CN103373916B - Environment-friendly preparation method for lipid-lowering drug ciprofibrate - Google Patents
Environment-friendly preparation method for lipid-lowering drug ciprofibrate Download PDFInfo
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Abstract
The invention provides an environment-friendly preparation method for a lipid-lowering drug ciprofibrate. The preparation method comprises the following steps of by taking hydroxyphenyl ethene as a raw material, carrying out Bargellini and annulation reaction to prepare the ciprofibrate. Compared with the traditional method, the method has the advantages of less reaction steps, short production cycle and high total yield, is easy to operate, mild and easy-control in conditions, convenient for postprocessing and environment-friendly, and is a brand new method for industrialized synthesis of the ciprofibrate.
Description
Technical field
The present invention relates to the preparation of blood lipid-lowering medicine, particularly, relate to a kind of environment-friendly preparation method thereof of Win-35833.
Background technology
Win-35833 (Ciprofibrate), have another name called chlorine ring third appropriate bright, belong to phenoxy acetic acid class hypolipidemic, effect is better than clofibrate, significantly can reduce extra-low density and low-density lipoprotein white level, and high density lipoprotein increasing level also has solution fibrin simultaneously and stops platelet aggregation.Chemical name is 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid, and its structural formula is as follows:
(I)
One is disclosed with compound 2,2-dichloro cyclopropyl-phenyl for raw material, through Friedel-Crafts acidylate in CN1514819; Baeyer-Villiger rearrangement is carried out with peroxy acid effect; obtain phenolic ester, after phenolic ester alcoholysis, obtain phenolic compound, then react obtained Win-35833 with a-bromo acid ester.The method uses aluminum chloride when Friedel-Crafts acidylate, and environmental friendliness is poor; And use peroxy acid when BV resets, there is larger dangerous hidden danger when industrial production.
And at Shenyang Pharmaceutical University's journal 25 (12); 2008; in the preparation method of a kind of Win-35833 disclosed in 929, be that raw material is successively through becoming ring, Friedel-Crafts acidylate, Baeyer-Villiger rearrangement, alcoholysis, Bargellini reaction, synthesis Win-35833 with vinylbenzene.Although the method is avoided using a large amount of peroxy acids, route is long, considerably increases the production cycle.
In CN20120372500.9, mention a kind of Win-35833 preparation method of environment-friendly type, its reaction scheme is:
Although the method meets eco-friendly condition, reactions steps is complicated, reaction scheme is longer.
Summary of the invention
In order to overcome above-mentioned defect of the prior art, this provides a kind of reactions steps succinct and the environment-friendly preparation method thereof of the efficient Win-35833 of reaction yield.
The process of synthetic method of the present invention can be summarized as follows:
The invention provides a kind of environment-friendly preparation method thereof of hypolipemic preparation Win-35833, comprise the following steps:
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
4-Vinyl phenol is dissolved in acetone, adds alkali and chloroform, after reacting completely, obtain product 2-methyl-2-(4-vinyl phenoxy group) propionic acid;
(2) preparation of Win-35833
2-methyl-2-(4-vinyl phenoxy group by obtained in step (1)) propionic acid dissolving, then add the aqueous solution of alkali, phase-transfer catalyst and chloroform, after reacting completely, obtain product Win-35833;
Preferably, the consumption of 4-Vinyl phenol described in step (1) and the amount ratio of described chloroform are 1:1-1:3, and the mass ratio of described 4-Vinyl phenol and described acetone is 1:3-1:10.
Preferably, the alkali described in step (1) is one or its mixture of sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide and potassium tert.-butoxide.
Preferably, alkali described in step (1) and the amount of substance of 4-Vinyl phenol are than being 1:1-5:1.
Preferably, the temperature of the reaction described in step (1) is-10-70 DEG C.
Preferably, the dissolving 2-methyl-2-(4-vinyl phenoxy group described in step (2)) solvent of propionic acid is one in water, methylene dichloride and Isosorbide-5-Nitrae-dioxane or its mixture.
