CN104003921A - Preparation method of ezetimibe intermediate - Google Patents
Preparation method of ezetimibe intermediate Download PDFInfo
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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Abstract
The invention discloses a preparation method of an ezetimibe intermediate. The preparation method comprises the following steps of 1, intermediate I preparation comprising that 4-[[(4-fluorophenyl)imino]methyl]-phenol as a raw material (M1) and a benzyl halide undergo a reaction under the action of an alkali to produce a benzyl-protected 4-[[(4-fluorophenyl)imino]methyl]-phenol, 2, intermediate II preparation comprising that (4S)-3-[5-(4-fluorophenyl)-1,5-oxoamyl]-4-phenyl-2-oxazolidinone (M2) as a raw material, propanedithiol and a solvent undergo a ketone group protection reaction under the action of lewis acid to produce an intermediate II, 3, intermediate III preparation comprising that the intermediate I, the intermediate II and a catalyst undergo a double-bond addition reaction under the action of a strong base to produce an intermediate III, 4, intermediate IV preparation comprising that the intermediate III and a cyclizing agent undergo a reaction under the action of a catalyst to produce a four-membered ring intermediate IV, and 5, EZ5 preparation comprising that the intermediate IV and a solvent undergo a reaction under the action of an acid so that a protection group is removed and EZ5 is obtained. The preparation method has simple and easily-controllable processes and a high reaction yield.
Description
Technical field
The present invention relates to a kind of preparation method of Ezetimible intermediate.
Background technology
Ezetimibe (Ezetimibe) is a kind of novel anticholesteremic agent, jointly researched and developed by Schering Plough and Merck & Co., Inc., went on the market through U.S. FDA approval in 2002, commodity are called Zetia, belong to new class 2-azetidinones.Its chemical name is: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxy phenyl)-2-azetidinone.Structure is suc as formula 1:
Formula 1
Hyperlipidaemia is the important risk factor that causes that the cardiovascular disorder such as atherosclerosis occurs, and a large amount of evidences show, reduces total cholesterol level in blood plasma and can reduce the danger of cardiovascular disorder.Novel fat-reducing medicament should be to reduce LDL-C, and T G level can not raise again.At present, the drug main of clinical treatment hyperlipidaemia will comprise cholesterol synthesis inhibitor (as Statins), fibric acid (class as special in shellfish), bile acid chelating agent (as QUESTRAN) and other (as nicotinic acid analogue).
Ezetimibe acts on the brush border of small intestine cells, and alternative suppresses the cholesterol absorption in biliary tract and food and do not affect the absorption to liposoluble vitamin, triglyceride level and cholic acid.Because ezetimibe has reduced picked-up and the absorption of intestinal epithelial cell to cholesterol, therefore make the Cholesterol Excretion in enteron aisle increase, reduced the transhipment of cholesterol to liver simultaneously.The effect feature of ezetimibe is: after oral absorption, enter liver sausage circulation, repeatedly enter the site of action of enteron aisle, its glucuronidation meta-bolites also has pharmaceutical activity, further stops the absorption of cholesterol.Ezetimibe is hardly by Cytochrome P450 enzymes metabolism, and few with other drug interphase interaction, security and tolerance are good.
In patent WO9508532 reported first ezetimibe and synthetic route thereof.In patent, report intermediate (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] synthetic method of azetidine-2-ketone (EZ5), as shown in Scheme1.In route, form docking reaction yield is low, and intermediate need pass through column purification, is difficult to carry out scale operation.
Scheme1
In patent US5856473, report the synthetic route of intermediate E Z5, as shown in Scheme2.The docking reaction of this route exists reaction yield low, complex operation, and product is difficult for the drawbacks such as processing, is unfavorable for carrying out suitability for industrialized production.
Scheme2
Patent WO2007072088 has reported the synthetic route of intermediate E Z5, as shown in Scheme3.This synthesis route is longer, and deprotection need be used expensive metal catalyst, is unfavorable for carrying out scale operation.
