FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
NOVEL PROCESS FOR THE SYNTHESIS OF (2 A,5B,7B,10B,13A)-4-ACETOXY-l3-
({(2R,3S)-3[(TERT-BUTOXYCARBONYL)AMINO]-2-HYDROXY-3-
PHENYLPROPANOYL}OXY)-l-HYDROXY-7,10-DIMETHOXY-9-OXO-5,20-
EPOXYTAX-ll-EN-2-YL BENZOATE AND NOVEL POLYMORPHS THEREOF
PANACEA BIOTEC LIMITED,
an Indian Company incorporated under the Companies Act 1956 Plot No. GEN - 72/3, TTC Industrial Area, Opp. Millennium Business Park Gate No 2, Mahape,
Navi Mumbai 400710, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention is related to the field of synthetic chemistry. It is related to process of synthesis of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyI}oxy)-l -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-I i -en-2-yI benzoate (Cabazitaxel) and its pharmaceutically acceptable salts and novel polymorphs thereof.
BACKGROUND:
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Cabazitaxel is a semi-synthetic taxoid derivative. It is marketed under the trade name JEVTANA® for the treatment of hormone-refractory prostate cancer. Cabazitaxel is chemically known as (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R;3S)-3[(tert-butoxycarbonyl) amino]-2-hydroxy-3-pheny!propanoyl}oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11 -en-2-yl benzoate - propan-2-one and is represented by the following structural Formula:

Cabazitaxel is a white to off-white powder with a molecular formula of C45H57NO14 .C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. Cabazitaxel API in the marketed formulation JEVTANA contains a nearly stoichiometric molecule of acetone as the solvate in the solid (lyophilized) state.
Cabazitaxel is partially synthesized as a single diastereoisomer from 10-deacetylbaccatin III, the major natural taxoid derived from the needles of various Taxus species.
Cabazitaxel was first disclosed in US patent number 5,847,170 (herein after US '170). The preparation of cabazitaxel disclosed therein involved the reaction of 4a-acetoxy-2a-benzoyioxy-5β,20-epoxy-lβ,13α-di hydroxy-7β,10β-dimethoxy-9-oxo-11-taxene with (2R, 4S,5R)-3-tert-

butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylic acid in
dicyclohexylcarbodiimide (DCC) and dimethylamino pyridine (DMAP) to obtain 4a-acetoxy-2a-benzoyloxy-5β,20-epoxy-l β-hydroxy-7β, l0β-dimethoxy-9-oxo-l l-taxen-13α-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate and further treating the thus obtained compound with 0.1N solution of hydrogen chloride in ethanol to obtain cabazitaxel in the form of an ivory-coloured foam.
The above disclosed process for the condensation of 4a-acetoxy-2a-benzoyloxy-5P,20-epoxy-lβ,13α-di hydroxy-7β,10β-dimethoxy-9-oxo-l 1-taxene with (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxy phenyl)-4-phenyl-l,3-oxazolidine-5-carboxylic acid is carried out in the presence of ethyl acetate. However, due to the use of such solvent the reaction takes longer time for completion and also results in the formation of by-products.
Another process disclosed in US '170, involved reducing 4α-acetoxy-2α-benzoy!oxy-5p,20-epoxy-1β-hydroxy-7β 10β-bis(methylthiomethoxy)-9-oxo-11 -taxen- 13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-pheny1-l,3-oxazolidine-5-carboxylate in anhydrous ethanol with Raney Nickel and further treating the obtained compound with 0.1N ethanolic solution of hydrochloric acid containing 3% of water to obtain Cabazitaxel in the form of a white foam.
The above two processes, involved the hydrolysis of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-lβ-hydroxy-7β,l Oβ-dimethoxy-9-oxo-l 1 -taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate using 0.1N HC1 in ethanol which resulted in longer reaction time and also in the formation of by-products.
US patent number 7,241,907 B2 discloses the acetone solvate of dimethoxy docetaxel (cabazitaxel) or 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-l-hydroxy-7β,10β-dimethoxy-9-oxo tax-ll-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and also its process of preparation.
US patent application number 2011/0105598 Al discloses a process for preparation of taxanes by minimizing the levels of the impurities, such as the epi-isomer at the 7-position of baccatin ring. This is achieved by carrying out isolation of the taxane derivative from reaction mixtures in the presence of one or more metal salts.

