CN101337951B - Method for preparing docetaxel anhydrous crystal - Google Patents
Method for preparing docetaxel anhydrous crystal Download PDFInfo
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- CN101337951B CN101337951B CN2007101281233A CN200710128123A CN101337951B CN 101337951 B CN101337951 B CN 101337951B CN 2007101281233 A CN2007101281233 A CN 2007101281233A CN 200710128123 A CN200710128123 A CN 200710128123A CN 101337951 B CN101337951 B CN 101337951B
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- docetaxel
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- anhydrous crystal
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Abstract
The invention provides a method for preparing (2R, 3S)-3-boc amino group-2-oxhydryl-3-phenylpropionic acid-4-carbethoxy-2Alpha-benzoyloxy-5Beta and 20-epoxide-1, 7Beta, 10Beta-trihydroxy-9-oxygen-taxus-11-alkene-13Alpha-ester (docetaxel) anhydrous crystallaria. The method uses mixed organic solvent composed of ethanol/aether or the mixed organic solvent composed of acetone/aether for recrystallization. The method has the characteristics of high yield, good product stability, easy drying and large scale production, etc.
Description
Technical field
The present invention relates to the preparation method of Docetaxel, be specifically related to the preparation method of docetaxel anhydrous crystal.
Background technology
The chemical name of Docetaxel (Docetaxel) is: (2R, 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1,7 β, 10 β-trihydroxy--9-oxygen-Japanese yew-11-alkene-13 α-ester, be s-generation taxanes cancer therapy drug, can promote tubulin to be assembled into microtubule and suppress its depolymerization, be shown as unique antitumour activity.
Those skilled in the art can easily prepare Docetaxel according to the disclosed technology contents of CN1931849A.
CN1151741A discloses the method for preparing the Docetaxel trihydrate with ethanol and water mixed solvent, this method is when drying, and needing being controlled at relative humidity is to carry out under 80% the condition, otherwise crystal water is easily lost, become non-trihydrate, be not easy to control quality product.
CN1548426A discloses the method for preparing the Docetaxel trihydrate with the mixed solvent of acetone and water, and this method is used P because of the degree of drying difference of suction filtration sample
2O
5After the vacuum-drying, within the moisture content that moisture content is difficult to be controlled at trihydrate requires.
Summary of the invention
When adopting system's solvents such as ethyl acetate, normal hexane, sherwood oil to carry out crystallization to prepare the anhydrous crystal thing of Docetaxel, crystallisate carries out drying under reduced pressure at normal temperatures, residual solvent wherein is difficult qualified, and when adopting the mode that improves temperature to handle residual solvent, crystallisate is degraded easily.The inventor finds through research pleasantly surprisedly, anhydride or three water crystallization things for Docetaxel, ethanol, acetone and ether are overflowed from crystallisate as recrystallisation solvent is easier comparatively speaking, and vacuum-drying at normal temperatures can reach the scope that product standard requires.
Therefore, the object of the present invention is to provide a kind of stable crystallization method, with the preparation docetaxel anhydrous crystal, this method is easy to dry and control moisture content, and residual solvent can meet national medicinal standard requirement.
The object of the present invention is to provide a kind of (2R, 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1,7 β, 10 β-trihydroxy--9-oxygen-Japanese yew-11-alkene-13 α-ester is the preparation method of docetaxel anhydrous crystal, and the Docetaxel of purifying through chromatogram in advance is dissolved in C
1-3Fatty Alcohol(C12-C14 and C12-C18) or C
1-3In the mixed solvent of Fatty Alcohol(C12-C14 and C12-C18)/ether, be heated to 10 ℃ of-40 ℃ of dissolvings, add ether, the gained crystallization under the pressure of 0.095MPa, is used P at＜40 ℃
2O
5C is preferably controlled in vacuum-drying
1-3The last volume ratio of Fatty Alcohol(C12-C14 and C12-C18) and ether is 1: 2 to 2: 1, more preferably 1: 1, and preferred described C
1-3Fatty Alcohol(C12-C14 and C12-C18) is an ethanol.
Another object of the present invention is to provide a kind of (2R, 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1,7 β, 10 β-trihydroxy--9-oxygen-Japanese yew-11-alkene-13 α-ester is the preparation method of docetaxel anhydrous crystal, the Docetaxel that passes through chromatogram purification in advance is dissolved in the mixed solvent of acetone or acetone, be heated to 10 ℃ of-40 ℃ of dissolvings, add ether, the last volume ratio of control acetone and ether is 1: 2 to 2: 1, and preferred 1: 1, the gained crystallization was at＜40 ℃, 0.095MPa pressure under, use P
2O
5Vacuum-drying.
The usage quantity of solvent does not have particular determination in the crystallization, is the 5-50 weight part with respect to the required solvent load of the Docetaxel of 1 weight part usually, preferably at the 20-25 weight part; The temperature range of dissolving and crystallization does not have particular determination during crystallization, and is for example preferred within 0-60 ℃ scope, is preferably 10-40 ℃; The crystallization time is generally 1 hour to one day; For the crystallization behind the crystallization, can filter according to the ordinary method of this area, drying obtains crystallization of the present invention.
Docetaxel anhydrous crystal of the present invention has satisfactory stability, can be used as the effective antitumour agent.
