CN104478717A - Purification method of fenofibrate - Google Patents
Purification method of fenofibrate Download PDFInfo
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- CN104478717A CN104478717A CN201410682048.5A CN201410682048A CN104478717A CN 104478717 A CN104478717 A CN 104478717A CN 201410682048 A CN201410682048 A CN 201410682048A CN 104478717 A CN104478717 A CN 104478717A
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- compound
- purification process
- fenofibrate
- organic solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a purification method of fenofibrate. A synthesis route of the purification method is shown as the following formulae which are as shown in the specification. The synthesis route comprises the following steps: (1) carrying out esterification reaction on a raw material 1 to generate a compound 2, wherein the purity of the compound 2 is greater than or equal to 96%; and (2) enabling the compound 2 to react with a compound 3 to generate a compound 4. The purification method comprises the following steps: washing a crude product of the compound 4 by using an organic solvent 1 and alkaline, then pulping the compound 4 by using an organic solvent 2. The purification method of fenofibrate at least has the following beneficial effects that the fenofibrate is high in purity, reaches the purity requirements of the raw medicine, is high in yield, free of poisonous reagent and low in emission of three wastes; the solvents can be reused.
Description
Technical field
The present invention relates to a kind of purification process of bulk drug, specifically, relate to a kind of purification process of fenofibrate.
Background technology
Fenofibrate is the important intermediate of synthesis blood lipid-lowering medicine fenofibrate, its purposes widely, usually with 4-hydroxyl-4 '-chlorobenzophenone, acetone and chloroform be raw material, obtained by condensation reaction.The current domestic existing report preparing fenofibrate, but acetone, mineral alkali, chloroform, sour consumption are large, thick product yield is 85%, need with re crystallization from toluene, cost is high, and the three wastes are many, solvent is not effectively addressed, the many not easily layerings of salt, affect subsequent reactions, the shortcomings such as industrializing implementation difficulty is large.
The people such as the Gu Caixian (synthesis of hypolipidemic Fenofibrate.Medicine industry, 1983, (6)) take mineral alkali as catalyzer, adopting 4-hydroxyl-4 '-chlorobenzophenone, chloroform, acetone is main raw material(s), obtains fenofibrate, the not clear and definite concrete mineral alkali product of the method through condensation, distillation, acidifying, filtration, recrystallization, drying, and its raw materials consumption is large, product cost is high, and the three wastes are large, cannot reach material purity requirement; (TEBA catalyzes and synthesizes fenofibrate to the people such as Qiao Deyang.Synthetic chemistry, 2009,17 (6)) aforesaid method is improved, the potassium hydroxide solution adopting about 50% is catalyzer, with 4-hydroxyl-4 '-chlorobenzophenone, chloroform, acetone is main raw material(s), TEBA is phase-transfer catalyst, and whole reaction is steadily carried out at liquid-liquid interface, achieve certain improvement effect, but it is large equally to there is raw materials consumption in this method, and product cost is high, cannot reach material purity requirement, the problem that the three wastes are large, affects its industrial applications and promotes.
Summary of the invention
The purification process of a kind of fenofibrate of the present invention, synthetic route is as follows:
Comprise the following steps:
(1) raw material 1 carries out esterification generation compound 2, purity >=96% of compound 2;
(2) compound 2 and 3 compound 3 reacting generating compound 4;
Purification process is: compound 4 crude product is used organic solvent 1, alkali liquid washing successively, is then pulled an oar by compound 4 organic solvent 2.
Further, in purification process, organic solvent 1 is ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.
Further, in purification process, organic solvent 2 is normal hexane or normal heptane.
Further, in purification process alkali lye to be massfraction be 5% sodium bicarbonate aqueous solution.
Further, when in step (2), compound 2 and compound 3 react, compound 3 is 1eq, and salt of wormwood is 4 ~ 6eq.
Compared with prior art, the purification process of fenofibrate provided by the invention at least has following beneficial effect: product purity is high, and reach bulk drug purity requirement, yield is high, and use without poisonous reagent, three waste discharge is few, and solvent for use can reuse.
Embodiment
Below will describe the present invention.But these embodiments do not limit the present invention, the conversion in the method that those of ordinary skill in the art makes according to these embodiments is all included in protection scope of the present invention.
Embodiment 1: synthetic compound 2
Add 1000g raw material 1,1960g Virahol and pyridine 5g to reaction flask, drip 925g thionyl chloride, heat release is obvious, control temperature 20 ~ 30 DEG C, 1h drips complete, is warming up to 80 ~ 85 DEG C, reaction 4 ~ 5h, is cooled to <40 DEG C, concentrated, add water and MTBE, organic layer massfraction is that 5% sodium hydrogen carbonate solution is washed, washing, drying, concentrated, rectifying obtains 1019.4g compound 2, yield: 87.3%, purity: 98.2%.