Chinese patent application number CN 102417491 A discloses a process wherein 10-DAB is reacted with chlorocarbonate-2,2,2-trichloro ethyl ester, thereby obtaining a product; reacting the product with DMAP (dimethylamino pyridine), DCC (dicyclohexyicarbodiimide) and (4S, 5R)-2,2-dimethyl-4-phenyl-3-tert-butoxycarbonyl-3.5-oxazolidine formic acid, thereby obtaining a product; reacting the product with acetic acid and zinc powder, and then methylating the product; and lastly, adding a p-methyl benzenesulfonic acid, thereby reacting and obtaining a cabazitaxel product.
Cabazitaxel, can give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of Cabazitaxel.
US patent application number 2011/0144362 Al discloses five different forms of anhydrous cabazitaxel, four different forms of ethanolic solvates or hetero-solvates and two different forms of hydrate forms.
International application publication number WO 2012/142117 Al, discloses forms I, II, III, IV and V for cabazitaxel. The application further discloses various solvate forms of these crystalline forms like toluene solvate, propanol solvate, butanol solvate, MTBE solvate and the process of preparation of same and also an amorphous form of cabazitaxel.
Chinese patent application number CN 102675257 A discloses the characteristic PXRD peaks of cabazitaxel crystal without solvent and crystal water.
Chinese patent application number CN 102746258 A provides the characteristic PXRD peaks of cabazitaxel with crystal forms J, G, and I. The crystal form J is prepared by dissolving cabazitaxel in C1-C6 ester, concentrating to saturation, crystallizing at low temperature, filtering, and drying. The crystal form G is prepared by dissolving cabazitaxel in C1-C5 halogenated alkane or/and C1-C4 alcohol, crystallizing at low temperature, filtering, and drying. The crystal form I is prepared by dissolving cabazitaxel in dichloromethane, adding cyciohexane (or dissolving cabazitaxel in dichloromethane-cyclohexane), crystallizing at low temperature, filtering, and drying.

None of the above mentioned prior arts disclose the improved process according to the present invention. The present invention provides an improved, commercially viable and industrially advantageous process for the synthesis of Cabazitaxel and its pharmaceutically acceptable salts that involves milder reaction conditions and high reaction efficiency and also provides novel polymorphic forms. The intermediates and the final crystalline forms obtained through the improved processes of this invention are obtained in a superior yield and high purity. Further the reaction time is dramatically reduced by following the improved process according to the present invention.
SUMMARY OF THE INVENTION
The present invention relates to improved, commercially viable and industrially advantageous processes for the synthesis of Cabazitaxel and its pharmaceutically acceptable salts. The present invention also relates to novel polymorphic forms of Cabazitaxel.
In one aspect, the present invention provides a process for the recrystallization of a compound of Formula I

which process comprises:
(i) dissolving the compound of formula I in a first solvent;
(ii) optionally adding a second solvent; and
(iii) drying.
In yet another aspect, the present invention provides a process for the preparation of compound of formula I

which comprises:
(i) reacting a compound of Formula II

in the presence of DCC, DMAP and a chlorinated hydrocarbon solvent, to obtain a compound of formula (IV);

(ii) converting the compound of formula (IV) to compound of formula I using hydrochloric acid
in ethanol and a chlorinated hydrocarbon solvent; and
(iii) dissolving compound of formula I obtained in step (ii) in a first solvent;
(ii) optionally adding a second solvent; and

(iii) drying.
In another embodiment, the present invention also provides novel substantially pure crystalline polymorphs of cabazitaxel.
In specific embodiments the present invention provides a novel polymorphic forms of cabazitaxel crystallized using acetonitrile (ACN) or dimethyl sulfoxide (DMSO).
In another aspect, the present invention provides a novel polymorphic form of cabazitaxel having an X-ray Powder Diffractogram, XRPD according to figure -1.
In another aspect, the present invention provides another novel polymorphic form of cabazitaxel having an X-ray Powder Diffractogram, XRPD according to figure -2.
In another aspect, the present invention provides yet another novel polymorphic form of cabazitaxel having an X-ray Powder Diffractogram, XRPD according to figure -3.
In another aspect, the present invention provides yet another novel polymorphic form of cabazitaxel having an X-ray Powder Diffractogram, XRPD according to figure -4,
The novel polymorphs of the present invention have advantageous properties like chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to limit the scope of the claimed subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an X-ray powder diffractogram (XRPD) of novel polymorphic form of cabazitaxel of the present invention obtained from DMSO.

