CN110483270A - A kind of preparation method of efficient green synthesis fenofibrate - Google Patents
A kind of preparation method of efficient green synthesis fenofibrate Download PDFInfo
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- CN110483270A CN110483270A CN201910849737.3A CN201910849737A CN110483270A CN 110483270 A CN110483270 A CN 110483270A CN 201910849737 A CN201910849737 A CN 201910849737A CN 110483270 A CN110483270 A CN 110483270A
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C—CHEMISTRY; METALLURGY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- 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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- C—CHEMISTRY; METALLURGY
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- C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
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Abstract
The invention discloses a kind of preparation methods of efficient green synthesis fenofibrate.Including following procedure: putting into the chloro- 4 '-dihydroxy benaophenonel of 4-, acetone and TEBA in the aqueous slkali of high concentration；40 degree of temperature of control or less dropwise addition chloroform drips Bi Huiliu 1-2 hours, and acetone is evaporated Hou Jiashui, is extracted twice with extractant by high temperature filtration salt after liquid phase detection is qualified, mother liquor, removes unreacted raw material, and extractant can be focused on recycled twice.Active carbon reflux decoloration is added in water, acid is adjusted to obtain fenofibrate solid.The present invention has many advantages, such as that simple process, yield with short production cycle are higher than pertinent literature, at low cost and environmental pollution is small.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of efficient green synthesis fenofibrate
Background technique
Fenofibrate is the important intermediate for synthesizing blood lipid-lowering medicine fenofibrate, and purposes is very extensive, at present city
Requirement of the field to its appearance, content, known impurities and unknown impuritie is also increasingly stringenter.Traditional handicraft is difficult once to reach market
Standard.Traditional handicraft is usually using the chloro- 4 '-dihydroxy benaophenonel of 4-, acetone and chloroform as raw material, in highly basic and phase transfer catalyst
Under the conditions of obtained by condensation reaction.Existing inorganic base domestic at present prepares the report of fenofibrate, but there are acetone, nothing
Machine alkali, chloroform, sour dosage are big, and crude product yield is 85%, need to use re crystallization from toluene, and at high cost, the three wastes are more, and solvent does not obtain
To being effectively treated, the disadvantages of salt is not easy to be layered more, influences subsequent reactions, and industrializing implementation difficulty is big.Gu Caixian et al. [reducing blood lipid
The synthesis medical industry of medicine Fenofibrate, 1983 ,] using inorganic base as catalyst, using 4- hydroxyl -4 '-chlorobenzophenone, chlorine
Imitative, acetone is main raw material(s), by condensation, distillation, acidification, filtering, recrystallizes, is dried to obtain fenofibrate, because of its original
The disadvantages of high material consumption, product needs to recrystallize, at high cost, and the three wastes are big and cannot achieve industrialization.Lee dares [a kind of with nothing
Machine alkali is the method application number 201410164268.9 of catalyst preparation fenofibrate] in proposition with sodium hydroxide be catalysis
Agent, but salt content is high in mother liquor, waste water is big, and post-processing is complicated, and the subsequent material that gets rid of introduces the malicious solvent toluene of new easy system, peculiar smell
Greatly, the problems such as material color is partially yellow still remains.
Summary of the invention:
In order to solve the problems, such as background technique, the present invention provides a kind of efficient green synthesis fenofibrates
Method, by this method, while reducing the three wastes, without purification, appearance and content directly reach market standard (height at present
Hold market demands appearance be white, content not less than the chloro- 4 '-dihydroxy benaophenonel of 99.5%, 4- be not higher than 0.2%, it is unknown miscellaneous
Matter is not higher than 0.2%).
The technical solution adopted by the invention is as follows:
The present invention the following steps are included:
1) 4- chloro-4-hydroxyl benzophenone, acetone and TEBA are put into the aqueous slkali of high concentration；TEBA is three second of benzyl
Ammonium chloride C13H22ClN。
2) solution temperature in step 1) is controlled to 40 DEG C or less dropwise addition chloroforms, drop is after Bi Huiliu 1-2 hours, while hot mistake
It filters salt (NaCl)；
3) acetone in the filtered mother liquor of step 2) is evaporated into Hou Jiashui, adjusts PH, is extracted twice and is removed using extractant
Unreacted raw material is removed, layer of fetching water；
4) in step 3) water layer extracted be added active carbon reflux decoloration, after filtering by mother liquor tune acid out go out obtain it is non-
Nobert acid solid.
Aqueous slkali in the step 1 is sodium hydroxide solution, mass percent concentration 40-70%, preferably 60%.