Preferably, the temperature of reaction described in step (2) is-5-70 DEG C.
Preferably, the alkali described in step (2) is one in sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide and potassium tert.-butoxide or its mixture.
Preferably, the consumption of alkali described in step (2) and described 2-methyl-2-(4-vinyl phenoxy group) amount ratio of propionic acid is 1:1-5:1.
Preferably, the phase-transfer catalyst described in step (2) is one or its mixture of benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18 hat 6,15 hats 5, cyclodextrin and Macrogol 2000.
Succinct and the environment-friendly preparation method thereof of the efficient Win-35833 of reaction yield of a kind of reactions steps provided by the invention, the advantage of present method is: only use conventional soda acid in whole reaction process, and the solvent of routine, harmless sodium-chlor or Repone K is obtained after acid-base neutralisation, organic solvent reclaims, unharmful substance discharges, environmental friendliness is high, and this reaction step number is few, with short production cycle, simple to operate, mild condition is easily controlled, convenient post-treatment, total recovery is higher, is a kind of method of brand-new industrialization green syt Win-35833.
Embodiment
In order to make those skilled in the art person understand the present invention better, and above-mentioned advantage of the present invention is become apparent more, below in conjunction with specific embodiment, the present invention is further detailed explanation.
Embodiment 1
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
1kg 4-Vinyl phenol is added, 3L acetone, 1kg sodium hydroxide in 10L flask, after stirring 30min, drip 1.5kg chloroform, dropwise rear stirring 30min and be warming up to 70 DEG C, after reacting completely, solvent evaporated, adds 4000ml water and 3000ml methylene dichloride, after water layer activated carbon decolorizing, PH to 2-3 is regulated with the hydrochloric acid of 2mol/L, separate out white product, solid collected by filtration obtains 2-methyl-2-(4-vinyl phenoxy group) propionic acid 1.6kg, molar yield 93%.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、5.22(d,1H)、5.67(d,1H)、6.69(m,1H)、6.92(d,2H)、7.35(d,2H)。
(2) preparation of Win-35833
By 653g2-methyl-2-(4-vinyl phenoxy group) propionic acid is dissolved in 900ml chloroform, adds 500ml water, 160gNaOH, 11g Tetrabutyl amonium bromide, is warming up to 40 DEG C, after reacting completely after stirring at room temperature 30min, add 500ml water, separatory, water layer activated carbon decolorizing, PH to 2-3 is regulated, extraction into ethyl acetate, anhydrous sodium sulfate drying with the hydrochloric acid of 6mol/L, filtering sodium sulfate, filtrate is spin-dried for, and normal hexane recrystallization obtains white solid product and Win-35833 (824g), yield 90%.The Win-35833 fusing point obtained is mp114-115 DEG C, and fusing point journey is less, illustrates that the purity of product is higher.