FIG. 2 is an X-ray powder diffractogram (XRPD) of another novel polymorphic form of
cabazitaxel of the present invention obtained from DMSO.
FIG. 3 is an X-ray powder diffractogram (XRPD) of yet another novel polymorphic form of
cabazitaxel of the present invention obtained horn DMSO.
FIG. 4 is an X-ray powder diffractogram (XRPD) of novel polymorphic form of cabazitaxel of
the present invention obtained from acetonitrile.
DETAILED DESCRIPTION OF THE INVENTION
As used herein and unless otherwise indicated, the terms "polymorph" and "polymorphic form" refer to solid crystalline forms of a compound or complex. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.

which process comprises:
(i) dissolving the compound of formula 1 in a first solvent;
(ii) optionally adding a second solvent; and
(iii) drying.
In an embodiment, the present invention provides a process for the recrystallization of a compound of Formula I

The details of the above embodiment are as follows:
The first solvent used in the step (i) of the above embodiment may be selected from the group comprising of acetonitrile, propylene glycol, diol, dimethyl sulfoxide, butyl acetate, ethyl formate, acetic acid, formic acid, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-l-propanol, propyl acetate, etc. In a very preferred embodiment the solvent used is acetonitrile or dimethyl sulfoxide.
The second solvent used in the step (i) of the above embodiment may be selected from water, hexane, toluene, ethers, heptane, etc. In a very preferred embodiment the solvent used is water. The drying as given in step (iii) of the above embodiment involves drying the residue under vacuum. The drying may be carried out at a temperature in the range of 45° - 50° C for about 6-8 hours.
In yet another preferred embodiment, the present invention provides a process for the recrystallization of a compound of Formula I

which process comprises:
(i) dissolving the compound of formula 1 in dimethyl sulphoxide; (ii) adding water; and (iii) drying.
In a preferred embodiment, the present invention provides a process for the recrystaJJization of a compound of Formula I


Formula I which process comprises:
(i) dissolving the compound of formula I in acetonitrile; (ii) adding water; and (iii) drying.

which comprises:
(i) reacting a compound of Formula II

with a compound of Formula III

in the presence of suitable reagents and solvents, to obtain a compound of formula (IV):
In yet another aspect, the present invention provides a process for the preparation of compound of formula I


(ii) converting the compound of formula (IV) to compound of formula I; and (iii) dissolving compound of formula I obtained in step (ii) in a first solvent; (iv) optionally adding a second solvent; and
(v) drying.
The details of the above embodiment are as follows;
Step (i) involves reacting a compound of formula II with a compound of formula III in the
presence of suitable reagents and solvents.
The suitable reagents that may be used in the above step may be selected from the group
comprising of DCC, DMAP or other carbodiimides such as N, N'-carbonyldiimidazole.
The dehydrating agents that may be used in the above step may be selected from the group
comprising of trifluoroacetic anhydride, mixed anhydrides, acid chlorides, 1-benzotriazolyloxy-
tris(dimethylamino)phosphonium hexafluorophosphate, PYBOP, 1-hydroxybenzotriazole, 1-
hydroxy-4-azabenzotriazole, 1 -hydroxy-7-azabenzotriazole, N-ethyl-N'-(3-(dimethylamino)-
propyl)carbodiimide hydrochloride, 3-hydroxy-3,4-dihydro-4-oxo-l,2,3-benzoiriazine, 0-
(benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate, 0-(7-azabenzotriazol-l-
yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 0-(7-azabenzotriazol-l-y l)-l, 1,3,3-
tetramethyluronium tetrafluoroborate, 0-( 1 H-benzotriazol-1 -yl)-l, 1,3,3-bis(tetramethy lene)-
uronium hexafluorophosphate or 0-(7-azabenzotriazol-l-yl)-l,l,3,3-bis(tetramethylene)uronium
hexafluorophosphate and combinations thereof.
Suitable solvents that may be used in the above step (i) may be selected from the group
comprising of chlorinated hydrocarbon solvents and/or dimethylformamide (DMF) or
tetrahydrofuran (THF) or acetonitrile or dimethyl sulfoxide (DMSO) and mixtures thereof.
The compound of formula III that is used in the above step (i) may be used in an amount more
than 1.3 moles per mole of the compound of formula II.
Step (ii) involves the conversion of compound of formula (IV) to (I).

