohol 170g are added to having electric stirring, thermometer, reflux
It in the four-hole boiling flask of condenser pipe, is warming up to Fenofibric Acid and is completely dissolved, activated carbon 0.6g is added, 10min is kept the temperature at 71 ± 1 DEG C,
Heat filter is cooled to 3 DEG C, dry that Fenofibric Acid, yield 82.5%, fusing point are 177.9~178.6 DEG C, content 99.88%.
Embodiment 2
I 55g of water, hydrogen-oxygen are added in the four-hole boiling flask for having electric stirring, thermometer, reflux condensing tube, constant pressure funnel
Change sodium 45g, rotating speed 450r/min, be cooled to 40 DEG C, I 55g of toluene, acetone 55g, 4- hydroxyl -4 '-chlorobenzophenone is added
40g, PEG-400,3g；Chloroform 32g is added dropwise at 48 ± 1 DEG C, keeps the temperature 0.5 h after being added dropwise at 48 ± 1 DEG C, then reheats
58-59 DEG C of 2.5 h of heat preservation；II 50g of water is added into reaction solution, II 50g of toluene is added into filtrate, uses hydrochloric acid for filtering（51g）
PH=3 are acidified to, III 60g of water is added, salt is promoted to be completely dissolved, standing divides sub-cloud water layer, upper layer feed liquid to be heated to
68 ± 1 DEG C, IV 50g of water is added to be cooled to 35 DEG C, standing divides sub-cloud water layer, the filtering of upper layer feed liquid, filter cake be washed with water to filtrate pH=
7, obtain wet product Fenofibric Acid；By gained wet product Fenofibric Acid, absolute ethyl alcohol 170g be added to have electric stirring, thermometer, return
It in the four-hole boiling flask for flowing condenser pipe, is warming up to Fenofibric Acid and is completely dissolved, activated carbon 0.6g is added, 5min is kept the temperature at 72 ± 1 DEG C,
Heat filter is cooled to 5 DEG C, dry that Fenofibric Acid, yield 83.3%, fusing point are 178.1~178.8 DEG C, content 99.92%.
Embodiment 3
I 58g of water, hydrogen-oxygen are added in the four-hole boiling flask for having electric stirring, thermometer, reflux condensing tube, constant pressure funnel
Change sodium 42g, rotating speed 450r/min, be cooled to 40 DEG C, I 60g of toluene, acetone 60g, 4- hydroxyl -4 '-chlorobenzophenone is added
40g, PEG-400,5g；Chloroform 30g is added dropwise at 49 ± 1 DEG C, keeps the temperature 0.5 h after being added dropwise at 49 ± 1 DEG C, then reheats
58-59 DEG C of 2.5 h of heat preservation；II 45g of water is added into reaction solution, II 60g of toluene is added into filtrate, uses hydrochloric acid for filtering（54g）
PH=2 are acidified to, III 50g of water is added, salt is promoted to be completely dissolved, standing divides sub-cloud water layer, upper layer feed liquid to be heated to
69 ± 1 DEG C, IV 55g of water is added to be cooled to 32 DEG C, standing divides sub-cloud water layer, the filtering of upper layer feed liquid, filter cake be washed with water to filtrate pH=
7, obtain wet product Fenofibric Acid；By gained wet product Fenofibric Acid, absolute ethyl alcohol 180g be added to have electric stirring, thermometer, return
It in the four-hole boiling flask for flowing condenser pipe, is warming up to Fenofibric Acid and is completely dissolved, activated carbon 0.4g is added, 8min is kept the temperature at 74 ± 1 DEG C,
Heat filter is cooled to 0 DEG C, dry that Fenofibric Acid, yield 83.8%, fusing point are 177.8~178.5 DEG C, content 99.88%.
Used in above-described embodiment 1-3：4- hydroxyls -4 '-chlorobenzophenone, sodium hydroxide, chloroform, acetone, toluene are
Content 95.0%；PEG-400, absolute ethyl alcohol are content 99.0%；Hydrochloric acid is mass concentration 36.0%；Activated carbon is medicinal.
