CN103965038A - Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid - Google Patents
Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid Download PDFInfo
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- CN103965038A CN103965038A CN201310027381.8A CN201310027381A CN103965038A CN 103965038 A CN103965038 A CN 103965038A CN 201310027381 A CN201310027381 A CN 201310027381A CN 103965038 A CN103965038 A CN 103965038A
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- fenofibric acid
- recrystallization
- mixed solvent
- fenofibric
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- 0 CC(C)(C(*)O)OC(**1)=CC=C1C(C(C=C1)=CCC1N)=O Chemical compound CC(C)(C(*)O)OC(**1)=CC=C1C(C(C=C1)=CCC1N)=O 0.000 description 1
- MQOBSOSZFYZQOK-UHFFFAOYSA-N CC(C)(C(O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O Chemical compound CC(C)(C(O)=O)Oc(cc1)ccc1C(c(cc1)ccc1Cl)=O MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 description 1
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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
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Abstract
The invention provides a refining method for a high-purity clofibric acid blood-lipid regulating drug--fenofibric acid and specifically relates to a method of three-step recrystallization of a crude fenofibric acid product for preparation of high-purity fenofibric acid, belonging to refining methods in the field of physics. According to the invention, the crude fenofibric acid product is subjected to organic solvent recrystallization, mixed solvent recrystallization and methanol recrystallization so as to prepare a finished fenofibric acid product. Solvents used in the method are frequently used solvents and are cheap and easily available, requirements on reaction equipment are low, so transformation production is facilitated. With the method, the finished fenofibric acid product with purity of no less than 99.9% can be obtained.
Description
Technical field:
The invention belongs to medical technical field.The present invention relates to a kind of exquisite method of high-purity chloro shellfish butanoic acid derivative class lipid regulating agent Fenofibric Acid, more specifically, relate to Fenofibric Acid crude product and obtain through three step recrystallizations the novel method of highly purified Fenofibric Acid.
Background technology:
Fenofibric Acid is chlorine shellfish butanoic acid derivative class blood lipid regulation medicine, is the interior metabolism product of fenofibrate.Chinese name: Fenofibric Acid or fenofibrate, English name: 2-(4-(4-chlorobenzoyl) phenoxy)-2-methyl-propanoicacid; Chemical name: 2-[4-(4-chlorobenzene formacyl) phenoxy group]-2 Methylpropionic acid, structural formula is as follows.
Fenofibrate is the activeconstituents that is insoluble in very much water, and its absorption in digestive tube is limited, and bioavailability is lower.And fenofibrate is also the activity form of medicine, there is higher solubleness in small intestine district, can obviously reduce serum total cholesterol (TC), triglyceride level (TG) and high density lipoprotein cholesterol (HDL-C) level, bring into play good tune fat effect, go through to go on the market in the U.S. in 2009.
The current effective means of Fenofibric Acid of preparing is that fenofibrate is commercial product by fenofibrate hydrolysis, and it can be by for example making the chloro-4 '-dihydroxy benaophenonel of 4-react to prepare (EP0245156B1) with the bromo-2 Methylpropionic acid isopropyl ester of 2-2
The general preparation method of report Fenofibric Acid is: acetone, the chloro-4 '-dihydroxy benaophenonel of 4-and mineral alkali are joined in reaction flask, 30 DEG C of dropping trichloromethanes of temperature control, drip and finish rear back flow reaction, TLC monitoring, steaming desolventizes, and adds water, 60 DEG C regulate pH=2 with 18% hydrochloric acid, filter washing, dry, obtain Fenofibric Acid crude product.Obtain Fenofibric Acid through recrystallization again.But the product purity that this route obtains is low, crystal formation is difficult to be consistent with listing preparation crystal formation used.
Summary of the invention:
The present invention seeks to overcome the shortcoming and defect of above-mentioned prior art, obtain the Fenofibric Acid of quality higher than listing preparation.
Technical scheme of the present invention: a kind of process for purification of high-purity chloro shellfish butanoic acid derivative class lipid regulating agent Fenofibric Acid, step is as follows:
(1) organic solvent recrystallization: by Fenofibric Acid crude product: organic solvent mass ratio is 1:4 ~ 9, refluxes entirely molten, activated carbon decolorizing, and cooling crystallization obtains off-white color Fenofibric Acid solid.
Related organic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ethyl acetate, acetone, methylene dichloride trichloromethane.
(2) mixed solvent recrystallization: the off-white color solid obtaining by upper step organic solvent recrystallization: mixed solvent mass ratio is 1:2 ~ 6, reflux entirely molten, the crystallization that cools obtains off-white color Fenofibric Acid solid.
Related mixed solvent is the mixed solvent of organic alcohols and ester class.Alcohols is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, the mixed solvent that ester class is ethyl acetate.
(3) recrystallizing methanol: the Fenofibric Acid crude product obtaining by mixed solvent recrystallization: methanol quality, than for 1:7 ~ 10, obtains Fenofibric Acid finished product through recrystallizing methanol.
Advantage of the present invention is that solvent used is for conventional solvent, cheap and easy to get, low to conversion unit requirement, is convenient to transform and produces.Can obtain highly purified Fenofibric Acid, and crystal formation and listing preparation crystal formation used are consistent.
Embodiment:
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
Embodiment 1
(1) organic solvent recrystallization: add 400g dehydrated alcohol and 50g Fenofibric Acid in the there-necked flask of 1000ml, reflux and dissolve, add 5g gac, decolouring 30min, filtered while hot, cooling crystallization, filters, and 60 DEG C are dry, obtain off-white color solid 38g, yield 76%, purity 99.30%.