Scheme3
Therefore,, for addressing the above problem, spy provides a kind of new technical scheme to satisfy the demands.
Summary of the invention
The invention provides a kind of preparation method of Ezetimible intermediate.
The technical solution used in the present invention is:
A preparation method for Ezetimible intermediate, the chemical equation of the method is:
, comprise successively following processing step: preparation, the preparation of intermediate IV and the preparation of EZ5 of the preparation of intermediate I, the preparation of intermediate II, intermediate III,
The preparation of described intermediate I: 5 taking 4-[[(4-fluorophenyl) imines] methyl]-phenol is as raw material (M1), under alkali effect, with halogenation benzyl and solvent reaction, obtains the 4-[[(4-fluorophenyl of benzyl protection) imines] methyl]-phenol;
The preparation of described intermediate II: with (4S)-3-[5-(4-fluorophenyl)-1,5-oxo amyl group]-4-phenyl-2-oxazolidone (M2) is raw material, under Lewis acid effect, carry out ketone carbonyl-protection with dimercaptopropane and solvent and react, obtain intermediate II;
The preparation of described intermediate III: intermediate I and intermediate II, under highly basic effect, add catalyzer and as in solvent, carry out two key addition reactions and obtain intermediate III;
The preparation of described intermediate IV: intermediate III, under catalyst action, forms four membered ring intermediate IV with cyclizing agent and solvent reaction;
The preparation of described EZ5: intermediate IV and solvent are sloughed protecting group and obtained EZ5 under acid effect.
Halo benzyl in the preparation of described intermediate I is Benzyl Chloride or cylite, alkali reagent is sodium carbonate, salt of wormwood, triethylamine or DIPEA, solvent is methylene dichloride, toluene, acetone or isopropyl ether, 4-[[(4-fluorophenyl) imines] methyl] mass ratio that feeds intake of-phenol and halogenation benzyl is 1:1.0 ~ 1.5.
Lewis acid in the preparation of described intermediate II is tosic acid or trifluoroacetic acid, and solvent is ethylene glycol, toluene, tetrahydrofuran (THF) or acetonitrile, and the mass ratio that feeds intake of intermediate I and dimercaptopropane is 1:2.0 ~ 3.
Highly basic in the preparation of described intermediate III is titanium tetrachloride; Described catalyzer is titanium isopropylate, and solvent is methylene dichloride, ether, acetone, toluene or tetrahydrofuran (THF), and the mass ratio that feeds intake of intermediate I, intermediate II and highly basic is 1 ~ 1.5:1:1 ~ 1.2.
Cyclizing agent in the preparation of described intermediate IV is N, the two trimethyl silicane yl acetamides of O-, catalyzer is tetrabutyl ammonium fluoride, Tetrabutyl amonium bromide or tetrabutylammonium iodide, solvent is methylene dichloride, ether, toluene, isopropyl ether or tetrahydrofuran (THF), and the mass ratio that feeds intake of intermediate III and cyclizing agent is 1:1.0 ~ 1.3.
Sour reagent in the preparation of described EZ5 is tosic acid, acetic acid, formic acid or trifluoroacetic acid, and solvent is methylene dichloride, ether, toluene, tetrahydrofuran (THF) or acetonitrile, and the mass ratio that feeds intake of intermediate IV and sour reagent is 1:0.5 ~ 0.9.
The invention has the beneficial effects as follows: this processing method route is brief, easy control simple to operate, reaction yield is high, and product purity is high, and cost is low, is suitable for large-scale industrial production.
Embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, and this embodiment only, for explaining the present invention, does not form limiting the scope of the present invention.