The above conversion can be effected by treating the compound of formula (IV) with
hydrochloric acid in the presence of a solvent selected from aliphatic alcohols and chlorinated
hydrocarbon solvents and/or DMF or THF or acetonitrile or DMSO and mixtures thereof.
The solvent used in the step (ii) of the above embodiment may be selected from the group
comprising of chlorinated hydrocarbon solvents, DMF, THF, acetonitrile, DMSO and
combinations thereof.
The first solvent used in the step (iii) of the above embodiment may be selected from the group
comprising ofacetonitrile, propylene glycol, diol, dimethy] sulfoxide, butyl acetate, ethyl formate,
acetic acid, formic acid, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl
ketone, methyl isobutyl ketone, 2-methyl-1-propanol propyl acetate, etc.
The second solvent used in the step (iv) of the above embodiment may be selected from water,
hexane, toluene, ethers, heptane, etc.
The drying as given in step (v) of the above embodiment involves drying the residue under
vacuum. The drying may be carried out at a temperature in the range of 45° - 50° C for about 6-8
hours.

which comprises:
(i) reacting a compound of Formula II

with a compound of Formula III
In a preferred embodime nt, the present invention provides a process for the preparation of compound of formula I

in the presence of DCC, DMAP and DCM, to obtain a compound of formula (IV);

(ii) converting the compound of formula (IV) to compound of formula I using hydrochloric acid
in ethanol and a chlorinated hydrocarbon solvent; and
(iii) recrystallizing the compound obtained in step (ii) using acetonitrile and water.
Another embodiment of the present invention provides a novel polymorphic form of cabazitaxel. The novel polymorphic form of cabazitaxel has been characterized by X-ray Powder Diffractogram, XRPD which produces a fingerprint of the particular crystallite form. Measurements of 28 values typically are accurate to within ±0.2 degrees.
In an embodiment, the present invention provides a novel polymorphic form of cabazitaxel characterized by an X-ray powder diffraction pattern with peaks at 8.7, 11.1, 12.4, 14.1, 15.3, 17.2,17.8,19.3 and 20.4 ±0.2 °2 theta.
In another embodiment, the present invention provides a process for the preparation of the novel polymorphic form of compound of formula I characterized by an X-ray powder diffraction pattern with peaks at 8.7, 11.1, 12.4, 14.1, 15.3, 17.2, 17.8, 19.3 and 20.4 ±0.2 °2 theta, which process comprises:
(i) dissolving compound of formula I in dimethyl sulphoxide;
(ii) adding water; and
(iii)drying.

A typical X-ray Powder Diffractogram, XRPD of the novel polymorphic form of cabazitaxel as described herein is shown in FIG, 1.
In an embodiment, the novel crystalline form of cabazitaxel of the present invention can be further characterized by XPRD data corresponding to Table-I shown below.
Table -1

Angle [2-Theta] d value [Angstrom] Relative Intensity [%]
7.0588 12.52322 23.36
8.7407 10.11690 100.00
10.3304 8.56330 37.40
11.1533 7.93331 96.71
12.4632 7.10228 75,64
14.1229 6.27116 94.96
15.3135 5.78614 47.35
17.2852 5.13032 88.08
17.8738 4.96268 61.50
18.5578 4.78128 40.21
19.3761 4.58117 63.54
20.3614 4.36166 52.45
23.3389 3.81152 38.88
24.8627 3.58126 22.53
25.64 3.47443 12.79
26.3568 3.38154 8.38
29.4079 3,03728 5.74
32.8641 2072533 5.68
35.8728 2.50336 6.80
42,1038 2.14618 5.72
49.0656 1.85518 4.31
A typical X-ray Powder Diffractogram, XRPD of another novel polymorphic form of cabazitaxel as described herein is shown in FIG. 2.
In an embodiment, the novel crystalline form of cabazitaxel of the present invention can be further characterized by XPRD data corresponding to Table-II shown below.
Table - II