(2) mixed solvent recrystallization: the mixed solvent that adds 140g dehydrated alcohol and ethyl acetate (volume ratio 1:1) in the there-necked flask of 250ml, add again step gained solid 35g, reflux entirely molten, cooling crystallization, filter, 60 DEG C dry, obtains off-white color solid 24.6g, yield 70.3%, purity 99.81%.
(3) recrystallizing methanol: the off-white color solid that adds 160g methyl alcohol and 20g mixed solvent recrystallization to obtain in the there-necked flask of 250ml, reflux entirely molten, cooling crystallization, filters, and 60 DEG C are dry, obtain white solid 15g, yield 75%, purity 99.92%.
Embodiment 2
(1) organic solvent recrystallization: add 350g acetone and 50g Fenofibric Acid in the there-necked flask of 1000ml, reflux and dissolve, add 5g gac, decolouring 30min, filtered while hot, cooling crystallization, filters, and 60 DEG C are dry, obtain off-white color solid 35g, yield 70%, purity 99.36%.
(2) mixed solvent recrystallization: add the mixed solvent of 90g dehydrated alcohol and ethyl acetate (volume ratio 1:1) in the there-necked flask of 250ml, then add step gained solid 30g, reflux entirely molten, cooling crystallization, filters, and 60 DEG C dry, obtain off-white color solid 22.2g, yield 74%, purity 99.76%.
(3) recrystallizing methanol: the off-white color solid that adds 160g methyl alcohol and 20g mixed solvent recrystallization to obtain in the there-necked flask of 250ml, reflux entirely molten, cooling crystallization, filters, and 60 DEG C are dry, obtain white solid 15.4g, yield 77%, purity 99. 90%.
Embodiment 3
(1) organic solvent recrystallization: add 340g trichloromethane and 50g Fenofibric Acid in the there-necked flask of 1000ml, reflux and dissolve, add 5g gac, decolouring 30min, filtered while hot, cooling crystallization, filters, and 60 DEG C are dry, obtain off-white color solid 32g, yield 64%, purity 99.27%.
(2) mixed solvent recrystallization: add the mixed solvent of 100g n-propyl alcohol and ethyl acetate (volume ratio 1:1) in the there-necked flask of 250ml, then add step gained solid 30g, reflux entirely molten, cooling crystallization, filters, and 60 DEG C dry, obtain off-white color solid 21g, yield 70%, purity 99.78%.
(3) recrystallizing methanol: the off-white color solid that adds 160g methyl alcohol and 20g mixed solvent recrystallization to obtain in the there-necked flask of 250ml, reflux entirely molten, cooling crystallization, filters, and 60 DEG C are dry, obtain white solid 15.2g, yield 76%, purity 99.91%.
The foregoing is only specific examples of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, its technical scheme that still can record aforementioned each embodiment is modified, or part technical characterictic is wherein equal to replacement.Within the spirit and principles in the present invention all, any amendment, the improvement etc. done, within all should being included in protection scope of the present invention.
Claims (5)
1. a process for purification for high-purity chloro shellfish butanoic acid derivative class lipid regulating agent Fenofibric Acid, chemical formula is
2. a high-purity chloro shellfish butanoic acid derivative class lipid regulating agent process for purification, is characterized in that following steps:
(1) organic solvent recrystallization: press Fenofibric Acid crude product, add solvent with minimum dissolving ratio under reflux temperature, decolour under reflux temperature, obtain purity and be >=99.2% Fenofibric Acid.(2) mixed solvent recrystallization: the Fenofibric Acid through a recrystallization passes through mixed solvent recrystallization again, obtains more than 99.8% Fenofibric Acid of purity.(3) recrystallizing methanol: mixed solvent recrystallization obtains Fenofibric Acid methyl alcohol and carries out recrystallization, obtains the Fenofibric Acid that purity is greater than 99.9%, and purity is better than the preparation that goes on the market.
3. method as claimed in claim 2, is characterized in that step (1) organic solvent used is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ethyl acetate, acetone, methylene dichloride or trichloromethane.Organic solvent mass ratio is 1:4 ~ 9.
4. method as claimed in claim 2, is characterized in that the related mixed solvent of step (2) is the mixed solvent of organic alcohols and ester class.Alcohols is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, and ester class is ethyl acetate.
Mixed solvent mass ratio is 1:2 ~ 6.
5. method as claimed in claim 2, is characterized in that step (3) methanol quality than being 1:7 ~ 10.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310027381.8A CN103965038A (en) | 2013-01-24 | 2013-01-24 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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| CN201310027381.8A CN103965038A (en) | 2013-01-24 | 2013-01-24 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447292A (en) * | 2014-10-31 | 2015-03-25 | 扬子江药业集团有限公司 | 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid polymorph as well as preparation method and pharmaceutical composition thereof |
| CN104628554A (en) * | 2015-02-09 | 2015-05-20 | 徐州工程学院 | Fenofibric acid crystal form and preparation method thereof |
-
2013
- 2013-01-24 CN CN201310027381.8A patent/CN103965038A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447292A (en) * | 2014-10-31 | 2015-03-25 | 扬子江药业集团有限公司 | 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid polymorph as well as preparation method and pharmaceutical composition thereof |
| CN108558655A (en) * | 2014-10-31 | 2018-09-21 | 扬子江药业集团有限公司 | 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph and preparation method thereof and pharmaceutical composition |
| CN108558655B (en) * | 2014-10-31 | 2021-06-29 | 扬子江药业集团有限公司 | 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof |
| CN104628554A (en) * | 2015-02-09 | 2015-05-20 | 徐州工程学院 | Fenofibric acid crystal form and preparation method thereof |
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Application publication date: 20140806 |