Embodiment
Explain the present invention in more detail below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
The preparation of embodiment 1 docetaxel anhydrous crystal
Add Docetaxel 15g in 35ml ethanol, make its dissolving 40 ℃ stirred in water bath, drip ether 35ml gradually, muddiness is arranged during dropping, need muddiness dissolving continuation dropping is again dripped and finishes back stirring 2 hours, it is cooled to 25 ℃ then, stirring is spent the night.Filter and collect the crystallization of separating out.With the mixing solutions 25ml wash crystallization of ethanol/ether=1: 1, then under the pressure of 0.095MPa, 30 ℃, P
2O
5Have dry 24 hours down, get 13.5g (90%) white crystals, fusing point: 182.5-184.5 ℃, D27=-44.8 ° (C 0.55, C in optically-active [α]
2H
2OH).
The GC analysis is carried out in the gained crystallization, and the dissolvent residual solvent in the sample meets 2005 editions Chinese Pharmacopoeia standards.
The preparation of embodiment 2 docetaxel anhydrous crystals
In 30ml acetone, add Docetaxel 15g, make its dissolving 40 ℃ stirred in water bath.Drip about ether 30ml after the dissolving gradually, have muddiness to need the muddiness dissolving is continued to drip again during dropping, dropping finishes the back stirred 2 hours, it was cooled to 25 ℃ then, and stirring is spent the night.Filter and collect the crystallization of separating out.Mixing solutions 25ml wash crystallization with acetone=1: 1.Then under the pressure of 0.095MPa, 30 ℃, P
2O
5Have dry 24 hours down, get 14g (93.3%) white crystals, fusing point: 182.0-184.0 ℃, D27=-44.5 ° (C 0.55, C in optically-active [α]
2H
2OH).
The GC analysis is carried out in the gained crystallization, and the dissolvent residual solvent in the sample meets 2005 editions Chinese Pharmacopoeia standards.
Claims (13)
1. (2R, 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1,7 β, 10 β-trihydroxy--9-oxygen-Japanese yew-11-alkene-13 α-ester is the preparation method of docetaxel anhydrous crystal, it is characterized in that the Docetaxel of purifying through chromatogram is dissolved in C in advance
1-3Fatty Alcohol(C12-C14 and C12-C18) or C
1-3In Fatty Alcohol(C12-C14 and C12-C18)/ether mixed solvent, be heated to 10-40 ℃ of dissolving, add ether, the gained crystallization is at＜40 ℃, under the pressure of 0.095MPa, and at P
2O
5Exist down, vacuum-drying obtains docetaxel anhydrous crystal.
2. (2R, 3S)-3-t-butoxycarbonyl amino-2-hydroxyl-3-phenylpropionic acid-4-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1,7 β, 10 β-trihydroxy--9-oxygen-Japanese yew-11-alkene-13 α-ester is the preparation method of docetaxel anhydrous crystal, it is characterized in that: the Docetaxel of purifying through chromatogram is dissolved in acetone or the acetone mixed solvent in advance, be heated to 10-40 ℃ of dissolving, add ether, the gained crystallization is at＜40 ℃, 0.095MPa pressure under, and P
2O
5Exist down, vacuum-drying obtains docetaxel anhydrous crystal.
3. in accordance with the method for claim 1, it is characterized in that C
1-3The last volume ratio of Fatty Alcohol(C12-C14 and C12-C18)/ether is 1: 2 to 2: 1.
4. in accordance with the method for claim 3, it is characterized in that C
1-3The last volume ratio of Fatty Alcohol(C12-C14 and C12-C18)/ether is 1: 1.
5. according to claim 1,3 or 4 described methods, it is characterized in that used C
1-3Fatty Alcohol(C12-C14 and C12-C18) is an ethanol.
6. in accordance with the method for claim 2, it is characterized in that the last volume ratio of acetone is 1: 2 to 2: 1.
7. in accordance with the method for claim 6, it is characterized in that the last volume ratio of acetone is 1: 1.
8. according to each described method of claim 1-4,6-7, it is characterized in that, during crystallization the consumption of solvent be Docetaxel weight 5-50 doubly.
9. in accordance with the method for claim 8, it is characterized in that, during crystallization the consumption of solvent be Docetaxel weight 20-25 doubly.
10. in accordance with the method for claim 5, it is characterized in that, during crystallization the consumption of solvent be Docetaxel weight 5-50 doubly.
11. in accordance with the method for claim 10, it is characterized in that, during crystallization the consumption of solvent be Docetaxel weight 20-25 doubly.
12., it is characterized in that the temperature range during crystallization is 0-60 ℃ according to claim 1-4,6-7, each described method of 9-11.
13. in accordance with the method for claim 12, it is characterized in that the temperature range during crystallization is 10-40 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101281233A CN101337951B (en) | 2007-07-06 | 2007-07-06 | Method for preparing docetaxel anhydrous crystal |
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|---|---|---|---|
| CN2007101281233A CN101337951B (en) | 2007-07-06 | 2007-07-06 | Method for preparing docetaxel anhydrous crystal |
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| CN101337951B true CN101337951B (en) | 2011-09-14 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030225291A1 (en) * | 2002-02-05 | 2003-12-04 | Sharma Arun Prakash | Process of purification of paclitaxel and docetaxel |
| US20070142457A1 (en) * | 2005-10-12 | 2007-06-21 | Alessandro Pontiroli | Crystalline forms of docetaxel and processes for their preparation |
-
2007
- 2007-07-06 CN CN2007101281233A patent/CN101337951B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030225291A1 (en) * | 2002-02-05 | 2003-12-04 | Sharma Arun Prakash | Process of purification of paclitaxel and docetaxel |
| US20070142457A1 (en) * | 2005-10-12 | 2007-06-21 | Alessandro Pontiroli | Crystalline forms of docetaxel and processes for their preparation |
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| CN101337951A (en) | 2009-01-07 |
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