Embodiment 2: synthesis and purifying compounds 4
700g compound 3 (4-chloro-4 is added in reaction flask,-dihydroxy benaophenonel), 1255g compound 2,2070g salt of wormwood and 800ml water, be warming up to 80-90 DEG C, reaction 36h, endpoint detection compound 3 content≤3%, underpressure distillation is except desolventizing, be cooled to 0 ~ 10 DEG C, add 1L water, stir 2-3h, suction filtration, filter cake 2L water wash, dry crude product 920g, crude product is pulled an oar at adding 1L Virahol 0-10 DEG C 2h, suction filtration, the drip washing of filter cake 1L normal heptane, dry white products 830g, the product tertiary ether of 4.5kg first dissolves, 2L 5%NaHCO
3washing, 2L 5% brine It, separatory, organic phase concentrates, and adds 1L normal heptane making beating 1h, suction filtration, dry 752g Fenofibrate compound 4, yield: 69.2%, purity: 99.96%.
Embodiment 3: synthesis and purifying compounds 4
700g compound 3 (4-chloro-4 is added in reaction flask,-dihydroxy benaophenonel), 1270g compound 2,2150g salt of wormwood and 800ml water, be warming up to 80-90 DEG C, reaction 40h, endpoint detection compound 3 content≤3%, underpressure distillation is except desolventizing, be cooled to 0 ~ 10 DEG C, add 1L water, stir 2-3h, suction filtration, filter cake 2L water wash, dry crude product 920g, crude product is pulled an oar at adding 1L Virahol 0-10 DEG C 2h, suction filtration, the drip washing of filter cake 1L normal heptane, dry white products 860g, the product tertiary ether of 4.5kg first dissolves, 2L 5%NaHCO
3washing, 2L 5% brine It, separatory, organic phase concentrates, and adds 1L normal heptane making beating 1h, suction filtration, dry 763g Fenofibrate compound 4, yield: 70.3%, purity: 99.97%.
Be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
Claims (5)
1. a purification process for fenofibrate, is characterized in that, synthetic route is as follows:
Comprise the following steps:
(1) raw material 1 carries out esterification generation compound 2, purity >=96% of compound 2;
(2) compound 2 and compound 3 reacting generating compound 4;
Purification process is: compound 4 crude product is used organic solvent 1, alkali liquid washing successively, is then pulled an oar by compound 4 organic solvent 2.
2. the purification process of fenofibrate according to claim 1, is characterized in that, in described purification process, organic solvent 1 is ethyl acetate, isopropyl acetate or methyl tertiary butyl ether.
3. the purification process of fenofibrate according to claim 1, is characterized in that, in described purification process, organic solvent 2 is normal hexane or normal heptane.
4. the purification process of fenofibrate according to claim 1, is characterized in that, in described purification process alkali lye to be massfraction be 5% sodium bicarbonate aqueous solution.
5. the purification process of fenofibrate according to claim 1, is characterized in that, when in step (2), compound 2 and compound 3 react, compound 3 is 1eq, and salt of wormwood is 4 ~ 6eq.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410682048.5A CN104478717A (en) | 2014-11-24 | 2014-11-24 | Purification method of fenofibrate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410682048.5A CN104478717A (en) | 2014-11-24 | 2014-11-24 | Purification method of fenofibrate |
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| CN104478717A true CN104478717A (en) | 2015-04-01 |
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| CN201410682048.5A Pending CN104478717A (en) | 2014-11-24 | 2014-11-24 | Purification method of fenofibrate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018018618A1 (en) * | 2016-07-29 | 2018-02-01 | 浙江工业大学 | Fenofibrate crystalline form and manufacturing method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0137327A2 (en) * | 1983-09-14 | 1985-04-17 | Hitachi, Ltd. | Liquid fuel cell |
| US20040073058A1 (en) * | 2001-02-02 | 2004-04-15 | Giuseppe Guazzi | Process for the preparation of fibrates |
-
2014
- 2014-11-24 CN CN201410682048.5A patent/CN104478717A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0137327A2 (en) * | 1983-09-14 | 1985-04-17 | Hitachi, Ltd. | Liquid fuel cell |
| US20040073058A1 (en) * | 2001-02-02 | 2004-04-15 | Giuseppe Guazzi | Process for the preparation of fibrates |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018018618A1 (en) * | 2016-07-29 | 2018-02-01 | 浙江工业大学 | Fenofibrate crystalline form and manufacturing method thereof |
| CN108026020A (en) * | 2016-07-29 | 2018-05-11 | 浙江工业大学 | A kind of crystal form of fenofibrate and preparation method thereof |
| CN108026020B (en) * | 2016-07-29 | 2021-10-08 | 浙江工业大学 | Crystal form of fenofibrate and preparation method thereof |
| US11427528B2 (en) | 2016-07-29 | 2022-08-30 | Hangzhou Solipharma Co., Ltd. | Fenofibrate crystalline form and manufacturing method thereof |
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Application publication date: 20150401 |