4- chloro-4-hydroxyl benzophenone: aqueous slkali: acetone: TEBA: the molar ratio of chloroform is 1:8-12:16:0.1:2.3,
Preferably 1:10:16:0.1:2.3.
Increase step filtering after haloform reaction is qualified in the step 2), for removing most of salt, makes salinity in mother liquor
It substantially reduces, reduces environmental protection pressure；The condition of haloform reaction qualification is the quality hundred of the chloro- 4 '-dihydroxy benaophenonel of 4- in solution
Divide specific concentration≤1.0%.
PH to 8-9 is adjusted in the step 3).
Extractant is using one of toluene, chlorobenzene, butyl acetate or methyl tertiary butyl ether(MTBE) in the step 3), preferably
Butyl acetate；Solvent quantity is 0.5-2 times, preferably 1 times of 4- chloro-4-hydroxyl benzophenone；Extractant can be with circulating sleeve
With twice, focus on.
The invention has the benefit that
1) present invention uses high-concentration caustic soda liquid, carries out reaction in liquid-liquid interface, and the presence of phase transfer catalyst, reaction is more
Heating and, the reaction time is shorter.
2) invention increases a steps to get rid of salt process, and the salt that reaction generates is removed, and it is high to solve salinity in subsequent waste water
The problem of, greatly reduce waste water usage amount.
3) present invention increases extractant extraction, because of the difference of solubility, raw material is far longer than in the solubility of extractant
The solubility of product keeps product purity higher to eliminate unreacted raw material.
4) invention increases a step activity carbon decoloring, product appearance and content is made disposably to reach market standard, reduced
Primary purification shortens process flow, improves product yield.
Specific embodiment
Below with reference to embodiment, the invention will be further described.
Embodiment one
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone, TEBA9 grams, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, evaporate mother by 400 grams of acetone
After acetone in liquid (filtrate), add 400 grams of water, tune PH is 8-9, and active carbon 3 is added after being extracted in two times with 100 grams of butyl acetates
Gram, 80 degree of filter activity charcoals after stirring 30 minutes, it to PH is 1-2 that mother liquor (filtrate), which adjusts sour (hydrochloric acid), and filtering drying obtains white solid
125.87 grams of body, molar yield 90%, purity 99.73%, content 99.93%, raw material (the chloro- 4 '-dihydroxy benaophenonel of 4-)
0.11%.
Embodiment two
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone 400 grams of acetone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, steam third
Ketone adds 400 grams of water, and tune PH is 8-9, and 3 grams of active carbon, 80 degree are added after being extracted in two times with 100 grams of butyl acetates in embodiment 1
Filter activity charcoal after stirring 30 minutes, mother liquor tune acid PH are 1-2, and filtering drying obtains 128.26 grams of white solid, molar yield
91%, purity 99.69%, content 99.89%, raw material 0.13%.
Embodiment three
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone 400 grams of acetone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, steam third
Ketone adds 400 grams of water, and tune PH is 8-9, and 3 grams of active carbon, 80 degree are added after being extracted in two times with 100 grams of butyl acetates in embodiment 2
Filter activity charcoal after stirring 30 minutes, mother liquor tune acid PH are 1-2, and filtering drying obtains 128.31 grams of white solid, molar yield
91%, purity 99.68%, content 99.91%, raw material 0.12%.
Comparative example one
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, steams acetone after dripping two hours of Bi Huiliu, add water 1000 by 400 grams of acetone
Gram, tune PH is 8-9, after extract in two times with 100 grams of butyl acetates plus 3 grams of active carbon, 80 degree stir 30 minutes after filter activity
Charcoal, mother liquor tune acid PH are 1-2, and filtering drying obtains 126.03 grams of white solid, molar yield 90%, purity 99.65%, content
99.87%, raw material 0.13%.
Comparative example two
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, steams acetone after dripping two hours of Bi Huiliu, add water 1000 by 400 grams of acetone
Gram, tune PH is 8-9, adds 3 grams of active carbon, and 80 degree filter activity charcoals after stirring 30 minutes, mother liquor tune acid PH is 1-2, filtering drying
Must be 128.19 grams of white solid, molar yield 91%, purity 99.17%, content 99.33%, raw material 0.45%.
Comparative example three
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone 400 grams of acetone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, steam third
Ketone, adds 400 grams of water, and tune PH is 8-9, adds 3 grams of active carbon, and 80 degree filter activity charcoals after stirring 30 minutes, mother liquor tune acid PH is 1-
2, filtering drying obtains 128.25 grams of white solid, molar yield 91%, purity 99.15%, content 99.31%, raw material 0.49%.
