CN103694111A - Method for preparing 4-(4-fluorobenzoyl) butyric acid - Google Patents
Method for preparing 4-(4-fluorobenzoyl) butyric acid Download PDFInfo
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- CN103694111A CN103694111A CN201310715098.4A CN201310715098A CN103694111A CN 103694111 A CN103694111 A CN 103694111A CN 201310715098 A CN201310715098 A CN 201310715098A CN 103694111 A CN103694111 A CN 103694111A
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- butyric acid
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- ZBQROUOOMAMCQW-UHFFFAOYSA-N OC(CCCC(c(cc1)ccc1F)=O)=O Chemical compound OC(CCCC(c(cc1)ccc1F)=O)=O ZBQROUOOMAMCQW-UHFFFAOYSA-N 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N O[C@@H](CC[C@H]([C@@H](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound O[C@@H](CC[C@H]([C@@H](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides
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Abstract
The invention discloses a method for preparing 4-(4-fluorobenzoyl) butyric acid. The method comprises the following steps: with the protection of an inert gas, dispersing fluobenzene and treated aluminum trichloride into an organic solvent to form a dispersion system, subsequently dropwise adding glutaric anhydride into the dispersion system, reacting at 10-30 DEG C after glutaric anhydride is added, and treating after the reaction is completed so as to obtain 4-(4-fluorobenzoyl) butyric acid. By controlling the moisture content and the grain fineness of aluminum trichloride, the conversion rate of the reaction is greatly improved, the production cost is lowered, and high industrial production operability is achieved.
Description
Technical field
The invention belongs to the synthetic field of pharmaceutical intermediate, be specifically related to the preparation method of a kind of 4-(4-fluoro benzoyl) butyric acid.
Background technology
Ezetimibe (ezetimibe), structure, as shown in formula I, is a kind of medicine that is used for the treatment of hypercholesterolemia and primary hypercholesterolemia, in November, 2002, by U.S. FDA approval, is gone on the market.Ezetimibe is the agent of a kind of selectivity cholesterol decrease uptake, is mainly used in blocking the exogenous absorption approach of cholesterol, is applicable to treatment, homozygote familial hypercholesterolemia (HoFH) and homozygote Sitosterolemia (or plant sterol mass formed by blood stasis).Ezetimibe suppresses the absorption of enteron aisle inner cholesterol by acting on cholesterol transport albumen, by cytochrome P 450 enzymes metabolism, security and tolerance are good hardly.（The?Discovery?of?Ezetimibe:A?View?from?Outside?the?Receptor,Clader,J.W.Journal?of?Medicinal?Chemistry2004,47,1―9；Synthesis?and?in?Vitro?Evaluation?of?inhibitors?of?Intestinal?Cholesterol?Absorption,L.
M.Werder,H.Hauser,E.M.Carreira,Journal?of?Medicinal?Chemistry2005,48,6035―6053；Niemann-Pick?C1Like1Protein?Is?Critical?for?Intestinal?Cholesterol?Absorption,S.W.Altmann,H.R.Davis,L.-j.Zhu,X.Yao,et?al.Science2004,303,1201―1204）。
Because Ezetimibe is applied to the bright prospects of the treatment of reducing blood-fat disease, future market demand is very large.The route of at present existing many synthetic Ezetimibes is in the news, and wherein, the disclosed synthetic route of US Patent No. 6207822B1 is because raw material is cheap, route is shorter and mild condition, has industrial prospect most.
It is starting raw material that US Patent No. 6207822B1 be take fluorobenzene and Pyroglutaric acid; [structure is as shown in formula II for butyric acid through Friedel-Crafts reaction, to obtain 4-(4-fluoro benzoyl); CAS:149437-76-3], this 4-(4-fluoro benzoyl) butyric acid obtains final product Ezetimibe through series of steps such as amidation, reduction again.
In the preparation process of the 4-of US Patent No. 6207822B1 (4-fluoro benzoyl) butyric acid, Pyroglutaric acid is dissolved in the fluorobenzene suspension that is added drop-wise to aluminum chloride in fluorobenzene, wherein, fluorobenzene is not only made reactant but also make solvent.The shortcoming of the method is: fluorobenzene toxicity is larger, and price is higher, and fluorobenzene to make solvent cumbersome in industrial production aftertreatment, increased production cost; And the productive rate of reporting in this patent is 79.3%, under identical condition, repeat to only have 24% productive rate.
Summary of the invention
The invention provides the preparation method of a kind of 4-(4-fluoro benzoyl) butyric acid, the solvent that this preparation method uses is cheap, and reaction yield is high, has reduced production cost.
The preparation method of a kind of 4-(4-fluoro benzoyl) butyric acid, comprise: under the protection of rare gas element, fluorobenzene and the aluminum chloride processed are distributed to and in organic solvent, form dispersion system, then in above-mentioned dispersion system, drip Pyroglutaric acid, after dripping off, react in 10～30 ℃, react completely and obtain described 4-(4-fluoro benzoyl) butyric acid by aftertreatment;
The treatment process of described aluminum chloride is as follows: aluminum chloride is ground in mortar, then through 20～40 eye mesh screens, screen and obtain aluminum chloride fine particle, then after 1～3 hour, under protection of inert gas, be cooled to room temperature at 100～120 ℃ of heated bakings.
