CN103601704A - Preparation method of amorphous cabazitaxel - Google Patents
Preparation method of amorphous cabazitaxel Download PDFInfo
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- CN103601704A CN103601704A CN201310594876.9A CN201310594876A CN103601704A CN 103601704 A CN103601704 A CN 103601704A CN 201310594876 A CN201310594876 A CN 201310594876A CN 103601704 A CN103601704 A CN 103601704A
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- cabazitaxel
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- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims abstract description 50
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000011521 glass Substances 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 8
- 239000000284 extract Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005086 pumping Methods 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940123237 Taxane Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- -1 Ester ethyl acetate Chemical class 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of amorphous cabazitaxel. The method comprises the steps of dissolving cabazitaxel in an organic solvent, putting in an appropriate vessel, volatilizing the solvent at normal pressure or pumping the solvent under reduced pressure, and drying to obtain the amorphous cabazitaxel. The cabazitaxel provided by the invention is good in appearance and stability and low in solvent residue; the preparation method is simple in operation and easy in industrialization.
Description
Technical field
The present invention relates to a kind of preparation method of bearing taxanes, particularly a kind of amorphous Cabazitaxel and preparation method thereof.
Background technology
Cabazitaxel is a kind of molecular design bearing taxanes, there is similar structures with Anti-cancer treatment taxol, by French Sanofi-Aventis drugmaker, developed, in June, 2010 is through U.S. FDA approval listing, for the second line treatment medicine of anti-prostate cancer.Its chemistry 4-acetoxyl group-2 α-benzoyloxy-5 β by name, 20-epoxy group(ing)-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo Japanese yew-11-alkene-13 α-Ji (2R, 3S)-3-tert-butoxycarbonyl amino-PLA ester.
Structural formula is as follows:
There is polymorphism in Cabazitaxel.
Chinese patent CN200480026128.X has characterized Cabazitaxel crystal form A, i.e. acetone solvate.This crystal formation is the unique medicinal crystal-form going on the market through FDA approval at present.This crystal formation is unstable, and easily part removes acetone.
Chinese patent CN101918385A has characterized other crystal formations of Cabazitaxel, comprises other solvate forms, anhydrate form, hydrate forms except acetone solvate.Crystal formation characterizing in this patent and preparation method thereof, can find out, the preparation method of these crystal formations all needs some specific test conditionss, is not suitable for suitability for industrialized production; And the physical and chemical states of each crystal formation is unstable, can mutually transform under certain condition.
The comprehensive Cabazitaxel ownership system Preparation Method of report at present, all finds, in the preparation process of crystallization, all to adopt traditional method crystallization, dry.Through the inventor's test and research discovery, no matter Cabazitaxel prepared by existing method is crystal habit or unformed form, and its solvent residual amount is difficult to reach high standard.
At present drug quality is required in more and more higher situation, dissolvent residual must reach high standard, and the present invention, for addressing this problem, has carried out the screening experiment of several different methods, finally developed a kind of operation simple and easy, the unformed solid of the residual extremely low Cabazitaxel of physical and chemical states solvent stability.
Summary of the invention
The present invention is directed to deficiency of the prior art, a kind of preparation method of amorphous Cabazitaxel is provided.
This amorphous Cabazitaxel dissolvent residual is low, and physical condition and stability are better than known crystal formation, and chemical stability is not second to known crystal formation.
According to research, unformed Cabazitaxel is better than the Cabazitaxel of crystal habit in stability, and the present invention is devoted to prepare amorphous Cabazitaxel for this reason, for obtaining the unformed Cabazitaxel that dissolvent residual is low, the invention provides a kind of method, and described method is as follows:
By by prior art, prepare or market on purchase available Cabazitaxel finished product, be dissolved in the organic solvents such as hydrocarbon, alcohol, ketone, organic acid, ester, ether, put decompression in furnace pot and extract solvent, drying under reduced pressure obtains a kind of unformed Cabazitaxel pressed powder again, can preparation for the preparation of preparation, dissolvent residual is extremely low after testing.
Wherein, the preferred methylene dichloride of described hydrocarbon, acetonitrile.Alcohol particular methanol, ethanol, Virahol.The preferred acetone of ketone, butanone.Organic acid preferable formic acid, acetic acid.Ester ethyl acetate, ethyl formate.The preferred tetrahydrofuran (THF) of ether, ether, isopropyl ether.
Wherein, preferably decompression to extract solvent temperature be 20-80 ℃.Drying temperature is 30-100 ℃.
Preferred, solvent is methyl alcohol, ethanol, and 30-50 ℃ of decompression extracts solvent, 40-60 ℃ of drying under reduced pressure.
Most preferred, solvent is methyl alcohol, and 30 ℃ of decompressions extract solvent, 40 ℃ of drying under reduced pressure.
The present invention compared to the prior art advantage is:
The method gained is a kind of amorphous Cabazitaxel pressed powder, good fluidity, and density is difficult for greatly the powder that wafts; Avoided the formation of solvate, be heated and storage process in there is not the problem of desolvation and transformation of crystal; Dissolvent residual is significantly less than product and solvate prepared by prior art, even no solvent residue;
Chemical stability is not second to current known crystal formation.
Amorphous Cabazitaxel provided by the invention and preparation method thereof, operates simple and easyly, and physical and chemical states is well stable, can better meet the commercial production conditions such as production, quality control, storage.
