CN102464669B - Amorphous everolimus and preparation method thereof - Google Patents
Amorphous everolimus and preparation method thereof Download PDFInfo
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- CN102464669B CN102464669B CN201010546471.4A CN201010546471A CN102464669B CN 102464669 B CN102464669 B CN 102464669B CN 201010546471 A CN201010546471 A CN 201010546471A CN 102464669 B CN102464669 B CN 102464669B
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- everolimus
- ether
- alkane
- naphthenic hydrocarbon
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- HKVAMNSJSFKALM-GJDYDICYSA-N C[C@H](CC(CC[C@H]1OCCO)C[C@H]1OC)C(CC([C@H](C)/C=C(\C)/[C@H]([C@H](C([C@H](C)C[C@H](C)/C=C/C=C/C=C(\C)/[C@H](CC(CC[C@H]1C)O[C@]1(C(C(N1[C@H]2CCCC1)=O)=O)O)OC)=O)OC)O)=O)OC2=O Chemical compound C[C@H](CC(CC[C@H]1OCCO)C[C@H]1OC)C(CC([C@H](C)/C=C(\C)/[C@H]([C@H](C([C@H](C)C[C@H](C)/C=C/C=C/C=C(\C)/[C@H](CC(CC[C@H]1C)O[C@]1(C(C(N1[C@H]2CCCC1)=O)=O)O)OC)=O)OC)O)=O)OC2=O HKVAMNSJSFKALM-GJDYDICYSA-N 0.000 description 1
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Abstract
The invention relates to an everolimus amorphous solid and a preparation process thereof. The preparation process comprises the following steps of: dissolving everolimus into ester; and dropwise adding alkane or cyclane for separating an amorphous solid out.
Description
Technical field
The present invention relates to a kind of everolimus amorphous solid and preparation technology thereof.
Background technology
Rapamycin is the large ring triene antibiotic being produced by streptomyces hygroscopicus, finds that it has in vitro and in vivo anti-mycotic activity, particularly anti-candida albicans [people such as C.Vezina, J.Antibiot.28,721 (1975); The people such as S.N.Sehgal, J.Antibiot.28,727 (1975); The people such as H.A.Baker, J.Antibiot.31,539 (1978); United States Patent (USP) 3,929,992 and United States Patent (USP) 3,993,749].
Rapamycin has antitumor (United States Patent (USP) 4, 885, 171 and 4, 401, 653) and immunosuppressive action [FASEB 3, 3411 (1989)], its purposes comprises prevention or transplantation in treating systemic erythema sore [United States Patent (USP) 5, 078, 999], pneumonia [United States Patent (USP) 5, 080, 899], insulin-dependent diabetes mellitus [the 5th international conference of inflammatory diseases research association (Fifth Int.Conf.Inflamm.Res.Assoc.) 121 (summaries), (1990)], inner membrance thickening [the Morris that smooth muscle cell proliferation and blood vessel injury cause, R.J. heart-lung transplant (Heart Lung Transplant) 11 (pt.2), 197 (1992)], adult HTL/lymphoma [EP525,960A1] and ophthalmia [EP532,862A1].Rapamycin and rapamycin derivative comprise everolimus (structural formula I) studied these and the Other diseases of being used for the treatment of always.
Everolimus has another name called 40-O-(2-hydroxyl) ethyl rapamycin, and English name everolimus, is the derivative of rapamycin, its synthetic United States Patent (USP) NO.5 that is described in, 665,772 and International Patent Publication NO.WO94/09010 in.Its refining purifying patent is described in United States Patent (USP) NO.6, and 605,613B2, with ethyl acetate and the refining crystal formation solid that obtains of normal hexane.
Summary of the invention
The object of the invention is to study a kind of everolimus amorphous solid and preparation technology thereof.
An aspect of of the present present invention, relates to a kind of amorphous solid of everolimus.The invention further relates to the everolimus amorphous solid of the X-ray diffraction spectrogram having shown in accompanying drawing 1.