In the present invention, through experiment, find that the water ratio of aluminum chloride and fineness affect greatly the reaction efficiency of this substrate, by aluminum chloride after special processing, strict water ratio and the particle fineness of controlling aluminum chloride, by fluorobenzene, changed reaction solvent into other cheap organic solvents simultaneously, the transformation efficiency that has improved widely reaction, reduces production cost greatly, and industrial production is workable.
The aluminum chloride caking that easily absorbs water, catalytic effect can reduce, and before experiment, will carry out pre-treatment to aluminum chloride.Aluminum chloride is pulverize in mortar, dries 1h and smolder to a large amount of white cigarettes at 110 ℃, is cooled to room temperature in baking oven.
This preparation method is expressed as follows with chemical equation:
Described rare gas element can be nitrogen or argon gas.
Described organic solvent is for to have better deliquescent solvent to reaction substrate, and preferred organic solvent is at least one in methylene dichloride, dithiocarbonic anhydride, oil of mirbane and toluene.
Described organic solvent is halogenated hydrocarbon solvent more preferably, is further preferably methylene dichloride or trichloromethane, most preferably is methylene dichloride, and wherein, when adopting methylene dichloride as solvent, reaction yield is higher than other solvents.When adopting above-mentioned solvent as reaction solvent, due to the aluminum trichloride (anhydrous) very thickness that can become in organic solvent, for reaction is effectively carried out, need mechanical stirring to promote reaction to carry out.
Preferably described organic solvent is the mixed solvent of methylene dichloride and oil of mirbane as other, and volume ratio is 5～10:1, and now, the yield of reaction can further improve.
As preferably, described aluminum chloride adopts 40 object screen clothes to screen.
As preferably, described Pyroglutaric acid is dissolved in described organic solvent, and concentration is 3～4mol/L.
As preferably, temperature when described Pyroglutaric acid drips is 0～5 ℃, controls Pyroglutaric acid and drips and can more effectively reduce side reaction.
As preferably, the time for adding of described Pyroglutaric acid is 30min～1h.
In above-mentioned reaction, for economizing in raw materials, guarantee carrying out completely of reaction simultaneously, as preferably, in molar weight, described Pyroglutaric acid: fluorobenzene: aluminum chloride=1:2～3:2～3.The consumption of described organic solvent, without strict especially requirement, can fully dissolve raw material, is generally 20～30 times of described Pyroglutaric acid molar weight.
As preferably, react and at room temperature carry out.
As preferably, the time of reaction is 4-12 hour.Long increase reaction cost of reaction times, contrary be difficult to guarantee reaction completely, in real reaction process, can adopt whether by thin-layer chromatography, carry out Real-Time Monitoring reaction complete.
After above-mentioned reaction completes, available last handling process comprises: frozen water washing, filter, and alkali lye removal of impurities, acidifying, last recrystallization obtains the higher product of purity.In above-mentioned preparation method, required raw material is existing compound, can adopt commercially available prod.
Compared with the existing technology, beneficial effect of the present invention is embodied in:
(1) this preparation method adopts special treatment step to aluminum chloride, controls fineness and the water ratio of aluminum chloride, has greatly improved the productive rate of reaction;
(2) adopt cheap organic solvent to replace fluorobenzene to react, reduced the usage quantity of expensive fluorobenzene, production cost is lower, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is 4-(4-fluoro benzoyl) butyric acid that obtains of the embodiment of the present invention 3
1hNMR figure;
Fig. 2 is 4-(4-fluoro benzoyl) butyric acid that the embodiment of the present invention 3 obtains
13cNMR figure.
Embodiment
Embodiment 1～11
The processing of aluminum chloride: by aluminum trichloride (anhydrous) (purchased from Chemical Reagent Co., Ltd., Sinopharm Group, production code member 10000862).Aluminum chloride is pulverize in mortar, adopts 40 eye mesh screens to sieve and obtains aluminum chloride fine particle, then this fine particle is dried at 110 ℃ to 1h and smolders to a large amount of white cigarettes, under nitrogen protection, is cooled to room temperature.