Angle [2-Theta] d value [Angstrom] Relative Intensity [%]
4.3592 20.27090 17.35
7.0427 12.55180 24.30
8.6465 10.22689 96.40
8.7776 10.07446 73.31
10.4123 8.49618 46.03
11.0925 7.97664 100.00
12.3478 7.16842 89.57
14.0034 6.32438 93.26
15.3643 5.76714 38.14
17.3102 5.12297 84.06
17.7663 4.99246 54.79
19.3934 4.57712 50.41
20.4629 4.34025 46.97
21.5282 4.12782 37.03
23.3298 3.81298 25.56
24.8217 3.58708 13.23
29.4545 30.03258 6.57
30.7525 2.90748 5.51
32.6659 2.74142 5.55
35.9737 2.49657 3.25
42.1025 2.14624 6.56
43.6189 2.07337 4.31
A typical X-ray Powder Diffractogram, XRPD of yet another novel polymorphic form of cabazitaxel as described herein is shown in FIG. 3.
In an embodiment, the novel crystalline form of cabazitaxel of the present invention can be further characterized by XPRD data corresponding to Table-Ill shown below.
Table - in

Angle [2-Theta] d value [Angstrom] Relative Intensity [%]
4.4891 19.68438 12.87
7.0729 12.49820 25.54

8.7525 10.10332 95.24
10.3632 8.53626 44.34
11.1717 7.92028 100.00
12.4160 7.12921 87.54
14.1309 6.26763 91.58
15.3961 5.75531 43.43
17.3408 5.11401 89.00
17.8749 4.96240 59.81
19.4819 4.55653 65.00
20.6775 4.29568 52.03
21.6200 4.11051 45.41
23.3865 3.80387 35.07
24.8213 3.58715 22.28
26.4211 3.37346 8.25
29.4162 3.03644 5.23
32.7258 2.73653 4.38
42.0568 2.14669 5.51
In yet another embodiment, the present invention provides a process for the preparation of the novel polymorphic forms characterised by a PXRD data according to Table-I, II or III, which process comprises:
(i) dissolving compound of formula I in dimethyl sulphoxide;
(ii) adding water; and
(iii) drying.
A still further embodiment of the present invention provides another novel polymorphic form of cabazitaxel. The novel polymorphic form of cabazitaxel has been characterized by X-ray Powder Diffractogram, XRPD which produces a fingerprint of the particular crystallite form. Measurements of 20 values typically are accurate to within ± 0.2 degrees.
In an embodiment, the present invention provides a novel polymorphic form of cabazitaxel characterized by an X-ray powder diffraction pattern with peaks at 7.3, 8.1, 8.9, 9.9, 11.1, 11.8, 12.7, 13.0, 13.6, 17.2, 18.6,21.3 and 24.8 ±0,2 °2 theta

A typical X-ray Powder Diffractogram. XRPD of the novel polymorphic form of cabazitaxel as described is shown in FIG. 4. The XPRD data corresponding to this Diffractogram is shown below in Table-IV.
Table-IV

Angle [2-Theta] d value [Angstrom] Relative Intensity [%]
7.3266 12.06609 31.37
7.7052 11.47100 12.54
8.1641 10.83011 100.00
8.9356 9.89659 7.24
9.9019 8.93288 26.14
10.238 8.64040 16.44
10.4225 8.48791 16.86
10.9351 8.09113 18.85
11.1563 7.93117 17.65
11.8087 7.49442 27.26
12.7395 6.94886 46.20
13.0356 6.79167 34.52
13.6876 6.46960 4.59
14.3547 6.17039 12.62
14.762 6.00107 3.32
15.1628 5.84334 6.89
15.357 5.76988 5.98
15.8672 5.58547 17.06
16.2889 5.44180 18.32
17.117 5.18036 23.19
17.2959 5.12717 22.16
17.6776 5.01733 21.57
18.6047 4.76935 33.52
18.8509 4.70761 13.28
19.2974 4.59969 8.31
19.7962 4.48489 11.14
20.5208 4.32814 15.89
20.9675 4.23693 3.47