Comparative example four
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone 400 grams of acetone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, steam third
Ketone adds 400 grams of water, and tune PH is 8-9, and after 100 grams of butyl acetates extract in two times, mother liquor tune acid PH is 1-2, and filtering drying obtains light
126.11 grams of yellow solid, molar yield 91%, purity 99.66%, content 99.88%, raw material 0.13%.
Comparative example five
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, steams acetone after dripping two hours of Bi Huiliu, add water 1000 by 400 grams of acetone
Gram, tune acid PH is 1-2, and filtering drying obtains 128.05 grams of faint yellow solid, molar yield 91%, purity 99.09%, content
99.24%, raw material 0.51%.
Comparative example six
280 gram of 60% sodium hydroxide solution is added in 2L there-necked flask, is cooled to room temperature, the chloro- 4 '-hydroxyl of 100 grams of 4- is added
Benzophenone 400 grams of acetone, 9 grams of TEBA, is added dropwise 120 grams of chloroform, filters salt while hot after dripping two hours of Bi Huiliu, steam third
Ketone, adds 400 grams of water, and tune acid PH is 1-2, and filtering drying obtains 128.21 grams of faint yellow solid, molar yield 91%, purity
99.11%, content 99.33%, raw material 0.45%.
According to the experimental data of above table:
1) when not getting rid of salt, in order to dissolve extra salt, it is necessary to increase water, wastewater flow rate is caused to become larger.
2) when not having to extractant extraction, product purity is lower, it is difficult to which the requirement for reaching existing market needs to re-refine one
It is secondary, yield will certainly be lost and increase energy consumption.
3) active carbon decoloring is not had to, material yellowish makes product and is also difficult to reach market demands.
To sum up it may be concluded that a step is added early period to get rid of salt and extraction, purity is can be improved in later period active carbon decoloring,
Waste water is reduced, appearance is improved, and then reduces energy consumption and reaches market demands simultaneously.
Above example is only preferred embodiment of the invention, is not that the invention has other forms of limitations, is appointed
What those skilled in the art changed or be modified as possibly also with the technology contents of the disclosure above equivalent variations etc.
Imitate embodiment.But without departing from the technical solutions of the present invention, according to the technical essence of the invention to above embodiments institute
Any simple modification made, still falls within the protection scope of technical solution of the present invention.
Claims (6)
1. a kind of preparation method of efficient green synthesis fenofibrate, which comprises the following steps:
1) 4- chloro-4-hydroxyl benzophenone, acetone and TEBA are put into the aqueous slkali of high concentration；
2) solution temperature in step 1) is controlled to 40 DEG C or less dropwise addition chloroforms, drop filters while hot after Bi Huiliu 1-2 hours
Salt；
3) acetone in the filtered mother liquor of step 2) is evaporated into Hou Jiashui, adjusts PH, is extracted twice using extractant, fetched water
Layer；
4) active carbon reflux decoloration is added in step 3) water layer extracted, goes out mother liquor tune acid out to obtain fenofibrate after filtering
Special acid solid.
2. a kind of preparation method of efficient green synthesis fenofibrate according to claim 1, which is characterized in that described
Aqueous slkali in step 1 is sodium hydroxide solution, mass percent concentration 40-70%.
3. a kind of preparation method of efficient green synthesis fenofibrate according to claim 1, which is characterized in that 4-
Chloro-4-hydroxyl benzophenone: aqueous slkali: acetone: TEBA: the molar ratio of chloroform is 1:8-12:16:0.1:2.3.
4. a kind of preparation method of efficient green synthesis fenofibrate according to claim 1, which is characterized in that described
PH to 8-9 is adjusted in step 3).
5. a kind of preparation method of efficient green synthesis fenofibrate according to claim 1, which is characterized in that described
Extractant is using one of toluene, chlorobenzene, butyl acetate or methyl tertiary butyl ether(MTBE), preferably butyl acetate in step 3)；Extraction
Taking agent dosage is 0.5-2 times of 4- chloro-4-hydroxyl benzophenone.
6. a kind of preparation method of efficient green synthesis fenofibrate according to claim 1, which is characterized in that described
The purity for the fenofibrate solid that step 4) obtains is 99.5% or more, and color 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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2019
- 2019-09-09 CN CN201910849737.3A patent/CN110483270B/en active Active
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 |
|---|
| 李敢等: "非诺贝特酸的相转移催化合成", 《广州化工》 * |
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