Claims (3)
1. a kind of method that phase transfer catalysis process prepares high-purity Fenofibric Acid, primary raw material includes 4- hydroxyls -4 '-chlorodiphenyl first
Ketone, acetone and chloroform, it is characterised in that：Phase transfer catalyst is PEG-400, and solvent is toluene；Specific preparation method is by as follows
Step carries out：
Step 1）I and of water is added in the four-hole boiling flask for having electric stirring, thermometer, reflux condensing tube, constant pressure funnel
Sodium hydroxide opens stirring, and rotating speed 400-450r/min is cooled to 40 DEG C, and toluene I, acetone, 4- hydroxyls -4 '-chlorine two is added
Benzophenone and PEG-400；
Step 2）Chloroform is added dropwise under the conditions of 46-50 DEG C, keeps the temperature 0.5h after being added dropwise at 46-50 DEG C, then reheats in 58-
60 DEG C of heat preservation 2-2.5h；
Step 3）Water II is added into reaction solution, toluene II is added into filtrate for filtering, is acidified to pH=2-3 with hydrochloric acid, then add
Enter water III, salt is promoted to be completely dissolved, standing divides sub-cloud water layer, upper layer feed liquid to be heated to 65-70 DEG C, and water IV is added to cool down
To 30-35 DEG C, standing divides sub-cloud water layer, the filtering of upper layer feed liquid, filter cake to be washed with water to filtrate pH=6-7, obtains wet product fenofibrate
Acid；
Step 4）By step 3）Gained wet product Fenofibric Acid and absolute ethyl alcohol sequentially add to have electric stirring, thermometer, return
It in the four-hole boiling flask for flowing condenser pipe, is warming up to Fenofibric Acid and is completely dissolved, activated carbon is added, 5-10 min are kept the temperature at 70-75 DEG C,
Heat filter, is cooled to 0-5 DEG C, dry Fenofibric Acid.
2. the method that a kind of phase transfer catalysis process according to claim 1 prepares high-purity Fenofibric Acid, it is characterised in that：
The acetone dosage is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Sodium hydroxide concentration is 1.0~1.2 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Chloroform dosage is 0.7~0.8 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
PEG-400 dosages are 0.07~0.13 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
I dosage of toluene is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
II dosage of toluene is 1.2~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Hydrochloric acid dosage is 1.1~1.4 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
I dosage of water is 1.3~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
II dosage of water is 1.0~1.3 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Water III, IV dosage of water are respectively 1.3~1.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Absolute ethyl alcohol dosage is 4.0~4.5 times of 4- hydroxyls -4 '-chlorobenzophenone weight；
Activated carbon dosage is 0.01~0.02 times of 4- hydroxyls -4 '-chlorobenzophenone weight.
3. the method that a kind of phase transfer catalysis process according to claim 1 prepares high-purity Fenofibric Acid, it is characterised in that：Institute
4- hydroxyls -4 '-chlorobenzophenone, sodium hydroxide, chloroform, acetone, the toluene stated are content 95.0%；PEG-400, absolute ethyl alcohol
For content 99.0%；Hydrochloric acid is mass concentration 36.0%；Activated carbon is medicinal.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483270A (en) * | 2019-09-09 | 2019-11-22 | 杭州新桂实业有限公司 | A kind of preparation method of efficient green synthesis fenofibrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951557A (en) * | 2014-04-22 | 2014-07-30 | 徐州工业职业技术学院 | Method for preparing fenofibric acid by using inorganic alkali as catalyst |
| CN107235837A (en) * | 2017-03-22 | 2017-10-10 | 扬子江药业集团有限公司 | A kind of preparation method of Fenofibric Acid |
-
2018
- 2018-03-16 CN CN201810217011.3A patent/CN108383709A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103951557A (en) * | 2014-04-22 | 2014-07-30 | 徐州工业职业技术学院 | Method for preparing fenofibric acid by using inorganic alkali as catalyst |
| CN107235837A (en) * | 2017-03-22 | 2017-10-10 | 扬子江药业集团有限公司 | A kind of preparation method of Fenofibric Acid |
Non-Patent Citations (1)
| Title |
|---|
| 李敢等: "非诺贝特酸的相转移催化合成", 《广州化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483270A (en) * | 2019-09-09 | 2019-11-22 | 杭州新桂实业有限公司 | A kind of preparation method of efficient green synthesis fenofibrate |
| CN110483270B (en) * | 2019-09-09 | 2022-05-20 | 杭州新桂实业有限公司 | Preparation method for efficient green synthesis of fenofibric acid |
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Application publication date: 20180810 |