21.3614 4.15968 4.13
22.0049 4.03947 15.55
22.6641 3.92344 17.58
23.1611 3.84037 10.54
24.3872 3.64999 9.33
24.8721 3.57992 6.68
25.4532 3.49951 9.90
25.6352 3.47506 6.82
26.2079 3.40012 6.33
27.063 3.29489 4.69
28.1548 3.16955 2.24
28.9222 3.08718 2.29
29.4757 3.03045 4.14
30.0124 2.97747 3.35
30.906 2.89338 2.32
31.2857 2.85914 6.45
32.0012 2.79682 2.67
33.2228 2.69672 2.78
34.4929 2.60028 0.87
35.8218 2.50681 0.88
36.5253 2.46013 1.61
43.617 2.07345 1.48
In a preferred embodiment, the present invention provides a process for the preparation of the
novel polymorphic form of a compound of formula I characterised by a PXRD data according to
Table-IV, which process comprises:
(i) dissolving compound of formula I in acetonitrile; and
(ii) drying.
The novel polymorphic forms are expected to be more stable than the prior reported forms. In another embodiment the present invention also relates to formulations of cabazitaxel using the novel polymorphic forms. Stability may be assessed by storing the API or formulations under preset conditions for a pre-determined period of time, and then analyzing the formulations after storage for changes in the amount of cabazitaxel or impurity levels. The changes in the amount of

cabazitaxel and impurity levels can be measured using techniques known in the art. For instance, one such technique is high performance liquid chromatography (HPLC). The skilled artisan would understand how to perform HPLC in order to measure the stability of the API or formulations. Using HPLC, stability may be assessed by analyzing the generated impurity profile. For example, one measure is the peak area % of the impurities detected by HPLC, or the total peak area % of all impurities detected by HPLC. These measurements may be compared to measurements of the API or formulation before storage, or may be compared to measurements of a formulation standard (e.g., the formulation for JEVTANA).
The moisture content (percent hydration) of the novel polymorphic forms of the present invention may be detected using techniques known to a person skilled in the art such as, but not limited to, DSC, TGA, and water by Karl Fisher technique and the like. While not restricted by the number of water molecules associated with the crystal forms, the present invention may be directed to anhydrous, monohydrate, d'ihydrate and the like. Further, the water percentage (percent hydration) in the crystals may vary depending on the relative humidity during storage.
The general reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-A:


EXAMPLES:
The invention is farther described by reference to the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention.
Example-1: Preparation of 4a-acetoxy-2α-benzoyloxy-5β,20-epoxy-lp-hydroxy-7β,10β-dimethoxy-9-oxo-ll-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazol)dine-5-carboxylate (compound of formula IV)
5 g of 4α-acetoxy-2a-benzoyloxy-5β,20-epoxy-lβ,13α-di hydroxy-7β,10β-dimethoxy-9-oxo-ll-taxene is stirred in 45 mi of dry DCM (dichloromethane) at 20-25° C and then 5.92 g of (2R, 4S, 5R)-tert- butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylic acid. 3.23 g of Dicyclohexylcorbodiimide (DCC) and 426 mg of Dimethylamino pyridine (DMAP) are charged. The reaction mixture is stirred at 20-25° C for 4-5 hrs. After the completion of the reaction completed, water is added and the DCM layer is separated. Recover DCM, add acetone, and filter it to remove Dicyclohexyl urea. From the filtrate product is purified using column chromatography using DCM and Ethyl acetate as mobile phase.
Example-2: Preparation of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R3S)-3[(tert-butoxy carbonyI)amino]-2-hydroxy-3-phenyipropanoyI}oxy)-l-faydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (compound of formula I)
1.4 g of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-lβ-hydroxy-7β,10β-dimethoxy-9-oxo-ll-taxen-13a-y](2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate (compound of formula IV) is charged in 38 ml of 0.1N HCl in ethanol and 17 mi of DCM is added. Stir the mixture for 4-5 hours at 20° -25° C. Reaction completed, add water, extract with DCM and pass through column chromatography using DCM-Ethyl acetate as mobile phase. Yield > 75%.
Exarople-3: Crystallization of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy carbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (compound of formula I)
532 mg of Cabazitaxel is dissolved in 16 ml of acetonitrile agitate and slowly add 48 ml of water drop wise in 1 hour at 25° -30° C. Agitate for 2 hours, filter, wash with water and dry under vacuum at 45° - 50° C for 6-8 hours. Purity > 99%.

