CN104387308A - Method for preparing high-purity ezetimibe by controlling generation of EZ-zanOH impurity - Google Patents
Method for preparing high-purity ezetimibe by controlling generation of EZ-zanOH impurity Download PDFInfo
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- CN104387308A CN104387308A CN201410656583.3A CN201410656583A CN104387308A CN 104387308 A CN104387308 A CN 104387308A CN 201410656583 A CN201410656583 A CN 201410656583A CN 104387308 A CN104387308 A CN 104387308A
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- ezetimibe
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 method for preparing high-purity ezetimibe by controlling generation of an EZ-zanOH impurity, relates to the field of medicinal chemistry, and particularly relates to a method for preparing high-purity ezetimibe by adding an alcohol solvent and an organic acid to a purification system and controlling generation of an ezetimibe impurity EZ-zanOH (cyclic ether impurity). The method is simple to operate and easy to control.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly relate to a kind of control EZ-zanOH impurity and produce the method preparing high purity Ezetimibe.
Background technology
Ezetimibe (Ezetimibe) is the novel cholesterol absorption inhibitor developed jointly by Schering Plough (Schering-Plough) drugmaker and Merck (Merck) company.In November, 2002 in Germany, U.S.'s listing, be applicable to various hyperlipidaemia and some heredity and drug induccd hyperlipidemia patient.
Ezetimibe, chinesization formal name used at school: (3R, 4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxy phenyl)-2-azetidinone; CAS registration number: 163222-32-0.Its structural formula is as follows:
The existing technique preparing Ezetimibe exist the technological difficulties of purifying.Especially, in Ezetimibe solvent, be easy to form impurity E Z-zanOH(cyclic ethers impurity), be thus difficult to obtain highly purified Ezetimibe finished product.
Ezetimibe impurity E Z-zanOH(cyclic ethers impurity) structure is as follows, and chemistry is by name: two (4-fluorophenyl)-2-(4-hydroxy phenyl) tetrahydrochysene-2H-pyrans-3-methane amide of (2R, 3R, 6S)-N, 6-.
Document Journal of Pharmaceutical and Biomedical Analysis, 2006 (41), 1037 ~ 1040 and J Fluoresc, 2012(22), 9 ~ 15 have carried out the introduction of analyzing and testing aspect to this impurity, but do not mention the formation how controlling this impurity in preparation process.
Summary of the invention
Existingly preparing in the technique of Ezetimibe for overcoming, especially in a solvent, being easy to form impurity E Z-zanOH(cyclic ethers impurity), be thus difficult in preparation process to technical problems such as highly purified Ezetimibe finished products.
The present invention is for solving the problem, and provide a kind of control EZ-zanOH impurity to produce the method preparing high purity Ezetimibe, the technical scheme that above-mentioned preparation method adopts needs following steps:
A. the present invention adopts (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone is starting raw material, and the Chinese invention patent being 94193466.7 according to application number obtains Ezetimibe crude product;
B. Ezetimibe crude product steps A obtained carries out purifying, 1-3 part Ezetimibe crude product is put in sealed reaction device, pour 14-26 part alcoholic solvent and 0.5-2 part organic acid again into, be warmed up to 65 DEG C-86 DEG C, filtered while hot after stirring 30min, adds 6-10 part water, be warming up to 60 DEG C-70 DEG C molten clear after, become after its heating for dissolving limpid after, naturally cool to 20-25 DEG C, namely separate out white Ezetimibe solid; Suction filtration after stirring 4-6h, vacuum-drying 4h at 45 DEG C, obtains pure white Ezetimibe solid;
As preferably, the alcoholic solvent in described step B is the one in methyl alcohol, ethanol, Virahol, isopropylcarbinol or propyl carbinol.
As preferably, the organic acid in described step B is the one of acetic acid, oxalic acid, citric acid or fumaric acid.
beneficial effect
The present invention have developed and can produce the method preparing high purity Ezetimibe by control EZ-zanOH impurity.The method has that technique is simple, good separating effect, pollution-free, low cost and other advantages.
