CN104447473A - Preparation method of Ezetimibe intermediate - Google Patents
Preparation method of Ezetimibe intermediate Download PDFInfo
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- CN104447473A CN104447473A CN201410623650.1A CN201410623650A CN104447473A CN 104447473 A CN104447473 A CN 104447473A CN 201410623650 A CN201410623650 A CN 201410623650A CN 104447473 A CN104447473 A CN 104447473A
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- C07—ORGANIC CHEMISTRY
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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: adding (3R,4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxo propyl] azacyclobutane-2-one which is called RM1 for short into a borane/dimethylsulfide reaction system; and then adding an oxidizing agent to react to generate the Ezetimibe intermediate. According to the preparation method, the RM1 is taken as a raw material, a dichloromethane solvent is taken as a raw material solvent and a (R)-MeCBS/methylbenzene solution is taken as a reaction catalyst, so that the reaction can be accelerated and the Ezetimibe intermediate yield can be improved.
Description
Technical field
The invention belongs to biomedicine technical field, relate to the preparation method of Ezetimibe intermediate and Ezetimibe intermediate.
Background technology
Ezetimibe (Ezetimibe) is the novel cholesterol absorption inhibitor developed jointly by Schering Plough drugmaker and Merck & Co., Inc..In November, 2002, the same period went on the market in the U.S. first in Germany's listing.This product is first cholesterol absorption selective depressant class medicine be approved listing by U.S. FDA, its chemistry (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone by name.
Ezetimibe can Selective depression small intestine cholesterol transporter, effectively reduces enteron aisle inner cholesterol and absorbs, reduce blood plasma cholesterol level and hepatic cholesterol reserves.Ezetimibe is the desirable companion of statin treatment, compared with doubling or use instead more potent statin, better LDL-C can be provided to treat compliance rate with statin dosage, and security and tolerance good." selectivity cholesterol absorption inhibitor clinical application China's Consensus of experts (2013) " is pointed out, can not the patient that maybe can not tolerate larger dose statin treatment up to standard for independent application statins cholesterol levels, combined utilization statin and Ezetimibe can be considered choose reasonable.Ezetimibe is also the preferred option of the high-risk and pole high-risk patient decreasing cholesterol second line treatment of coronary heart disease.
The method of synthesis Ezetimibe has a lot, but difficult point is the structure of chirality S-hydroxyl in molecule.The maximum method of current use is exactly first build latent chiral intermediate arone.The general problem of the existing method preparing Ezetimibe intermediate one of existing is exactly that recovery rate is not high, and this not only can cause the waste of raw material, the impurity that contains in medicine also can be made many, and then affect the safety and stability of medicine.
Summary of the invention
The object of the invention is to for above-mentioned the deficiencies in the prior art, provide a kind of preparation method preparing the necessary intermediate of Ezetimibe and this intermediate, to solve the low problem of the recovery rate that exists in existing technique.
The present invention takes following technical scheme to realize above-mentioned purpose.
The invention provides a kind of Ezetimibe intermediate, for having the compound of structural formula I:
The preparation method of above-mentioned Ezetimibe intermediate is, in a solvent, (the 3R of formula II will be had, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone, be called for short RM1, join the reaction system of borine/dimethyl sulphide, then add the Ezetimibe intermediate that oxidant reaction generation has structural formula I, its reaction scheme is as follows:
Wherein, above-mentioned solvent is methylene dichloride; Above-mentioned oxygenant is hydrogen peroxide.
First the present invention gives the structural formula of Ezetimibe intermediate, and those skilled in the art, under the guidance of structure above, can obtain the compound with structure above in several ways.Although the present invention does not give too much restriction to the processing condition of the preparation method of above-mentioned Ezetimibe intermediate, under the guiding theory of said synthesis route, those skilled in the art can obtain above-mentioned Ezetimibe intermediate.The preparation method of the Ezetimibe intermediate that the present invention provides is the preferred version provided on a large amount of Research foundation, has the advantage that technique is simple, cost is low, recovery rate is high.