1H-NMR（500MH，zCDCl
3）δ:1.65(s,6H)、1.81(dd,1H)、1.98(dd,1H)、2.86(dd,1H)、6.93(d,2H)、7.18(d,2H)。
Embodiment 2
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
1kg 4-Vinyl phenol is added, 5L acetone, 1.8kg potassium hydroxide in 10L flask, after stirring 30min, drip 2.0kg chloroform, dropwise rear stirring 30min, temperature control 30-40 DEG C, after reacting completely, solvent evaporated, add 5000ml water and 3000ml methylene dichloride, after water layer activated carbon decolorizing, regulate PH to 2-3 with the hydrochloric acid of 3mol/L, separate out white product, solid collected by filtration obtains 2-methyl-2-(4-vinyl phenoxy group) propionic acid 1.63kg, molar yield 94.5%.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、5.22(d,1H)、5.67(d,1H)、6.69(m,1H)、6.92(d,2H)、7.35(d,2H)。
(2) preparation of Win-35833
By 653g2-methyl-2-(4-vinyl phenoxy group) propionic acid is dissolved in 1000ml chloroform, add 500ml water, 280g potassium hydroxide, 20g benzyltriethylammoinium chloride, 40 DEG C are warming up to after stirring at room temperature 30min, after reacting completely, add 500ml water, separatory, water layer activated carbon decolorizing, PH to 2-3 is regulated, extraction into ethyl acetate, anhydrous sodium sulfate drying with the hydrochloric acid of 6mol/L, filtering sodium sulfate, filtrate is spin-dried for, and normal hexane recrystallization obtains white solid product and Win-35833 (834g), yield 91.1%.Obtaining Win-35833 fusing point is mp114-115 DEG C, and its fusing point journey is less, illustrates that Win-35833 purity is higher.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、1.81(dd,1H)、1.98(dd,1H)、2.86(dd,1H)、6.93(d,2H)、7.18(d,2H)。
Embodiment 3
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
1kg 4-Vinyl phenol is added in 10L flask, 5L acetone, temperature control 0 DEG C, add 3kg potassium tert.-butoxide in batches, after stirring 30min, temperature control 0-10 DEG C drips 2.0kg chloroform, dropwises rear stirring 30min, temperature control 30-40 DEG C, after reacting completely, solvent evaporated, after adding 5000ml frozen water, add 3000ml methylene dichloride again, after water layer activated carbon decolorizing, regulate PH to 2-3 with the hydrochloric acid of 3mol/L, separate out white product, solid collected by filtration obtains 2-methyl-2-(4-vinyl phenoxy group) propionic acid 1.63kg, molar yield 94.5%.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、5.22(d,1H)、5.67(d,1H)、6.69(m,1H)、6.92(d,2H)、7.35(d,2H)。
(2) preparation of Win-35833
By 653g2-methyl-2-(4-vinyl phenoxy group) propionic acid is dissolved in 1000ml chloroform, add 500ml water, 20g18 hat 6, after stirring at room temperature 30min, temperature control 0-10 DEG C, adds potassium tert.-butoxide 500g in batches, adds the rear room temperature that naturally rises to reacting completely, add 500ml water, separatory, water layer activated carbon decolorizing, regulates PH to 2-3 with the hydrochloric acid of 6mol/L, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtering sodium sulfate, filtrate is spin-dried for, normal hexane recrystallization obtains white solid product and Win-35833 (851g), yield 93%.Fusing point is mp114-115 DEG C.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、1.81(dd,1H)、1.98(dd,1H)、2.86(dd,1H)、6.93(d,2H)、7.18(d,2H)。
Embodiment 4
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
1kg 4-Vinyl phenol is added in 10L flask, 6L acetone, temperature control 5 DEG C, add 3kg sodium tert-butoxide in batches, after stirring 30min, temperature control 0-10 DEG C drips 1.8kg chloroform, dropwises rear stirring 30min, temperature control 30-40 DEG C, after reacting completely, solvent evaporated, after adding 5000ml frozen water, add 3000ml methylene dichloride again, after water layer activated carbon decolorizing, regulate PH to 2-3 with the hydrochloric acid of 3mol/L, separate out white product, solid collected by filtration obtains 2-methyl-2-(4-vinyl phenoxy group) propionic acid 1.57kg, molar yield 91.1%.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、5.22(d,1H)、5.67(d,1H)、6.69(m,1H)、6.92(d,2H)、7.35(d,2H)。
(2) preparation of Win-35833
By 653g2-methyl-2-(4-vinyl phenoxy group) propionic acid is dissolved in 1000ml chloroform, add 500ml water, 20g15 hat 5, after stirring at room temperature 30min, temperature control 0-10 DEG C, adds sodium tert-butoxide 500g in batches, adds the rear room temperature that naturally rises to reacting completely, add 500ml water, separatory, water layer activated carbon decolorizing, regulates PH to 2-3 with the hydrochloric acid of 6mol/L, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtering sodium sulfate, filtrate is spin-dried for, normal hexane recrystallization obtains white solid product and Win-35833 (823.5g), yield 90%.Fusing point is mp114-115 DEG C.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、1.81(dd,1H)、1.98(dd,1H)、2.86(dd,1H)、6.93(d,2H)、7.18(d,2H)。
Embodiment 5
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
1kg 4-Vinyl phenol is added in 10L flask, 5L acetone, temperature control 10 DEG C, add 1.5kg sodium methylate in batches, after stirring 30min, temperature control 0-10 DEG C drips 2kg chloroform, dropwises rear stirring 30min, temperature control 30-40 DEG C, after reacting completely, solvent evaporated, after adding 5000ml frozen water, add 3000ml methylene dichloride again, after water layer activated carbon decolorizing, regulate PH to 2-3 with the hydrochloric acid of 3mol/L, separate out white product, solid collected by filtration obtains 2-methyl-2-(4-vinyl phenoxy group) propionic acid 1.59kg, molar yield 92.3%.
