AU2013205442B2 - Crystalline forms of dimethoxy docetaxel and methods for preparing same - Google Patents
Crystalline forms of dimethoxy docetaxel and methods for preparing same Download PDFInfo
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- AU2013205442B2 AU2013205442B2 AU2013205442A AU2013205442A AU2013205442B2 AU 2013205442 B2 AU2013205442 B2 AU 2013205442B2 AU 2013205442 A AU2013205442 A AU 2013205442A AU 2013205442 A AU2013205442 A AU 2013205442A AU 2013205442 B2 AU2013205442 B2 AU 2013205442B2
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- 238000000034 method Methods 0.000 title abstract description 9
- -1 dimethoxy docetaxel Chemical compound 0.000 title abstract description 5
- 229960003668 docetaxel Drugs 0.000 title abstract description 5
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- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 claims abstract description 16
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- 238000002360 preparation method Methods 0.000 abstract description 3
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005102 attenuated total reflection Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical group CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- OZUCDJFMALKZOS-UHFFFAOYSA-N 2-(butoxycarbonylamino)-2-hydroxy-3-phenylpropanoic acid Chemical compound CCCCOC(=O)NC(O)(C(O)=O)CC1=CC=CC=C1 OZUCDJFMALKZOS-UHFFFAOYSA-N 0.000 description 1
- GOTMYRUZLYVSPC-UHFFFAOYSA-N 2-hydroxy-2-isocyanato-3-phenylpropanoic acid Chemical compound C(=O)=NC(C(=O)O)(CC1=CC=CC=C1)O GOTMYRUZLYVSPC-UHFFFAOYSA-N 0.000 description 1
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- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
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- Epoxy Compounds (AREA)
Abstract
Abstract Crystalline Forms of Dimethoxy Docetaxel and Methods for Preparing Same. The invention relates to anhydrides, solvates and ethanol hetero-solvates and hydrates of dimethoxy docetaxel or (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-i -hydroxy-7p, 1 0p-dimethoxy-9-oxo-tax- 11 -ene 13a-yle, and to the preparation thereof.
Description
1 CRYSTALLINE FORMS OF DIMETHOXY DOCETAXEL AND METHODS FOR PREPARING THE SAME The reader's attention is also directed to our related parent Australian patent specification No. 2009227081. 5 The present invention relates to crystalline forms of dimethoxy docetaxel or 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and to methods for the preparation thereof. 4-Acetoxy-2a-benzoyloxy-5p,20-epoxy- 1-hydroxy-73, 10f-dimethoxy 10 9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate exhibits notable anticancer and antileukaemic properties. 4-Acetoxy-2a-benzoyloxy-5p,20-epoxy- 1-hydroxy-73, 10f-dimethoxy 9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate is prepared according to the method which is described more particularly 15 in PCT International Application WO 96/30355 or PCT International Application WO 99/25704. According to the method described in these applications, the product is not crystallized and is not characterized. It was found that the acetone solvate of 4-acetoxy-2a-benzoyloxy-53,20 epoxy-1-hydroxy-73, 10 -dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxy 20 carbonylamino-2-hydroxy-3-phenylpropionate (called form A) was completely determined and characterized according to the patent published under number W02005/028462. The present invention relates to new crystalline forms, with the exclusion of the acetonate form, the only one known to date. 25 Summary of the Invention In one aspect, the invention provides crystalline forms of 4-acetoxy-2a benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, wherein they are 30 ethanolic solvate, heterosolvate or hydrate forms. In another aspect, the invention provides crystalline forms of 4-acetoxy-2a- 2 benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax- 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, wherein they are ethanolic solvate or heterosolvate forms. In another aspect, the invention provides an ethanolate form B of 4-acetoxy 5 2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10f-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1 ± 0.2 degrees 2-theta. In another aspect, the invention provides an ethanolate form D of 4-acetoxy 10 2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10f-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9 ± 0.2 degrees 2-theta. In another aspect, the invention provides an ethanolate form E of 4-acetoxy 15 2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10f-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta. In another aspect, the invention provides an ethanol/water heterosolvate form 20 F of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10f-dimethoxy-9-oxotax 11-en- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2 ± 0.2 degrees 2-theta. In another aspect, the invention provides crystalline forms of 4-acetoxy-2a 25 benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, wherein they are hydrate forms. In another aspect, the invention provides a monohydrate form C of 4 acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax- 11-en 30 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3 ± 0.2 degrees 2-theta. In another aspect, the invention provides a Dihydrate form C of 4-acetoxy 2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-7 ,10 -dimethoxy-9-oxotax- 11-en-13a-yl 3 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of the invention, characterized by a PXRD diagram exhibiting characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta. 5 Description In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application. 10 According to the present invention, it has now been found that certain anhydrous forms, certain ethanolic solvates or heterosolvates and hydrated forms have been completely characterized from a physical and chemical structure point of view. According to the invention, among the anhydrous forms of 4-acetoxy-2a benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax- 11-en-13a-yl 15 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, five different forms have been identified, among the ethanolic solvates or heterosolvates of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax 11-en- 13ca-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, four different forms have been identified and among the hydrates of 4-acetoxy-2a 20 benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, two different forms have been identified. The five anhydrous forms identified were obtained according to the following methods: 25 - The anhydrous form B by a method which consists in heating the acetone form or form A obtained according to the patent mentioned above, between 100 and 1 10'C under vacuum or nitrogen sweeping. This treatment is preferably carried out for at least 9 hours before a return to ambient temperature without inducing chemical decomposition. Its melting point by DSC is approximately 30 150'C. The PXRD diagram of the anhydrous form B exhibits characteristic lines located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9 ± 0.2 degrees 2-theta.