Preparation method's concrete steps of the Ezetimibe intermediate that the present invention provides are as follows: under nitrogen protection atmosphere, be cooled to-5 ~ 5 DEG C, will fill the reaction vessel of methylene dichloride, add borine/dimethyl sulphide, after stirring, add catalyzer, temperature raises about 3 DEG C, stirs; Control temperature, at-5 ~ 5 DEG C, drips the solution of RM1 and methylene dichloride, continues to be stirred to RM1 and disappear after dropwising; Then control temperature drips methyl alcohol at-5 ~ 0 DEG C, dropwises rear continuation and stirs 1h, add 5%H
2o
2the aqueous solution and pure water, stir 1h; Leave standstill separatory, in the water layer after being separated, add dichloromethane extraction, then merge the organic phase after the organic phase after separatory and extraction, then through washing, dry, filter, after concentrated, recrystallization white powder is Ezetimibe intermediate.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, above-mentioned catalyzer is R-2-methyl-CBS-oxazaborolidine/toluene solution ((R)-MeCBS/ toluene solution), and what adopt in preferred implementation be concentration is 1M (R)-MeCBS toluene solution.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, the proportionlity of above-mentioned borine/dimethyl sulphide and RM1 is 0.2ml:1g; The mass ratio of above-mentioned (R)-MeCBS/ toluene solution and RM1 is 0.2ml:1g.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, adopt hydrogen peroxide that structural for RM1 double bond=O structure is broken into singly-bound-OH hydroxyl structure, wherein-OH is from methyl alcohol, and the methyl alcohol of dropping and the proportionlity of RM1 are 0.2ml:1g; The mass ratio of above-mentioned hydrogen peroxide and RM1 is 1:(10 ~ 15).
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, what solvent adopted is methylene dichloride, for dissolving RM1, as long as its amount reaches dissolves completely.In a preferred embodiment, the ratio of adding 7ml methylene dichloride for the methylene dichloride dissolving RM1 according to every 1gRM1 is carried out.Above-mentioned methylene dichloride also can adopt trichloromethane to substitute, but effect is undesirable.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, the proportionlity of the methylene dichloride added during beginning and borine/dimethyl sulphide is 1ml:1ml.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, what borine/dimethyl sulphide adopted is concentration is the borine/dimethyl sulphide of 10M.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, oxygenant is hydrogen peroxide.Oxygenant can also select potassium perchlorate, but effect is undesirable.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, the method detecting RM1 disappearance is, after dripping the organic solution being dissolved with RM1, often stir 1 ~ 2 hour, add TLC (developping agent, petrol ether/ethyl acetate mixes according to volume ratio 3:1) monitor raw material RM1, if monitoring is less than RM1, illustrate that RM1 disappears.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, extraction agent is methylene dichloride, and extraction agent also can adopt trichloromethane etc.
Specifically prepare in the method for Ezetimibe intermediate above-mentioned, above-mentioned washing, drying, filtration, the conventional means that concentrated, recrystallization can adopt this area.The present inventor is again on this basis, and be optimized above-mentioned technique, the concrete scheme that the present invention takes is as follows: (1) washing comprises washing and saturated common salt water washing, according to material quantity, first uses appropriate pure water, then uses appropriate saturated common salt water washing; (2) anhydrous sodium sulfate drying is adopted to remove water; (3) concentrated employing underpressure distillation concentration method, vacuum distillation temperature is 30 ~ 65 DEG C, and underpressure distillation pressure is not higher than 0.10MPa, is concentrated into without methylene dichloride liquid, only surplus solid substance; (4) recrystallization method is first the material after concentrated is added proper amount of methanol backflow to dissolve (as long as the amount adding methyl alcohol is by the substance dissolves after concentrated), be cooled to 5 ~ 15 DEG C of recrystallizations again, after recrystallization terminates again 65 ~ 75 DEG C, pressure is not dried to white powder constant weight higher than 0.08MPa condition.
Ezetimibe intermediate technical scheme provided by the invention has following beneficial effect: in the preparation process of Ezetimibe intermediate, with (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone (being called for short RM1) makes raw material, methylene dichloride makes Materials Solvents as solvent, make catalysts with (R)-MeCBS/ toluene solution, can accelerate reaction; And improve the recovery rate of Ezetimibe intermediate.