The preparation of 4-(4-fluoro benzoyl) butyric acid: under nitrogen protection; according to the proportioning raw materials of table 1, in 500mL three-necked bottle, add aluminum chloride, fluorobenzene and organic solvent 100mL after processing, mixing and stirring, is placed in three-necked bottle under ice bath; drip wherein Pyroglutaric acid solution; wherein, Pyroglutaric acid solution solvent used with dissolve the identical of fluorobenzene, consumption is 48mL; 1h left and right drips completely; after dropping, withdraw from ice bath, recover room temperature, according to the reaction conditions of table 2, react.After having reacted, reaction solution is poured in 2L beaker, added ice cube, till slowly adding dilute hydrochloric acid (2N) to adjust pH to 1, filter and obtain crude product (wherein having maroon dope is the complex compound of aluminium); Crude product is dissolved in to the saturated NaHCO of 600mL at twice again
3(NaHCO in the aqueous solution
3suitably excessive), in boiling water bath, heat 2 hours to there being a large amount of red dopes to float on the surface, filtered while hot yellow solution; and add concentrated hydrochloric acid to adjust pH to 1, and a large amount of bubbles are emerged, and adularescent solid is separated out; filter, use cold water washing, dry, obtain 4-(4-fluoro benzoyl) butyric acid.Reactive chemistry equation is as follows:
The characterization data of the 4-obtaining (4-fluoro benzoyl) butyric acid is as follows:
1h NMR (400MHz, TMS, CDCl
3) δ: 10.36 (bs, 1H), 8.01-7.98 (m, 2H), 7.13 (t, J=8.8Hz, 2H), 3.06 (t, J=7.2Hz, 2H), 2.51 (t, J=6.8Hz, 2H), 2.12-2.05 (m, 2H);
13cNMR (100MHz, TMS, CDCl
3) δ: 197.7,179.3,167.1,164.5,133.2 (d, J
cF=2.9Hz), 130.7,130.6,115.9,112.6,37.2,33.0,19.0.
The consumption of table 1 raw material and catalyzer
ain this embodiment, fluorobenzene is as reaction solvent, and consumption is 110ml, and operating process is identical with US6207822B1.
Table 2 reaction conditions and productive rate
In comparative example 1; aluminum chloride does not pass through special processing; directly adopt commercially available aluminum trichloride (anhydrous); in comparative example 2; commercially available aluminum trichloride (anhydrous) is only through 110 ℃ of heated bakings 1 hour; in comparative example 3; directly under protection of inert gas; after being ground, commercially available aluminum trichloride (anhydrous) sieves; other conditions are identical with embodiment 3; the productive rate of comparative example 1～3 is all much lower than the productive rate of embodiment 3, shows that the fineness of aluminum chloride and water ratio all have larger impact, water content and fineness to cross on reaction and mostly can not get higher productive rate.
Claims (10)
1. the preparation method of a 4-(4-fluoro benzoyl) butyric acid, it is characterized in that, comprise: under the protection of rare gas element, fluorobenzene and the aluminum chloride processed are distributed to and in organic solvent, form dispersion system, then in above-mentioned dispersion system, drip Pyroglutaric acid, after dripping off, react in 10～30 ℃, react completely and obtain described 4-(4-fluoro benzoyl) butyric acid by aftertreatment;
The treatment process of described aluminum chloride is as follows: aluminum chloride is ground in mortar, then through 20～40 eye mesh screens, screen and obtain aluminum chloride fine particle, then after 1～3 hour, under protection of inert gas, be cooled to room temperature at 100～120 ℃ of heated bakings.
2. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, described organic solvent is methylene dichloride or trichloromethane.
3. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, described organic solvent is the mixed solvent of methylene dichloride and oil of mirbane, and volume ratio is 5～10:1.
4. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, described aluminum chloride adopts 40 object screen clothes to screen.
5. according to the preparation method of the 4-described in claim 1～4 any one (4-fluoro benzoyl) butyric acid, it is characterized in that, described Pyroglutaric acid is dissolved in described organic solvent, and concentration is 3～4mol/L.
6. the preparation method of 4-according to claim 5 (4-fluoro benzoyl) butyric acid, is characterized in that, temperature when described Pyroglutaric acid drips is 0～5 ℃.
7. the preparation method of 4-according to claim 6 (4-fluoro benzoyl) butyric acid, is characterized in that, the time for adding of described Pyroglutaric acid is 30min～1h.
8. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, in molar weight, and described Pyroglutaric acid: fluorobenzene: aluminum chloride=1:2～3:2～3.
9. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, reaction is at room temperature carried out.
10. the preparation method of 4-according to claim 1 (4-fluoro benzoyl) butyric acid, is characterized in that, the time of reaction is 4-12 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778117A (en) * | 2020-12-17 | 2021-05-11 | 江苏阿尔法药业有限公司 | Method for synthesizing 4- (4-fluorobenzoyl) butyric acid and analogue thereof in continuous flow microreactor |
| CN115960054A (en) * | 2022-12-15 | 2023-04-14 | 南通常佑药业科技有限公司 | Preparation method of ezetimibe intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102849770A (en) * | 2012-10-15 | 2013-01-02 | 扬州大学 | Method for synthesizing anhydrous aluminum chloride by recycling aluminum chloride hexahydrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102849770A (en) * | 2012-10-15 | 2013-01-02 | 扬州大学 | Method for synthesizing anhydrous aluminum chloride by recycling aluminum chloride hexahydrate |
Non-Patent Citations (4)
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| 刘毓宏等: "选择性胆固醇吸收抑制剂-依泽替米贝的合成工艺改进", 《广东化工》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778117A (en) * | 2020-12-17 | 2021-05-11 | 江苏阿尔法药业有限公司 | Method for synthesizing 4- (4-fluorobenzoyl) butyric acid and analogue thereof in continuous flow microreactor |
| CN115960054A (en) * | 2022-12-15 | 2023-04-14 | 南通常佑药业科技有限公司 | Preparation method of ezetimibe intermediate |
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