In another aspect of this invention, relate to the method for preparing everolimus (everolimus) amorphous solid, it is characterized in that everolimus to be dissolved in ethers, drip wherein alkane or naphthenic hydrocarbon, separate out amorphous solid, if the crystal solution by this containing solid is evaporated to 1/3～1/2 volume, yield also will improve accordingly.
In a preferred embodiment of the invention, the preferred C of described ether
4～C
16symmetry or asymmetrical ether, more preferably ether, propyl ether, isopropyl ether and/or methyl tertiary butyl ether.
Preferably alkane or the naphthenic hydrocarbon described in it is C
5～C
12alkane or naphthenic hydrocarbon, more preferably alkane or the cycloalkane such as normal hexane, normal heptane, hexanaphthene.
In a preferred embodiment of the invention, the ratio of preferred described everolimus and ether (quality: volume) is 1: 5～1: 100, is more preferably 1: 10～1: 50; The ratio (quality: volume) of preferred described everolimus and alkane or naphthenic hydrocarbon is 1: 10～1: 100, is more preferably 1: 10～1: 50.Quality involved in the present invention and the ratio unit of volume are g/ml.
In embodiment of the present invention, relate to that refinement mother liquor is recyclable to be re-refined, be about to separate out solid mother liquor afterwards and be concentrated into approximately 1/3 original volume, according to the quality of everolimus crude product, add again alkane or the naphthenic hydrocarbon of approximately 1 volume ether and approximately 10 volumes, this refined soln of reconcentration everolimus of can re-refining out from mother liquor.
The synthetic United States Patent (USP) NO.5 that is described in of everolimus, 665,772 and International Patent Publication NO.WO94/09010, take rapamycin as starting raw material, in methylene dichloride, under diisopropylethylamine exists, react with trifluoromethanesulfonic acid tertiary butyl dimethyl Si base ethyl ester, through hydrolysis, by conventional processing, obtain everolimus product.
The inventive method is easy to operate; The sample size of processing is large, is convenient to industrialization; Mother liquor can reclaim and re-refine, and can reduce the loss to the full extent, improves the yield of product.
Accompanying drawing explanation
The amorphous everolimus that accompanying drawing 1: embodiment 1 method purifying obtains
Wherein, X-coordinate is 2 θ angles, and ordinate zou is peak intensity.
Specific embodiment
The instrument of spectrogram, working method shown in accompanying drawing 1
Instrument: Rigaku D/max-2200
Working method: Cu target continuous sweep sweep velocity: 4 °/minute
Sweep limit: 3 °～40 °
Embodiment 1:
1g everolimus crude product is dissolved in to 20ml methyl tertiary butyl ether, and stirring at room, slowly drips 40ml normal hexane, separate out solid, filter, vacuum-drying obtains 0.46g off-white color amorphous everolimus, purity > 99%, its X-ray diffraction spectrum as shown in Figure 1.
Embodiment 2:
1g everolimus crude product is dissolved in to 40ml methyl tertiary butyl ether, and stirring at room, slowly drips 40ml normal heptane, be evaporated to 2/5 approximately original volume, separate out a large amount of solids, filter, vacuum-drying obtains 0.8g off-white color amorphous everolimus, purity > 99%.The spectrogram of products obtained therefrom is with embodiment 1.
Embodiment 3:
10g everolimus crude product is dissolved in to 200ml methyl tertiary butyl ether, stirring at room, slowly drips 400ml normal hexane, separates out solid, filter, mother liquor is concentrated into 1/3rd volumes, adds 100ml normal hexane, 10ml methyl tertiary butyl ether, reconcentration to three/mono-volume, filter, vacuum-drying obtains 8.2g off-white color amorphous everolimus altogether, purity > 99%, and its X-ray diffraction spectrum is as shown in Figure 1.
Embodiment 4:
According to embodiment 2, methyl tertiary butyl ether is replaced to isopropyl ether, obtain off-white color amorphous everolimus, purity > 99%.The spectrogram of products obtained therefrom is with embodiment 1.
Embodiment 5:
According to embodiment 1, methyl tertiary butyl ether is replaced to ether, obtain off-white color amorphous everolimus, purity > 99%.The spectrogram of products obtained therefrom is with embodiment 1.