Embodiment
In order to make the object, technical solutions and advantages of the present invention clearly, below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment one
By 40ml methylene dichloride mechanical lysis, under nitrogen protection atmosphere, be cooled to-5 DEG C, add 40ml 10M borine/dimethyl sulphide, add 40ml 1M (R)-MeCBS toluene solution after stirring 10min, temperature raises about 3 DEG C, stirs 30min; Control temperature is at-5 DEG C, and under whipped state, drip 200gRM1/1400ml dichloromethane solution, about 1.5h dropwises, and then continues to stir 1h, adds TLC and monitors raw material RM1 disappearance; Then control temperature drips 400ml methyl alcohol at-5 DEG C, and a large amount of gas of overflowing, about 1h dropwises, and rear continuation is stirred to 1h, then adds 5%H
2o
2aqueous solution 13.3ml and pure water 500ml stirs 1h; Leave standstill separatory, 300ml dichloromethane extraction is added in the water layer after separation, then the organic phase after separatory and the organic phase after extraction is merged, again through 300ml washing, the water washing of 300ml saturated common salt, 10g anhydrous sodium sulfate drying, filter, in 30 DEG C, 0.1MPa is evaporated to without methylene dichloride, adds the dissolving of 1000ml methanol eddy, then be cooled to 5 DEG C of crystallization 2h, products obtained therefrom through 65 DEG C, the dry 6h of 0.08MPa obtains white powder 152.5 ± 0.3g and is Ezetimibe intermediate.
Pass through formula: yield=[(Ezetimibe intermediate/499.55) ÷ (RM1/497.53)] × 100% yield obtaining above-mentioned preparation method is 76.0 ± 0.1%.
Embodiment two
The Ezetimibe intermediate that the present embodiment is prepared with above-described embodiment 1, for raw material, prepares Ezetimibe product.
150.0g Ezetimibe intermediate is added in 10L reaction vessel, add 3000ml methyl alcohol again, magnetic agitation, nitrogen replacement air, add 15g 10% palladium charcoal, hydrogen exchange nitrogen to control hydrogen flowing quantity be that 0.5L/ divides, controlling stirring velocity is 85 revs/min, 2h is reacted under temperature 13 DEG C of conditions, after add TLC (developping agent: petrol ether/ethyl acetate=1:1) monitor Ezetimibe intermediate disappear, stop passing into hydrogen, nitrogen replacement hydrogen, filter, 50ml methanol wash filter cake, Recover palladium carbon, filtrate continues pad 40g activated carbon filtration, 100ml methanol wash filter cake, control temperature is at 40 DEG C, under pressure 0.1MPa condition, concentrated filtrate is about 500ml to containing methyl alcohol, control temperature drips 250ml pure water at 40 DEG C, dropwise rear Temperature fall to room temperature, continue to be cooled to 0 DEG C and stir 1h, filter, the solution washing that 100ml is mixed to get according to volume ratio 2:1 by methyl alcohol and pure water, decompression drying obtains 97.0 ± 0.3g Ezetimibe crude product.
Pass through formula: yield=[(Ezetimibe crude product/409.43) ÷ (Ezetimibe intermediate/499.55)] × 100% yield obtaining above-mentioned preparation method is 78 ± 1.5%.
The Ezetimibe crude product 97.0 ± 0.3g obtained is joined in 485ml methyl alcohol, magnetic agitation is dissolved, control temperature drips pure water 485ml (pure water meets Chinese Pharmacopoeia two regulation) at 40 DEG C, dropwise rear Temperature fall to room temperature, continuation ice bath is cooled to 5 DEG C and stirs 1h, through solution washing that 100ml is mixed to get according to volume ratio 2:1 by methyl alcohol and pure water after filtration, repeat above-mentioned dissolving-crystallization-washing step, finally in 70 DEG C, namely the dry 6h of 0.08MPa obtain the Ezetimibe 91 ± 0.3g of purifying.
