CN102030676A - Synthesis method of bezafibrate for regulating blood fat - Google Patents
Synthesis method of bezafibrate for regulating blood fat Download PDFInfo
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- CN102030676A CN102030676A CN2009101450616A CN200910145061A CN102030676A CN 102030676 A CN102030676 A CN 102030676A CN 2009101450616 A CN2009101450616 A CN 2009101450616A CN 200910145061 A CN200910145061 A CN 200910145061A CN 102030676 A CN102030676 A CN 102030676A
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Abstract
The invention relates to the field of medicinal chemistry and discloses a synthesis method of bezafibrate for regulating blood fat. In the synthesis method, stabilized p-hydroxybenzene ethylamine hydrochloride and p-chlorobenzene formyl halide are used as initial raw materials to be substituted, hydrolyzed and condensed to obtain a target compound. The synthesis method has the advantages of low cost, mild reaction conditions, controllable processes and stable quality and is beneficial to industrialized production, the raw materials can be easily obtained and are relatively stabilized, the purity reaches 99.5% by the detection of the high performance liquid chromatography (HPLC), and the total yield is 48.1%.
Description
One, technical field
The present invention relates to the pharmaceutical chemistry field, the particularly preparation method of phenoxy acetic acid class blood lipid regulation medicine, the synthetic method of specifically a kind of blood lipid regulation medicine-bezafibrate (I).
Two, background technology
Bezafibrate (I) is a s-generation phenoxy acetic acid class modulation medicine (Bezafibrate), can reduce blood low-density lipoprotein and cholesterol, is mainly used in the treatment of IIb, III, IV type hyperlipidemia.
The bezafibrate synthetic route of patent and bibliographical information mainly contains following several at present:
1. under the water condition, operate, adopt phase-transfer catalyst, the reduction running cost (Wu Jie, etc., patent publication No.: CN 101353315A).
2. use p-Hydroxybenzaldehyde and Nitromethane 99Min. to be main raw material, through chemical reactions such as condensations, hydrogenation, acidylate, obtain bezafibrate (Ceng Zhirong, etc., Chinese Journal of Pharmaceuticals, 1997,28 (12): 533-534; Chen Yaping, Liaoning chemical industry, 2007,36 (11): 733-736).
The aforesaid method weak point is, use p-Hydroxybenzaldehyde and Nitromethane 99Min. to be main raw material, in reduction hydroxy-beta-nitrostyrolene generation Uteramin has all been adopted metal (Zn, Fe etc.) and hydrochloric acid condition in reacting, increased the post-processing difficulty of " three wastes "; At acidylate and condensation step, adopt phase-transfer catalyst and use water as solvent, long reaction time, technology stability is poor, and by product is more, and is difficult for purifying.
The inventor is through experimental study repeatedly; find a kind of from the Uteramin hydrochloride; carry out the salt acidifying in advance; make the stability of raw material obtain protection, for the productive rate that improves subsequent step provides condition, simultaneously; be reflected in the anhydrous pyridine and carry out; and effectively utilize the reaction that is hydrolyzed of ethanol instead of methanol, thus researched and developed preparation bezafibrate (I) novel method, finish the present invention thus.
Three, summary of the invention
The technical problem to be solved in the present invention is intended to overcome the deficiency in the above-mentioned synthetic preparation process, a kind of novel method for synthesizing of bezafibrate is provided, and instruct suitability for industrialized production with this method, this method is that research and design is the synthetic method of feedstock production bezafibrate with the Uteramin hydrochloride of stabilization, this method provides a kind of process Muriatic stable raw material earlier, in reaction process, selected chlorobenzene acetyl halide (X=Cl simultaneously, Br, I), the alternative and the economy of reaction have been enlarged, improved the yield of reaction, in hydrolysis reaction, use the ethanol instead of methanol in addition, reduced " three wastes " and difficulty of post-processing.
The invention provides target product is:
Reaction conditions gentleness in the reaction process of the present invention, controllability is strong, and the product purity height does not need loaded down with trivial details purification devices to handle, and prepared target product bezafibrate (I) purity has obtained (HPLC detection) more than 99.5%.
Therefore, the object of the present invention is to provide a kind of synthetic method for preparing bezafibrate;
Another object of the present invention is to use hydrochloric acid earlier with the phydroxybenzeneactamide stabilization, use the hydrogenchloride of anhydrous pyridine absorption reaction release again, with the reaction of raising single step and total reaction yield and the synthetic cost that reduces bezafibrate, more help suitability for industrialized production.
This process is shown below:
Following example in detail the better method of preparation The compounds of this invention, but cited embodiment is illustrated the present invention, and is not the restriction scope that the present invention protected.
Under design prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.Except as otherwise noted, percentage ratio involved in the present invention refers to weight percentage.