1H-NMR（500MHz，CDCl
3）δ:1.65(s,6H)、5.22(d,1H)、5.67(d,1H)、6.69(m,1H)、6.92(d,2H)、7.35(d,2H)。
(2) preparation of Win-35833
By 653g2-methyl-2-(4-vinyl phenoxy group) propionic acid is dissolved in 1, 4-dioxane 500ml, chloroform 500ml, water 500ml, 40g tetradecyl trimethyl ammonium chloride, after stirring at room temperature 30min, temperature control 0-10 DEG C, add sodium methylate 250g in batches, add the rear room temperature that naturally rises to reacting completely, add 500ml water, separatory, water layer activated carbon decolorizing, PH to 2-3 is regulated with the hydrochloric acid of 6mol/L, extraction into ethyl acetate, anhydrous sodium sulfate drying, filtering sodium sulfate, filtrate is spin-dried for, normal hexane recrystallization obtains white solid product and Win-35833 (819g), yield 89.5%.Fusing point is mp114-115 DEG C
1h-NMR(500MHz, CDCl
3) δ: 1.65 (s, 6H), 1.81 (dd, 1H), 1.98 (dd, 1H), 2.86 (dd, 1H), 6.93 (d, 2H), 7.18 (d, 2H).
The suitable aftertreatment that the present invention mentions, refers to conventional aftertreatment, such as: can add water as required; PH value is regulated to depend on the formation of product to 1-13(as required); The extraction such as mixture ethyl acetate, chloroform or methylene dichloride will respectively be separated; The common siccative such as organic phase anhydrous sodium sulphate or anhydrous magnesium sulfate carry out drying; Can be processed by the method for underpressure distillation and obtain product, product can be purified by silica gel chromatography and/or recrystallization, and Rf value obtains on silica gel.
The fusing point mp obtaining Win-35833 product in the embodiment of the present invention is 114-115 DEG C, and its fusing point journey is less, illustrates that Win-35833 purity is higher.The environment-friendly preparation method thereof of a kind of Win-35833 provided by the invention, utilizes 4-Vinyl phenol for raw material, prepares Win-35833 through Bargellini and annulation two step.As in embodiment mention, the method is by some simple intermediate reactions, with the yield of 2 step overall yield of reaction about 80% (document Shenyang Pharmaceutical University journal 25 (12), 2008, the yield of 929 is 56.2%, CN1514819 reacts through 4 steps, total recovery is 63%) obtain logical formula I 2-[4-(2, 2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid, i.e. Win-35833, the method has the following advantages compared with traditional method: reaction step number is few, with short production cycle, simple to operate, mild condition is easily controlled, convenient post-treatment, environmental friendliness, total recovery is higher, it is a kind of green method of brand-new industrialization synthesis Win-35833.
The above; be only the specific embodiment of the present invention, protection scope of the present invention is not limited thereto, and is anyly familiar with those skilled in the art in the technical scope that the present invention discloses; the change that can expect easily or replacement, all should be encompassed within protection scope of the present invention.Therefore, the protection domain that protection scope of the present invention should define with claim is as the criterion.