Embodiment 1
A preparation method for Ezetimible intermediate, the chemical equation of the method is:
, comprise successively following processing step: preparation, the preparation of intermediate IV and the preparation of EZ5 of the preparation of intermediate I, the preparation of intermediate II, intermediate III,
The preparation of intermediate I: in reaction flask, add 20g 4-[[(4-fluorophenyl) imines] methyl]-phenol, 20.6g cylite, 31.1g salt of wormwood and 300mL toluene, stir, and is warming up to 70 DEG C of reactions, TLC monitors reaction, react complete, room temperature when cooling, suction filtration, with a small amount of toluene wash filter cake, mother liquor is evaporated to dry, obtains 25.8g solid phase prod, yield 91%;
The preparation of intermediate II: in reaction flask, add 22g (4S)-3-[5-(4-fluorophenyl)-1, 5-oxo amyl group]-4-phenyl-2-oxazolidone, 15.9g 1, 3-dimercaptopropane, 1g tosic acid and 100mL toluene, stir, be cooled to 10 DEG C, drip 6.5g trimethylchlorosilane, drip and finish, rising to room temperature reacts, TLC monitors reaction, react complete, 80mL saturated sodium bicarbonate solution washing for reaction solution, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtain thick product, this solid is pulled an oar with isopropyl ether, obtain 21g white solid product, yield 82%,
The preparation of intermediate III: under anhydrous and oxygen-free condition, in reaction flask, 6.0g titanium tetrachloride and 1g metatitanic acid four isopropyl esters are placed in to 50mL methylene dichloride, stir, be cooled to-15 DEG C, then drip successively the dichloromethane solution of 50mL intermediate II, drip again 6.1g triethylamine, drip and finish, stir 30 minutes, then drip the dichloromethane solution of 30mL intermediate I; Drip and finish, reaction at-15 DEG C, TLC monitors reaction, react complete, drip 10mL Glacial acetic acid and carry out cancellation, then rise to room temperature reaction, stir, 50mL saturated sodium bicarbonate solution washing for reaction solution, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtain crude product, 20mL Virahol making beating for this crude product, obtains 14g white solid product, yield 62%;
The preparation of intermediate IV: in reaction flask, add successively 13g intermediate III, 4.0g N, the two trimethyl silicane yl acetamides of O-and 60mL tetrahydrofuran (THF), stir, be warming up to 50 DEG C of reactions, react after 1 hour, add 0.5g tetrabutyl ammonium fluoride, stirring reaction, TLC monitors reaction, reacts complete, be cooled to room temperature, add methyl alcohol to carry out cancellation, solvent evaporated, add 100mL ethyl acetate, stir, by 30mL water washing organic phase, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtains 9.3g oily product;
The preparation of EZ5: in reaction flask, add successively 8.5g intermediate IV, 2.1g tosic acid, 30mL tetrahydrofuran (THF) and 10mL water, stir, be warming up to 45 DEG C of reactions, TLC monitors reaction; React complete, be cooled to room temperature, remove tetrahydrofuran (THF) under reduced pressure, add 50mL ethyl acetate, leave standstill separatory, 20mL ethyl acetate extraction for water layer, merges organic phase, with 45mL saturated sodium bicarbonate solution, 45mL water washing, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtain 6.5g oily product, yield: 86%.