Embodiment 1:
(1) N, O-two (4-chlorobenzene formacyl) tyrasamine
Get Uteramin hydrochloride 101.3g (0.58mol), add sodium hydroxide 25g and 500ml anhydrous pyridine respectively in the reaction flask, stirring drips parachlorobenzoyl chloride 220g (1.26mol) at 25 ℃, drips to finish to be warming up to 98-100 ℃, reacts 15 minutes.Be cooled to 35 ℃, pour in the 2000g mixture of ice and water, the hcl acidifying with 15% to pH be 6, separate out white solid; water, the washing of 10% sodium bicarbonate successively, drying, product N; O-two (4-chlorobenzene formacyl) tyrasamine (2) 168.7 grams, productive rate 70.2%, fusing point: 200-202 ℃.
(2) N-(4-chloro-benzoyl chloride) tyrasamine
Get the potassium hydroxide 510ml of (2) 150g (0.36mol), ethanol 1500ml, 2M, be heated to 40 ℃, reacted 1 hour, TLC follows the tracks of reaction, reaction is finished, and cooling adds the hydrochloric acid neutralization of 2M, respectively water, 10% sodium bicarbonate washing, drying, ethyl alcohol recrystallization gets N-(4-chloro-benzoyl chloride) tyrasamine (3) 90.2 grams, productive rate 90.8%, fusing point: 172-174 ℃.
(3) bezafibrate
(65g, 0.24mol), acetone 1000ml, sodium hydroxide 140g, (10g 0.05mol), drips the 130g chloroform down at 30 ℃ to TEBA, drips to finish and stirs 3 hours, and TLC follows the tracks of reaction to add (3) successively.Reaction is finished, and the pressure reducing and steaming solvent adds water 1500ml, is stirred to solid and dissolves fully, adds 15% hcl acidifying, separates out white solid, adds acetone recrystallization, gets bezafibrate (I) 64.4 grams, productive rate 75.5%; Fusing point: 180-184 ℃, purity 99.5% (HPLC detection).Ultimate analysis C
19H
20ClNO
4, calculated value (%): C 63.02, and H 5.53, and N 3.87; Measured value (%): C63.11, H5.49, N3.82.
Claims (7)
1. the synthetic method of a general formula bezafibrate (I) is characterized in that: this method comprises and adopts the Uteramin hydrochloride (1) of hydrochloric acid stabilization to carry out substitution reaction as starting raw material and 4-chlorobenzene acetyl halide earlier; (3) compound is mixed into the rearrangement reaction with chloroform, acetone under alkaline condition, under acidulated condition, obtains bezafibrate (I) again:
2. according to the method for claim 1, it is characterized in that: raw material Cl-C
6H
5X among the-COX is respectively Cl, Br, I.
3. according to the method for claim 1, it is characterized in that: reacting described solvent is to carry out under protic solvent, and this protic solvent is selected from methyl alcohol, ethanol, isopropylcarbinol, or the mixture of two or more solvents wherein.
4. according to the process of claim 1 wherein that the solvent of hydrolysis reaction carries out under the ethanol condition.
5. according to the process of claim 1 wherein what substitution reaction was carried out under the pyridine that drying is crossed.
6. require a kind of method for preparing bezafibrate (I) according to claim 1, it is characterized in that: described preparation method may further comprise the steps:
Step 1: the Uteramin hydrochloride with the hydrochloric acid stabilization is a starting raw material, through substitution reaction, carries out under the anhydrous pyridine condition, gets N, O-two (4-chlorobenzene formacyl) tyrasamine (2);
Step 2: potassium hydroxide and ethanolic soln are reacted with (2), and acidifying prepares N-(4-chloro-benzoyl chloride) tyrasamine (3) again;
Step 3: (3) under alkaline condition, are carried out the compound that condensation, rearrangement reaction prepare formula (I) with chloroform, sodium hydroxide, acetone, be target compound-bezafibrate.
7. bezafibrate preparation method according to claim 6 is characterized in that: hydrochloric acid need transfer to 15% concentration during acidifying, and washing transfers to 10% concentration with sodium bicarbonate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101450616A CN102030676A (en) | 2009-09-25 | 2009-09-25 | Synthesis method of bezafibrate for regulating blood fat |
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| CN2009101450616A CN102030676A (en) | 2009-09-25 | 2009-09-25 | Synthesis method of bezafibrate for regulating blood fat |
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| CN102030676A true CN102030676A (en) | 2011-04-27 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108569979A (en) * | 2017-03-14 | 2018-09-25 | 浙江九洲药业股份有限公司 | A kind of preparation process of Bezafibrate class compound |
-
2009
- 2009-09-25 CN CN2009101450616A patent/CN102030676A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108569979A (en) * | 2017-03-14 | 2018-09-25 | 浙江九洲药业股份有限公司 | A kind of preparation process of Bezafibrate class compound |
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Application publication date: 20110427 |
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Address after: Science and Technology Industrial Park D-5 No. 168 high tech Zone camphor road in Hefei city of Anhui Province in 230088 Applicant after: Hefei Huafang Pharmaceutical Sciences & Technology Co., Ltd. Address before: Tianda high tech Zone 230088 Hefei Road, Anhui province No. 71 Huayi Science Park G block four building Applicant before: Hefei Huafang Pharmaceutical Sciences & Technology Co., Ltd. |