Pass through formula: yield=[(Ezetimibe fine work/409.43) ÷ (Ezetimibe intermediate/499.55)] × 100% yield obtaining above-mentioned preparation method is 74 ± 0.5%.
Above-described embodiment is prepared Ezetimibe intermediate and is adopted the method for this Intermediate Preparation Ezetimibe to have the following advantages compared with traditional Ezetimibe preparation method:
(1) in the preparation method of Ezetimibe intermediate, with (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone (being called for short RM1) makes raw material, methylene dichloride makes Materials Solvents as solvent, make catalysts with (R)-MeCBS/ toluene solution, can accelerate reaction; And Ezetimibe intermediate [white powder] yield can be made to rise to 76 soil 0.1% from 62 soil 2%.
(2) prepare in crude product method in Ezetimibe intermediate, adopt methanol as solvent, 10%Pd/C makes reactant, control temperature is at 10 ± 3 DEG C of reaction 2hr, adopt in simultaneous reactions process and prevent air oxidation reaction, namely first use nitrogen replacement air, midway passes into hydrogen, finally uses the method for nitrogen replacement hydrogen; Ezetimibe crude product [white powder] yield can be made to rise to more than 78% from 65 soil 2%, even can reach 86 ~ 87%.
(3) in Ezetimibe crude product refining method, by carrying out purifying to Ezetimibe crude product, Ezetimibe fine work [white powder] yield can be made to rise to more than 74% from 68 soil 2%, even can reach 86 ~ 87%.
In sum, what provided by the application is prepared Ezetimibe intermediate and adopts the method for this Intermediate Preparation Ezetimibe, greatly can improve the recovery rate of Ezetimibe intermediate and Ezetimibe product, and then the effective dose of Ezetimibe in raising medicament, not only reduce cost like this, be more suitable for promoting; And the patient treatment time can be shortened, reduce patient economy burden and mental burden.
Those of ordinary skill in the art will appreciate that, embodiment described here is to help reader understanding's principle of the present invention, should be understood to that protection scope of the present invention is not limited to so special statement and embodiment.Those of ordinary skill in the art can make various other various concrete distortion and combination of not departing from essence of the present invention according to these technology enlightenment disclosed by the invention, and these distortion and combination are still in protection scope of the present invention.
Claims (8)
1. the preparation method of an Ezetimibe intermediate, it is characterized in that, in a solvent, (the 3R of formula II will be had, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone, is called for short RM1, joins the reaction system of borine/dimethyl sulphide, add oxidant reaction again and generate Ezetimibe intermediate, its reaction scheme is as follows:
Wherein, described solvent is methylene dichloride; Described oxygenant is hydrogen peroxide.
2. the preparation method of Ezetimibe intermediate according to claim 1, it is characterized in that being specially: under nitrogen protection atmosphere, be cooled to-5 ~ 5 DEG C, the reaction vessel of methylene dichloride will be filled, add borine/dimethyl sulphide, after stirring, add catalyzer, temperature raises 3 DEG C, stirs; Control temperature, at-5 ~ 5 DEG C, drips the solution of RM1 and methylene dichloride, continues to be stirred to RM1 and disappear after dropwising; Then control temperature drips methyl alcohol at-5 ~ 0 DEG C, dropwises rear continuation and stirs 1h, add 5%H
2o
2the aqueous solution and pure water, stir 1h; Leave standstill separatory, in the water layer after being separated, add dichloromethane extraction, then merge the organic phase after the organic phase after separatory and extraction, then through washing, dry, filter, after concentrated, recrystallization white powder is Ezetimibe intermediate;
Described catalyzer is R-2-methyl-CBS-oxazaborolidine/toluene solution;
The proportionlity of described borine/dimethyl sulphide and RM1 is 0.2ml:1g; The proportionlity of described R-2-methyl-CBS-oxazaborolidine/toluene solution and RM1 is 0.2ml:1g; The methyl alcohol of described dropping and the proportionlity of RM1 are 0.2ml:1g; The mass ratio of described hydrogen peroxide and RM1 is 1:(10 ~ 15).