Embodiment 2
A preparation method for Ezetimible intermediate, the chemical equation of the method is:
, comprise successively following processing step: preparation, the preparation of intermediate IV and the preparation of EZ5 of the preparation of intermediate I, the preparation of intermediate II, intermediate III,
The preparation of intermediate I: in reaction flask, add 30g 4-[[(4-fluorophenyl) imines] methyl]-phenol, 22.6g Benzyl Chloride, 34.2g DIPEA and 500mL isopropyl ether, stir, temperature rising reflux reaction, TLC monitors reaction, react complete, room temperature when cooling, suction filtration, with a small amount of toluene wash filter cake, mother liquor is evaporated to dry, obtains 37.4g white solid product, yield: 88%;
The preparation of intermediate II: in reaction flask, add 33g (4S)-3-[5-(4-fluorophenyl)-1, 5-oxo amyl group]-4-phenyl-2-oxazolidone, 23.9g 1, 3-dimercaptopropane, 1g tosic acid and 300mL acetonitrile, stir, be cooled to 10 DEG C, drip 9.8g trimethylchlorosilane, drip and finish, rising to room temperature reacts, TLC monitors reaction, react complete, evaporated under reduced pressure solvent, add 300mL ethyl acetate, organic phase is used respectively 100mL saturated sodium bicarbonate solution and 100mL water washing, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtain thick product, this solid is pulled an oar with isopropyl ether, obtain 32.3g white solid product, yield 84%,
The preparation of intermediate III: under anhydrous and oxygen-free condition, in reaction flask, 8.8g titanium tetrachloride and 1.2g metatitanic acid four isopropyl esters are placed in to 100mL methylene dichloride, stir, be cooled to-15 DEG C, then drip successively the dichloromethane solution of 80mL intermediate II, drip successively again 2g trimethylchlorosilane and 8.1g triethylamine, drip and finish, stir 30 minutes, then drip the dichloromethane solution of 50mL intermediate I, drip and finish, reaction at-15 DEG C, TLC monitors reaction, react complete, drip 20mL 50% sulfuric acid and carry out cancellation, then rise to room temperature reaction, stir, 100mL saturated sodium bicarbonate solution washing for reaction solution, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtain thick product, this thick product is pulled an oar with Virahol, obtain 31.3g solid phase prod, yield 60%,
The preparation of intermediate IV: in reaction flask, add successively 10.8g intermediate III, 3.4g N, the two trimethyl silicane yl acetamides of O-and 50mL isopropyl ether, stir, be warming up to 50 DEG C of reactions, react after 1 hour, add 0.6g tetrabutylammonium iodide, stirring reaction, TLC monitors reaction; React complete, be cooled to room temperature, add methyl alcohol to carry out cancellation, with 30mL water washing organic phase, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtains 8.0g oily product;
The preparation of EZ5: in reaction flask, add successively 6.8g intermediate IV, 1.1g trifluoroacetic acid, 30mL acetonitrile and 10mL water, stir, be warming up to 45 DEG C of reactions, TLC monitors reaction, reacts complete, be cooled to room temperature, remove acetonitrile under reduced pressure, add 50mL ethyl acetate, leave standstill separatory, 30mL ethyl acetate extraction for water layer, merges organic phase, with 45mL saturated sodium bicarbonate solution, 45mL water washing, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtains 5.0g oily product, yield: 83%.
Embodiment 3
A preparation method for Ezetimible intermediate, the chemical equation of the method is:
, comprise successively following processing step: preparation, the preparation of intermediate IV and the preparation of EZ5 of the preparation of intermediate I, the preparation of intermediate II, intermediate III,
The preparation of intermediate I: in reaction flask, add 52g 4-[[(4-fluorophenyl) imines] methyl]-phenol, 90g cylite, 47.5g triethylamine and 1000mL acetone, stir, and is warming up to 70 DEG C of reactions, TLC monitors reaction, react complete, room temperature when cooling, suction filtration, with a small amount of toluene wash filter cake, mother liquor is evaporated to dry, obtains 34.3g solid phase prod, yield 93%;
The preparation of intermediate II: in reaction flask, add 31g (4S)-3-[5-(4-fluorophenyl)-1, 5-oxo amyl group]-4-phenyl-2-oxazolidone, 26.7g 1, 3-dimercaptopropane, 1g tosic acid and 300mL tetrahydrofuran (THF), stir, be cooled to 10 DEG C, drip 9.1g trimethylchlorosilane, drip and finish, rising to room temperature reacts, TLC monitors reaction, react complete, 80mL saturated sodium bicarbonate solution washing for reaction solution, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtain thick product, this solid is pulled an oar with isopropyl ether, obtain 30.1g white solid product, yield 84%,