The present invention adds appropriate alcohol and organic acid under the processing condition of uniqueness, and it has been obtained by reacting white high purity Ezetimibe solid, and almost do not have impurity in solid, its HPLC purity can reach more than 99.67%.It can thus be appreciated that the present invention, can inhibition of impurities EZ-zanOH(cyclic ethers impurity greatly relative to prior art) generation.
Accompanying drawing explanation
Fig. 1 is Ezetimibe impurity E Z-zanOH(cyclic ethers impurity) molecular structure;
Fig. 2 is Ezetimibe impurity E Z-zanOH(cyclic ethers impurity) 1HNMR spectrogram;
Fig. 3 is Ezetimibe impurity E Z-zanOH(cyclic ethers impurity) LCMS spectrogram;
Fig. 4 is the HPLC spectrogram adding acetic acid (acetic acid) in Ezetimibe purification system;
Fig. 5 is the HPLC spectrogram not adding acetic acid (acetic acid) in Ezetimibe purification system.
Embodiment
Below in conjunction with appended with drawings, by the following example, the invention will be further described:
Embodiment 1: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 2 parts of Ezetimibe crude products, pour 21.4 parts of methyl alcohol and 0.74 part of acetic acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 75 DEG C, filtered while hot after stirring 30min, 10 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 65 DEG C again, molten clear after, naturally cool to 23 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 5h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.67%(is shown in accompanying drawing 4).
Embodiment 2: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first by 1 part of (weight part, every part can be 1 gram, 10 grams, 100 grams or more, down together) Ezetimibe crude product is placed in sealed reaction vessel, pour 14 parts of methyl alcohol and 0.5 part of acetic acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 65 DEG C, filtered while hot after stirring 30min, 6 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 60 DEG C again, molten clear after, naturally cool to 20 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 4h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.51%(is see accompanying drawing 4)
Embodiment 3: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 3 parts of Ezetimibe crude products, pour 26 parts of ethanol and 2 parts of oxalic acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 86 DEG C, filtered while hot after stirring 30min, 10 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 70 DEG C again, molten clear after, naturally cool to 25 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 6h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.52%(is see accompanying drawing 4)
Embodiment 4: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 2 parts of Ezetimibe crude products, pour 20 parts of Virahols and 1 part of citric acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 75 DEG C, filtered while hot after stirring 30min, 10 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 65 DEG C again, molten clear after, naturally cool to 23 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 5h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.56%(is see accompanying drawing 4).
Embodiment 5: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 2 parts of Ezetimibe crude products, pour 20 parts of propyl carbinols and 1 part of citric acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 75 DEG C, filtered while hot after stirring 30min, 10 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 65 DEG C again, molten clear after, naturally cool to 23 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 5h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.57%(is see accompanying drawing 4).
Embodiment 6: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product;
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 2 parts of Ezetimibe crude products, pour 12 parts of methyl alcohol and 0.74 part of acetic acid again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 65 DEG C, filtered while hot after stirring 30min, 8 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 60 DEG C again, molten clear after, naturally cool to 20 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 4h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain white high purity Ezetimibe solid.Its HPLC purity: 99.63%(is see accompanying drawing 4)
Comparative example 1: first the present invention adopts (3R, 4S) azetidine-2-ketone is starting raw material to-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl], and the Chinese invention patent that application reference number is 94193466.7 obtains Ezetimibe crude product.
Secondly, obtained Ezetimibe crude product is carried out purifying: first place in sealed reaction vessel by 2 parts of Ezetimibe crude products, pour 21.4 parts of methyl alcohol again into, until Ezetimibe crude product molten clear after, reaction vessel interior temperature is risen to 65 DEG C, filtered while hot after stirring 30min, 8 parts of water are added in reaction vessel, mixing stoste temperature in reaction vessel is warming up to 65 DEG C again, molten clear after, naturally cool to 20 DEG C, mixing stoste can form solid-liquid stratification state, upper strata is waste liquid, namely lower floor separates out the higher white Ezetimibe solid of purity, again be uniformly mixed stoste 4h, filter flask is selected to carry out suction filtration to mixing stoste, finally will mix stoste vacuum-drying 4h at 45 DEG C after suction filtration, obtain 1.12 parts of white high purity Ezetimibe solids.(there is impurity E Z-zanOH, see accompanying drawing 5 in HPLC display).