Claims (10)
1. a preparation method for hypolipemic preparation Win-35833, is characterized in that, comprises the following steps:
(1) 2-methyl-2-(4-vinyl phenoxy group) preparation of propionic acid
4-Vinyl phenol is dissolved in acetone, adds alkali and chloroform, after reacting completely, obtain product 2-methyl-2-(4-vinyl phenoxy group) propionic acid;
(2) preparation of Win-35833
2-methyl-2-(4-vinyl phenoxy group by obtained in step (1)) propionic acid dissolving, then add the aqueous solution of alkali, phase-transfer catalyst and chloroform, after reacting completely, obtain product Win-35833.
2. the preparation method of a kind of Win-35833 according to claim 1, it is characterized in that, the quality of 4-Vinyl phenol described in step (1) and the mass ratio of described chloroform are 1:1-1:3, and the mass ratio of described 4-Vinyl phenol and described acetone is 1:3-1:10.
3. the preparation method of a kind of Win-35833 according to claim 1, is characterized in that, the alkali described in step (1) is one or its mixture of sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide and potassium tert.-butoxide.
4. the preparation method of a kind of Win-35833 according to claim 1 or 3 any one, is characterized in that, alkali described in step (1) is 1:1-5:1 with the amount of substance ratio of 4-Vinyl phenol.
5. the preparation method of a kind of Win-35833 according to claim 1, is characterized in that, the temperature of the reaction described in step (1) is-10-70 DEG C.
6. the preparation method of a kind of Win-35833 according to claim 1, it is characterized in that, dissolving 2-methyl-2-(4-vinyl phenoxy group described in step (2)) solvent of propionic acid is one in water, methylene dichloride and Isosorbide-5-Nitrae-dioxane or its mixture.
7. the preparation method of a kind of Win-35833 according to claim 1, is characterized in that, the temperature of reaction described in step (2) is-5-70 DEG C.
8. the preparation method of a kind of Win-35833 according to claim 1, is characterized in that, the alkali described in step (2) is one in sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide and potassium tert.-butoxide or its mixture.
9. the preparation method of a kind of Win-35833 according to claim 8, is characterized in that, the consumption of alkali described in step (2) and described 2-methyl-2-(4-vinyl phenoxy group) ratio of the amount of substance of propionic acid is 1:1-5:1.
10. the preparation method of a kind of Win-35833 according to claim 1, it is characterized in that, the phase-transfer catalyst described in step (2) is one or its mixture of benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18 hat 6,15 hats 5, cyclodextrin and Macrogol 2000.
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| CN103613498B (en) * | 2013-11-20 | 2015-08-26 | 浙江三门恒康制药有限公司 | The synthetic method of Win-35833 |
| CN105175250B (en) * | 2015-10-28 | 2016-09-21 | 浙江耐司康药业有限公司 | A kind of new method synthesizing ciprofibrate |
| CN105237389B (en) * | 2015-10-28 | 2017-09-15 | 成都丽凯手性技术有限公司 | A kind of method that use p-Coumaric Acid prepares hypolipidemic ciprofibrate |
| CN106928047B (en) * | 2017-03-14 | 2023-04-28 | 南京工业大学 | Synthesis method of hypolipidemic ciprofibrate |
| CN109534528B (en) * | 2018-11-20 | 2021-11-12 | 新昌县泰如科技有限公司 | Method for treating ciprofibrate process wastewater |
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Effective date of registration: 20151216 Address after: 201203 Edison road Shanghai, Pudong New Area Zhangjiang hi tech Park No. 274 Patentee after: SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENGINEERING CO., LTD. Address before: 215000, Jiangsu, Suzhou province Wujiang Fen Lake Economic Development Zone, Fen Lake Road, No. 558 Fen Lake Science and Technology Pioneer Park R & D building, building 1 Patentee before: Suzhou Huihe Pharmaceutical Co., Ltd. |