The preparation of intermediate III: under anhydrous and oxygen-free condition, in reaction flask, 15.8g titanium tetrachloride and 2.5g metatitanic acid four isopropyl esters are placed in to 150mL ether, stir, be cooled to-15 DEG C, then drip successively the dichloromethane solution of 150mL containing 30g intermediate II, drip again 14g triethylamine, drip and finish, stir 30 minutes, then drip the dichloromethane solution of 150mL containing 31.4 intermediate I; Drip and finish, reaction at-15 DEG C, TLC monitors reaction, react complete, drip 30mL Glacial acetic acid and carry out cancellation, then rise to room temperature reaction, stir, 150mL saturated sodium bicarbonate solution washing for reaction solution, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtain crude product, 60mL Virahol making beating for this crude product, obtains 32.7g white solid product, yield 63%;
The preparation of intermediate IV: in reaction flask, add successively 25g intermediate III, 7.7g N, the two trimethyl silicane yl acetamides of O-and 130mL ether, stir, be warming up to 50 DEG C of reactions, react after 1 hour, add 1.2g Tetrabutyl amonium bromide, stirring reaction, TLC monitors reaction, reacts complete, be cooled to room temperature, add methyl alcohol to carry out cancellation, solvent evaporated, add 300mL ethyl acetate, stir, by 30mL water washing organic phase, anhydrous sodium sulfate drying, evaporated under reduced pressure, obtains 18.2g oily product;
The preparation of EZ5: in reaction flask, add successively 17g intermediate IV, 4.2g formic acid, 70mL toluene and 20mL water, stir, be warming up to 45 DEG C of reactions, TLC monitors reaction; React complete, be cooled to room temperature, remove tetrahydrofuran (THF) under reduced pressure, add 100mL ethyl acetate, leave standstill separatory, 50mL ethyl acetate extraction for water layer, merges organic phase, with 80mL saturated sodium bicarbonate solution, 80mL water washing, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure, obtain 12.8g oily product, yield: 85%.
Alkali reagent in the preparation of intermediate I can also be sodium carbonate, and solvent can also be methylene dichloride;
Lewis acid in the preparation of intermediate II is tosic acid or trifluoroacetic acid, and solvent can also be ethylene glycol;
Solvent in the preparation of intermediate III can also be acetone, toluene or tetrahydrofuran (THF);
Solvent in the preparation of intermediate IV is methylene dichloride or toluene;
Sour reagent in the preparation of EZ5 can also be acetic acid, and solvent can also be methylene dichloride or ether;
The invention has the beneficial effects as follows: this processing method route is brief, easy control simple to operate, reaction yield is high, and product purity is high, and cost is low, is suitable for large-scale industrial production.
The above, be only preferred embodiment of the present invention, is not the restriction of the present invention being made to any other form, and according to any amendment or equivalent variations that technical spirit of the present invention is done, still belong to the present invention's scope required for protection.
Claims (6)
1. a preparation method for Ezetimible intermediate, is characterized in that: the chemical equation of the method is:
, comprise successively following processing step: preparation, the preparation of intermediate IV and the preparation of EZ5 of the preparation of intermediate I, the preparation of intermediate II, intermediate III,
The preparation of described intermediate I: 5 taking 4-[[(4-fluorophenyl) imines] methyl]-phenol is as raw material (M1), under alkali effect, with halogenation benzyl and solvent reaction, obtains the 4-[[(4-fluorophenyl of benzyl protection) imines] methyl]-phenol;
The preparation of described intermediate II: with (4S)-3-[5-(4-fluorophenyl)-1,5-oxo amyl group]-4-phenyl-2-oxazolidone (M2) is raw material, under Lewis acid effect, carry out ketone carbonyl-protection with dimercaptopropane and solvent and react, obtain intermediate II;
The preparation of described intermediate III: intermediate I and intermediate II, under highly basic effect, add catalyzer and as in solvent, carry out two key addition reactions and obtain intermediate III;
The preparation of described intermediate IV: intermediate III, under catalyst action, forms four membered ring intermediate IV with cyclizing agent and solvent reaction;
The preparation of described EZ5: intermediate IV and solvent are sloughed protecting group and obtained EZ5 under acid effect.