Adopt petrol ether/ethyl acetate system, with the ratio of above-mentioned white Ezetimibe solid in (3:1), as the developping agent of thin-layer chromatographic analysis after mixing, white Ezetimibe solid is separated, obtain 0.4 part of impurity E Z-zanOH(molecular structure and see accompanying drawing 1, itself 1HNMR and LCMS is shown in accompanying drawing 2, accompanying drawing 3).
MS(molecular formula: C24H21F2NO3): m/z=410(M+H+).
1HNMR (DMSO-d6, 400MHz) δ 9.95 (s, 1H), 9.36 (s, 1H), 7.41~7.47 (m, 4H), 7.14~7.21 (m, 4H), 7.04~7.08 (t, 2H), 6.66~6.69 (d, 2H), 4.61~4.64 (m, 2H), 2.72~2.75 (m, 1H), 1.96~2.12 (m, 3H) , 1.52~1.56 (m, 1H)。
Prepare in Ezetimibe Finished product processThe in comparative example, can inevitably occur impurity E Z-zanOH, affect final product quality.Petrol ether/ethyl acetate system must be adopted, in the ratio of (3:1), as the developping agent of thin-layer chromatographic analysis after mixing, white Ezetimibe solid is separated, just can obtains purer Ezetimibe finished product.
Finally it should be pointed out that above embodiment is only the more representational example of the present invention.Obviously, the invention is not restricted to above-mentioned embodiment, many distortion can also be had.Every above embodiment is done according to technical spirit of the present invention any simple modification, equivalent variations and modification, all should think and belong to protection scope of the present invention.
Claims (2)
1. control EZ-zanOH impurity produces the method preparing high purity Ezetimibe, and its technical scheme adopted needs following steps:
A. the present invention adopts (3R, 4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl] azetidine-2-ketone is starting raw material, and the Chinese invention patent being 94193466.7 according to application number obtains Ezetimibe crude product;
B. Ezetimibe crude product steps A obtained carries out purifying, 1-3 part Ezetimibe crude product is put in sealed reaction device, pour 14-26 part alcoholic solvent and 0.5-2 part organic acid again into, be warmed up to 65 DEG C-86 DEG C, filtered while hot after stirring 30min, adds 6-10 part water, be warming up to 60 DEG C-70 DEG C molten clear after, become after its heating for dissolving limpid after, naturally cool to 20-25 DEG C, namely separate out white Ezetimibe solid; Suction filtration after stirring 4-6h, vacuum-drying 4h at 45 DEG C, obtains pure white Ezetimibe solid;
A kind of control EZ-zanOH impurity as claimed in claim 1 produces the method preparing high purity Ezetimibe, and the alcoholic solvent that it is characterized in that in described step B is the one in methyl alcohol, ethanol, Virahol, isopropylcarbinol or propyl carbinol.
2. a kind of control EZ-zanOH impurity as claimed in claim 1 produces the method preparing high purity Ezetimibe, and the organic acid that it is characterized in that in described step B is the one of acetic acid, oxalic acid, citric acid or fumaric acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986806A (en) * | 2017-04-07 | 2017-07-28 | 四川智强医药科技开发有限公司 | The process for purification of Ezetimibe |
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2014
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986806A (en) * | 2017-04-07 | 2017-07-28 | 四川智强医药科技开发有限公司 | The process for purification of Ezetimibe |
| CN106986806B (en) * | 2017-04-07 | 2019-12-31 | 四川智强医药科技开发有限公司 | Ezetimibe refining method |
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