Example-4: Crystallization of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy carbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,0-epoxytax-ll-en-2-yl benzoate (compound of formula I)
1 g of Cabazitaxel is dissolved in 3.5 ml of DMSO at room temperature and 10.5 ml of water was added dropwise to the solution at room temperature. The solution is agitated for 2 hours, filtered, washed with water and dried under vacuum at 55°C for 12 hours.
Example-5: Crystallization of (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy carbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,0-epoxytax-ll-en-2-yl benzoate (compound of formula I)
1 g of Cabazitaxel is dissolved in 30 ml of Acetonitrile at room temperature. The solution is agitated for 2 hours and then the solvent recovered under vacuum to get the dried product.


We claim:
1, A process for the recrystallization of a compound of formula I
which process comprises:
(i) dissolving the compound of formula J in a first solvent;
(ii) optionally adding a second solvent; and
(iii) drying.
2. The process according to claim 1 wherein the first solvent is selected from the group comprising of acetonitrile, propylene glycol, diol, dimethyl sulfoxide, butyl acetate, ethyl formate, acetic acid, formic acid, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, propyl acetate and mixtures thereof and the second solvent is selected from water, hexane, toluene, ethers, heptane and mixtures thereof.
3. The process according to claim 2, wherein the first solvent is dimethyl sulphoxide and the second solvent is water.
4. The process according to claim 2, wherein the first solvent is acetonitrile and the second solvent is water.

which comprises:
(i) reacting a compound of Formula 11
5. A process for the preparation of compound of formula I




with a compound of Formula III
in the presence of DCC, DMAP and Dichloromethane, to obtain a compound of formula (IV);
(ii) converting the compound of formula (IV) to compound of formula I using hydrochloric acid
in ethano! and a chlorinated hydrocarbon solvent; and (iii) dissolving compound of formula I obtained in step (ii) in a first solvent; (iv) optionally adding a second solvent; and (v) drying.
6. The process according to claim 5, wherein the first solvent used in step (iii) is selected from the group comprising of acetonitrile, propylene glycol, diol, dimethyl sulfoxide, butyl acetate, ethyl formate, acetic acid, formic acid, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-l-propanol, propyl acetate and mixtures thereof and the second solvent used in step (iv) is selected from water, hexane, toluene, ethers, heptane and mixtures thereof.


7. A novel polymorphic form of compound of formula 1
characterized by an X-ray powder diffraction pattern with peaks at 8.7, 11.1, 12.4, 14.1, 15.3, 17.2, 17.8,19.3 and 20.4 ±0.2 °2 theta.
8. A process for the preparation of the novel polymorphic form of compound of formula I

characterized by an X-ray powder diffraction pattern with peaks at 8.7, 11.1, 12.4, 14.1. 15.3, 17.2,17.8,19.3 and 20.4 ±0.2 °2 theta, which process comprises:
(i) dissolving compound of formula I in dimethyl sulphoxide;
(ii) adding water; and
(iii) drying.
9. A novel polymorphic form of a compound of formula I

characterized by an X-ray powder diffraction pattern with peaks at 7.3, 8.1, 8.9, 9.9, 11.1, 11.8, 12.7, 13.0, 13.6,17.2, 18.6, 21.3 and 24.8 ±0.2 °2 theta.
10. A process for the preparation of the novel polymorphic form of a compound of formula I


characterized by an X-ray powder diffraction pattern with peaks at 7.3, 8.1, 8.9, 9.9, 11.1, 11.8, 12.7,13.0, 13.6, 17.2, 18.6, 21.3 and 24.8 ±0.2 °2 theta, which process comprises:
(i) dissolving compound of formula I in acetonitrile; and
(ii) drying.