3. the preparation method of Ezetimibe intermediate according to claim 2, is characterized in that the proportionlity of methylene dichloride and the borine/dimethyl sulphide added when starting is 1ml:1ml.
4., according to the preparation method of the Ezetimibe intermediate of Claims 2 or 3, it is characterized in that the methylene dichloride for dissolving RM1 carries out according to every 1gRM1 interpolation 7ml methylene dichloride ratio.
5., according to the preparation method of the Ezetimibe intermediate of Claims 2 or 3, it is characterized in that described methylene dichloride is substituted by trichloromethane.
6., according to the preparation method of claim 4 Ezetimibe intermediate, it is characterized in that described methylene dichloride is substituted by trichloromethane.
7. according to the preparation method of the Ezetimibe intermediate described in Claims 2 or 3, it is characterized in that the concrete grammar detecting RM1 disappearance is: after dripping the solution of RM1 and methylene dichloride, often stir setting-up time, add developping agent to monitor raw material RM1, if monitoring, less than RM1, illustrates that RM1 disappears; Described developping agent by sherwood oil and ethyl acetate formulated according to volume ratio 3:1.
8. the preparation method of the Ezetimibe intermediate described in Claims 2 or 3, is characterized in that described recrystallization method is first the material after concentrated is added methanol eddy to dissolve, then is cooled to 5 ~ 15 DEG C of recrystallizations.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017119A (en) * | 2015-07-23 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Lipid-lowering drug ezetimibe compound |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007119106A2 (en) * | 2005-12-22 | 2007-10-25 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
| WO2008096372A2 (en) * | 2007-02-06 | 2008-08-14 | Ind-Swift Laboratories Limited | Process for preparing highly pure ezetimibe using novel intermediates |
| WO2010097350A1 (en) * | 2009-02-24 | 2010-09-02 | Adamed Sp. Z O.O. | A process for the preparation of an aldehyde beta-lactam compound |
| CN102531986A (en) * | 2012-02-23 | 2012-07-04 | 苏州朗科生物技术有限公司 | Preparation method for ezetimibe |
| CN102775366A (en) * | 2011-05-10 | 2012-11-14 | 上海医药工业研究院 | Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one |
| CN102952055A (en) * | 2011-08-16 | 2013-03-06 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of ezetimibe and its intermediate |
| CN103086938A (en) * | 2011-10-28 | 2013-05-08 | 沈阳药科大学 | Ezetimibe synthesis method |
| CN103755616A (en) * | 2013-12-31 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Method for preparing ezetimibe isomer |
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
-
2014
- 2014-11-06 CN CN201410623650.1A patent/CN104447473B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007119106A2 (en) * | 2005-12-22 | 2007-10-25 | Medichem, S.A. | Processes for preparing intermediate compounds useful for the preparation of ezetimibe |
| WO2008096372A2 (en) * | 2007-02-06 | 2008-08-14 | Ind-Swift Laboratories Limited | Process for preparing highly pure ezetimibe using novel intermediates |
| WO2010097350A1 (en) * | 2009-02-24 | 2010-09-02 | Adamed Sp. Z O.O. | A process for the preparation of an aldehyde beta-lactam compound |
| CN102775366A (en) * | 2011-05-10 | 2012-11-14 | 上海医药工业研究院 | Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one |
| CN102952055A (en) * | 2011-08-16 | 2013-03-06 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of ezetimibe and its intermediate |
| CN103086938A (en) * | 2011-10-28 | 2013-05-08 | 沈阳药科大学 | Ezetimibe synthesis method |
| CN102531986A (en) * | 2012-02-23 | 2012-07-04 | 苏州朗科生物技术有限公司 | Preparation method for ezetimibe |
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
| CN103755616A (en) * | 2013-12-31 | 2014-04-30 | 北京万全德众医药生物技术有限公司 | Method for preparing ezetimibe isomer |
Non-Patent Citations (1)
| Title |
|---|
| C.H.V.A.SASIKALA等: "An Improved and Scalable Process for the Synthesis of Ezetimibe: An Antihypercholesterolemia Drug", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017119A (en) * | 2015-07-23 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Lipid-lowering drug ezetimibe compound |
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