2. the preparation method of a kind of Ezetimible intermediate according to claim 1, it is characterized in that: the halo benzyl in the preparation of described intermediate I is Benzyl Chloride or cylite, alkali reagent is sodium carbonate, salt of wormwood, triethylamine or DIPEA, solvent is methylene dichloride, toluene, acetone or isopropyl ether, 4-[[(4-fluorophenyl) imines] methyl] mass ratio that feeds intake of-phenol and halogenation benzyl is 1:1.0 ~ 1.5.
3. the preparation method of a kind of Ezetimible intermediate according to claim 1, it is characterized in that: the Lewis acid in the preparation of described intermediate II is tosic acid or trifluoroacetic acid, solvent is ethylene glycol, toluene, tetrahydrofuran (THF) or acetonitrile, and the mass ratio that feeds intake of intermediate I and dimercaptopropane is 1:2.0 ~ 3.
4. the preparation method of a kind of Ezetimible intermediate according to claim 1, is characterized in that: the highly basic in the preparation of described intermediate III is titanium tetrachloride; Described catalyzer is titanium isopropylate, and solvent is methylene dichloride, ether, acetone, toluene or tetrahydrofuran (THF), and the mass ratio that feeds intake of intermediate I, intermediate II and highly basic is 1 ~ 1.5:1:1 ~ 1.2.
5. the preparation method of a kind of Ezetimible intermediate according to claim 1, it is characterized in that: the cyclizing agent in the preparation of described intermediate IV is N, the two trimethyl silicane yl acetamides of O-, catalyzer is tetrabutyl ammonium fluoride, Tetrabutyl amonium bromide or tetrabutylammonium iodide, solvent is methylene dichloride, ether, toluene, isopropyl ether or tetrahydrofuran (THF), and the mass ratio that feeds intake of intermediate III and cyclizing agent is 1:1.0 ~ 1.3.
6. the preparation method of a kind of Ezetimible intermediate according to claim 1, it is characterized in that: the sour reagent in the preparation of described EZ5 is tosic acid, acetic acid, formic acid or trifluoroacetic acid, solvent is methylene dichloride, ether, toluene, tetrahydrofuran (THF) or acetonitrile, and the mass ratio that feeds intake of intermediate IV and sour reagent is 1:0.5 ~ 0.9.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107488165A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Ezetimibe intermediate compound |
| CN107488138A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Ezetimibe synthetic method |
| 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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| WO2008106900A1 (en) * | 2007-03-02 | 2008-09-12 | Zentiva, A.S. | Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone |
| CN101423515A (en) * | 2007-10-30 | 2009-05-06 | 杜焕达 | Novel preparation method of Ezetimibe |
| WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
| CN103159751A (en) * | 2011-12-13 | 2013-06-19 | 重庆华邦胜凯制药有限公司 | A preparation method for the derivates of phenylpyruvic acid amide ketals |
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| WO2008106900A1 (en) * | 2007-03-02 | 2008-09-12 | Zentiva, A.S. | Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone |
| CN101423515A (en) * | 2007-10-30 | 2009-05-06 | 杜焕达 | Novel preparation method of Ezetimibe |
| WO2009067960A2 (en) * | 2007-11-30 | 2009-06-04 | Zentiva, A.S. | A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates |
| CN103159751A (en) * | 2011-12-13 | 2013-06-19 | 重庆华邦胜凯制药有限公司 | A preparation method for the derivates of phenylpyruvic acid amide ketals |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107488165A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Ezetimibe intermediate compound |
| CN107488138A (en) * | 2016-06-10 | 2017-12-19 | 山东新时代药业有限公司 | A kind of Ezetimibe synthetic method |
| 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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