Below by contrast experiment's data declaration beneficial effect of the present invention:
The detection method of dissolvent residual is as follows:
Chromatographic column: DB-624 capillary column
Detector: FID260 ℃
Gasification temperature: 260 ℃
Column temperature: 40 ℃ keep 6min; 15 ℃/min speed heats up 120 ℃; 25 ℃/min speed heats up 230 ℃ and keeps 5min
Post flow: 2ml/min
Splitting ratio: 10
Blank: DMSO
For trying: 0.5g → 5ml(DMSO)
Direct injection 1 μ l
Accompanying drawing explanation:
Fig. 1: amorphous Cabazitaxel XRPD figure prepared by the embodiment of the present invention 1 method
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but does not therefore limit the present invention among described scope of embodiments.
The preparation of embodiment 1 amorphous Cabazitaxel
1g Cabazitaxel is dissolved in 10ml methyl alcohol, puts in watch-glass, and 30 ℃ of normal pressure volatilizations, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Methanol solvate is residual: 0%(limit 0.3%)
The preparation of embodiment 2 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 10ml methylene dichloride, puts in watch-glass, and 30 ℃ of normal pressure volatilizations, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Dichloromethane solvent is residual: 0.03%(limit 0.06%)
The preparation of embodiment 3 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 10ml acetone, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Acetone solvent is residual: 0.26%(limit 0.5%)
The preparation of embodiment 4 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 50ml ethanol, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Residual ethanol solvent: 0.06%(limit 0.5%)
The preparation of embodiment 5 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 100ml ethyl acetate, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Ethyl acetate solvent is residual: 0.34%(limit 0.5%)
The preparation of embodiment 6 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 50ml acetonitrile, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Acetonitrile solvent is residual: 0.01%(limit 0.04%)
The preparation of embodiment 7 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 100ml Virahol, puts in watch-glass, and 40 ℃ of decompressing and extracting, heat up 50 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Isopropanol solvent is residual: 0.3%(limit 0.5%)
The preparation of embodiment 8 amorphous Cabazitaxels
1g Cabazitaxel is dissolved in 50ml butanone, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.Butanone solvent is residual: 0.3%(limit 0.5%).
Claims (10)
1. a preparation method for Cabazitaxel amorphous substance, is characterized in that, Cabazitaxel is dissolved in to organic solvent, puts in suitable vessel normal pressure volatilization or decompression and extracts solvent, dry, obtains.
2. method according to claim 1, is characterized in that, described organic solvent is selected from hydrocarbon, alcohol, ketone, organic acid, ester, ether.
3. method according to claim 2, is characterized in that, described hydrocarbon is selected from methylene dichloride, acetonitrile; Described alcohol is selected from methyl alcohol, ethanol, Virahol; Described ketone is selected from acetone, butanone; Described organic acid is selected from formic acid, acetic acid; Described ester is selected from ethyl acetate, ethyl formate; Described ether is selected from tetrahydrofuran (THF), ether, isopropyl ether.
4. method according to claim 2, is characterized in that, normal pressure volatilization or decompression extract solvent temperature 20-80 ℃.
5. method according to claim 2, is characterized in that, drying temperature 30-100 ℃.
6. method according to claim 2, is characterized in that, solvent is methyl alcohol or ethanol, and 30-50 ℃ of decompression extracts solvent, 40-60 ℃ of drying under reduced pressure.
7. method according to claim 2, is characterized in that, solvent is methyl alcohol, and 30 ℃ of decompressions extract solvent, 40 ℃ of drying under reduced pressure.
8. method according to claim 2, is characterized in that, step is as follows: 1g Cabazitaxel is dissolved in 10ml methyl alcohol, puts in watch-glass, and 30 ℃ of normal pressure volatilizations, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.
9. method according to claim 2, is characterized in that, step is as follows: 1g Cabazitaxel is dissolved in 50ml ethanol, puts in watch-glass, and 30 ℃ of decompressing and extracting, heat up 40 ℃ and be dried, and obtain the amorphous Cabazitaxel of 0.9g.
10. method according to claim 2, is characterized in that, step is as follows: 1g Cabazitaxel is dissolved in 10ml methylene dichloride, acetone, ethyl acetate, acetonitrile, Virahol or butanone, put in watch-glass, 30 ℃ of normal pressure volatilizations, heat up 40 ℃ and are dried, and obtain the amorphous Cabazitaxel of 0.9g.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
| CN101415697A (en) * | 2006-01-02 | 2009-04-22 | 株式会社三养吉尼克斯 | Method for preparation of amorphous, anhydrous crystalline or hydrated crystalline docetaxel |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| WO2011114210A2 (en) * | 2010-03-15 | 2011-09-22 | Jubilant Life Sciences Limited | Processes for the preparation of linezolid |
| CN102659722A (en) * | 2012-05-04 | 2012-09-12 | 江苏恒瑞医药股份有限公司 | Amorphous cabazitaxel and preparation method thereof |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
-
2013
- 2013-11-22 CN CN201310594876.9A patent/CN103601704B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
| CN101415697A (en) * | 2006-01-02 | 2009-04-22 | 株式会社三养吉尼克斯 | Method for preparation of amorphous, anhydrous crystalline or hydrated crystalline docetaxel |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| WO2011114210A2 (en) * | 2010-03-15 | 2011-09-22 | Jubilant Life Sciences Limited | Processes for the preparation of linezolid |
| CN102659722A (en) * | 2012-05-04 | 2012-09-12 | 江苏恒瑞医药股份有限公司 | Amorphous cabazitaxel and preparation method thereof |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
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