4 The anhydrous form C is obtained by maturation of the acetone solvate form A, or of the anhydrous form B, in water followed by drying at up to 50'C and maintaining between 0 and 5% RH at ambient temperature. Its melting point by DSC is approximately 146'C. The PXRD diagram of the anhydrous 5 form C exhibits characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ± 0.2 degrees 2-theta. It is, among the various anhydrous forms, the least stable of all the forms described in the present invention. In the presence of a relative humidity of greater than 5%, it changes to a hydrated form. 10 - The anhydrous form D is obtained according to a first method by crystallization of the form A in an oil (especially Miglyol), following by rinsing with an alkane, for example heptane; the second preparation method consists in leaving a solution of 4-acetoxy-2a-benzoyloxy-53,20-epoxy-1 hydroxy-73,10 -dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert 15 butoxycarbonylamino-2-hydroxy-3-phenylpropionate in a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably a 25/25/50 mixture) to crystallize for approximately 48 hours. Its boiling point by DSC is approximately 175'C (cf. Figure 1) and is found to be the highest of all the anhydrous forms isolated. The PXRD diagram of the anhydrous form D (cf. 20 Figure 2) exhibits characteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6, 10.8, 11.1 and 12.3 ± 0.2 degrees 2-theta. The FTIR spectrum of the anhydrous form D exhibits characteristic bands located at 979, 1072, 1096, 1249, 1488, 1716, 1747, 3436 ± 1 cm 1 (cf. Figure 3). Among all the forms described in the present invention, it is the most stable anhydrous form. 25 - The anhydrous form E is obtained at ambient temperature by maturation of the acetone form or form A in ethanol so as to intermediately form an ethanolic form which is subsequently desolvated under nitrogen sweeping or by heating at approximately 100'C for 2 hours. Its melting point by DSC is approximately 157 0 C. The PXRD diagram of the anhydrous form E exhibits 30 characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7, 13.2, 13.4 and 13.9 ± 0.2 degrees 2-theta. The anhydrous form F is obtained by desolvating the ethanol/water heterosolvate at 120'C under a nitrogen atmosphere for 24 hours and then maintaining in a dry environment at 0% RH at ambient temperature. Its 35 melting point by DSC is approximately 148'C. The PXRD diagram of the 5 anhydrous form F exhibits characteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ± 0.2 degrees 2-theta. There are four crystalline forms identified in ethanolic solvate or 5 heterosolvate form: - The ethanolate form B is obtained at ambient temperature by maintaining the anhydrous form B in an ethanol-vapour-saturated environment. The PXRD diagram of the ethanolate form B exhibits characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1 ± 0.2 degrees 2-theta. 10 - The ethanolate form D is obtained at ambient temperature by maintaining the anhydrous form D in an ethanol-vapour-saturated environment. The PXRD diagram of the ethanolate form D (cf. Figure 4) exhibits characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9 ± 0.2 degrees 2-theta. 15 - The ethanolate form E is obtained at ambient temperature by maturation of the acetonate form A in ethanol. The PXRD diagram of the ethanolate form E (cf. Figure 5) exhibits characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta. - The ethanol/water heterosolvate form F is obtained by maintaining the form B 20 in a minimum amount of ethanol at reflux, slow cooling and isolation at ambient temperature and ambient relative humidity. The PXRD diagram of the ethanol/water heterosolvate form F exhibits characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2 ± 0.2 degrees 2-theta. 25 There are two crystalline forms identified in hydrate form: - The monohydrated forms C are obtained at ambient temperature by maintaining the anhydrous form C in an atmosphere containing at least 10% relative humidity. The PXRD diagram of the monohydrate form C exhibits characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 30 13.3 ± 0.2 degrees 2-theta. - The dihydrate form C is obtained at ambient temperature by maintaining the anhydrous form C in an atmosphere containing at least 60% relative humidity. The PXRD diagram of the dihydrate form C exhibits characteristic lines located at 6 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta. Other, nonethanolic, solvates of the form B were prepared, such as in particular those obtained with the following solvents: dichloromethane, diisopropyl ether, n-propanol, isopropanol, toluene, methyl isobutyl ketone, tetrahydrofuran, 5 dimethylformamide, ethyl acetate, etc. The present invention will be described more fully by means of the following examples which should not be considered to limit the invention. Experimental analysis conditions: 10 Differential Scanning Calorimetry (DSC): The measurements were carried out on a T.A. Instruments DSC2010 thermal analyser. The sample is subjected to temperature programming from 25'C to 225'C with a heating rate of 5 0 C/min. The product is placed in a crimped aluminium capsule and 