Embodiment 6:
According to embodiment 2, methyl tertiary butyl ether is replaced to propyl ether, obtain off-white color amorphous everolimus, purity > 99%.The spectrogram of products obtained therefrom is with embodiment 1.
Embodiment 7:
According to embodiment 2, normal heptane is replaced to hexanaphthene, obtain off-white color amorphous everolimus, purity > 99%.The spectrogram of products obtained therefrom is with embodiment 1.
Claims (9)
1. a method of preparing everolimus amorphous solid, comprises, everolimus is dissolved in ether, drips wherein alkane or naphthenic hydrocarbon, separates out amorphous solid, and this everolimus has XPRD collection of illustrative plates as shown in Figure 1; Wherein, described ether refers to C
4～C
16symmetry or asymmetrical ether; Described alkane or naphthenic hydrocarbon refer to C
5～C
12alkane or naphthenic hydrocarbon.
2. method according to claim 1, wherein said ether is selected from ether, propyl ether, isopropyl ether and/or methyl tertiary butyl ether.
3. method according to claim 1, the alkane described in it or naphthenic hydrocarbon are selected from normal hexane, normal heptane or hexanaphthene.
4. according to the method described in claim 1-3 any one, the ratio of everolimus and ether described in it (quality: volume) is 1: 5～1:100, and its unit is g/ml.
5. method according to claim 4, the ratio of everolimus and ether described in it (quality: volume) is 1:10～1:50, its unit is g/ml.
6. according to the method described in claim 1-3 any one, the ratio of everolimus and alkane or naphthenic hydrocarbon described in it (quality: volume) is 1:5～1:100, and its unit is g/ml.
7. method according to claim 6, the ratio of everolimus and alkane or naphthenic hydrocarbon described in it (quality: volume) is 1:10～1:50, its unit is g/ml.
8. method according to claim 1, is characterized in that, after dripping alkane or naphthenic hydrocarbon, the crystal solution obtaining is carried out to concentrating under reduced pressure remove portion solvent.
9. method according to claim 1, is characterized in that, separates out after solid that remaining refinement mother liquor is recyclable to be re-refined.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010546471.4A CN102464669B (en) | 2010-11-17 | 2010-11-17 | Amorphous everolimus and preparation method thereof |
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| CN201010546471.4A CN102464669B (en) | 2010-11-17 | 2010-11-17 | Amorphous everolimus and preparation method thereof |
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| CN102464669A CN102464669A (en) | 2012-05-23 |
| CN102464669B true CN102464669B (en) | 2014-04-16 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2016519086A (en) | 2013-03-15 | 2016-06-30 | バイオセンサーズ インターナショナル グループ、リミテッド | Purification of rapamycin derivatives |
| CN106146535B (en) * | 2015-04-25 | 2019-07-26 | 山东新时代药业有限公司 | A kind of preparation method of everolimus |
| CN104892632B (en) * | 2015-06-03 | 2017-12-26 | 道中道（菏泽）制药有限公司 | A kind of everolimus of crystal form and preparation method thereof |
| CN106478663A (en) * | 2015-08-26 | 2017-03-08 | 博瑞生物医药（苏州）股份有限公司 | A kind of drying meanss of everolimuses |
| CN108129490B (en) * | 2017-12-11 | 2020-12-01 | 成都海创药业有限公司 | Method for preparing everolimus amorphous solid |
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| GB9221220D0 (en) * | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
| GB9618952D0 (en) * | 1996-09-11 | 1996-10-23 | Sandoz Ltd | Process |
| US6939376B2 (en) * | 2001-11-05 | 2005-09-06 | Sun Biomedical, Ltd. | Drug-delivery endovascular stent and method for treating restenosis |
| CN100369920C (en) * | 2003-03-31 | 2008-02-20 | 特瓦药厂私人有限公司 | Crystallization and purification of macrolides |
| CN1856500A (en) * | 2003-07-24 | 2006-11-01 | 特瓦药厂私人有限公司 | Method of purifying macrolides |
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