15 the amount of product analysed is between 2 and 5 mg. Constant nitrogen sweeping at 55 mL/min is used in the oven chamber. Powder X-Ray Diffraction (PXRD): 20 The analyses were carried out on a Panalytical X'Pert Pro diffractometer with a reflection-mode Bragg-Brentano focusing geometry (0-20) assembly. The product analysed is deposited as a thin layer on a silicon single crystal. A copper anticathode tube (45 kV/40 mA) supplies an incident radiation Cu Ku (k = 1.5406 A). The beam 25 is collimated using Sollers slits which improve the parallelism and variable slits which limit scattering. An X'Celerator detector completes the device. The diagram recording characteristics are the following: sweeping from 2 to 30 degrees 20, counting time from 100 to 500 seconds per step with a step of 0.0170. 30 7 Fourier Transform InfraRed (FTIR) spectrometry: The solid samples were analysed using a Nicolet Nexus spectrometer. The analysis is carried out by attenuated total reflectance (ATR) using a Smart Orbit accessory from 5 the company Thermo (single reflection diamond crystal ATR accessory). The spectral range swept is between 4000 and 400 cm- 1 with a resolution of 2 cm- 1 and an accumulated scan number of 20. Example 1 10 Two tests of dissolution of approximately 550 mg of 4-acetoxy-2a benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10 -dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 14 g of Miglyol 812 Neutral oil, Sasol are carried out. Magnetic stirring is carried out at 500 rpm for 24 hours at ambient temperature. 15 After one week, the samples are vacuum-filtered and rinsed with heptane. Each sample is analysed by PXRD for confirmation of the form obtained. After filtration, between 300 and 350 mg of anhydrous form D are obtained. Example 2 Approximately 3 g of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy 20 7f,10f-dimethoxy-9-oxotax- 11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate are dissolved in a mixture of 50 mL ethanol + 50 mL Polysorbate 80, pH 3.5. 100 mL of water are added to the previous mixture and the whole is homogenized. After storage for 48 hours at ambient temperature, crystals of anhydrous form D appeared. The amount of crystallized product recovered by 25 filtration is approximately 2.45 g. A comparative stability study was carried out between the acetone solvate form A and the anhydrous form D. The comparison of the PXRD analyses carried out on the A and D forms immediately after production and after having maintained said forms at 40'C for one month gives the following results: 30 - Form A: partial desolvation resulting in a mixture of the acetone solvate form A and of the anhydrous form B being obtained.
8 - Form D: no change detected after maintaining at 40'C for one month. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless 5 specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. 10
Claims (3)
1. Crystalline forms of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-7,10 dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino
2-hydroxy-3-phenylpropionate, wherein they are ethanolic solvate, heterosolvate or 5 hydrate forms. 2. Crystalline forms of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-7,10 dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate, wherein they are ethanolic solvate or heterosolvate forms. 10 3. Ethanolate form B of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy- 1-hydroxy-73, 10f dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9,
13.4, 14.2, 14.7 and 15.1 ± 0.2 degrees 2-theta. 15 4. Ethanolate form D of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy- 1-hydroxy-73, 10 dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and 11.9 ±0.2 degrees 2-theta. 20 5. Ethanolate form E of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-7,10 dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5, 13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta. 25 6. Ethanol/water heterosolvate form F of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1 hydroxy-73,10 -dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert butoxycarbonylamino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2 ± 0.2 degrees 2-theta. 30 7. Crystalline forms of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-7,10 dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino- 10 2-hydroxy-3-phenylpropionate, wherein they are hydrate forms. 8. Monohydrate form C of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy 7f,10f-dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate according to Claim 7, characterized by a PXRD 5 diagram exhibiting characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1, 11.9, 12.2, 12.6 and 13.3 ± 0.2 degrees 2-theta. 9. Dihydrate form C of 4-acetoxy-2a-benzoyloxy-5 ,20-epoxy-1-hydroxy-73,10f dimethoxy-9-oxotax-11-en-13a-yl (2R,3S)-3-tert-butoxycarbonylamino 2-hydroxy-3-phenylpropionate according to Claim 7, characterized by a PXRD 10 diagram exhibiting characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta.
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| CAIRA M R, Topics in Current Chemistry, 1998, 198, 165-166 * |
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