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 (2A,5B,7B,10B,13A)-4-ACETOXY-13-
({(2R,3S)-3[(TERTBUTOXYCARBONYL)AMINO]-2-HYDROXY-3-
PHENYLPROPANOYL}OXY)-l-HYDROXY-7,10-DIMETHOXY-9-OXO-5,20-
EPOXYTAX-11-EN-2-YL BENZOATE
PANACEA BIOTEC LIMITED,
an Indian Company incorporated under the Companies Act 1956 B-l Ext. A-27. Mohan Co-operative Industrial Estate, Mathura Road,
New Delhi-110 044,
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-phenylpropanoyl}oxy)-l-hydroxy-7.10-dimethoxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate (Cabazitaxel) and its pharmaceutically acceptable salts.
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[(tenbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,0-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 C45H57NO4 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-benzoyloxy-
5P,20-epoxy-lβ,13α-dihydroxy-7β,10β-dimethoxy-9-oxo-ll-taxene with (2R,4S,5R)-3-tert-
butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid in
dicyclohexyl carbodiimide (DCC) and dimethylamino pyridine (DMAP) to obtain of 4α-acetoxy-2a-benzoyloxy-5β,20-epoxy-1 P-hydroxy-7β, 10β-dimethoxy-9-oxo-11 -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-2α-benzoyloxy-5β, 20-epoxy-lβ, 13α-di hydroxy-7β, 10p-dimethoxy-9-oxo-ll-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 4a-acetoxy-2ct-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β, 10β-bis(methylthiomethoxy)-9-oxo-11 -taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-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 1% of water to obtain Cabazitaxel in the form of a white foam.
The above two processes, involved the hydrolysis of 4α-acetoxy-2a-benzoyloxy-5p,20-epoxy-1β-hydroxy-7β,l0β-dimethoxy-9-oxo-11 -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-oxotax-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 (dicyclohexylcarbodiimide) 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.
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. The intermediates and the final end products .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 pharmaceutic ally acceptable salts.
In one aspect, the present invention provides a process for the preparation of cabazitaxel, represented by the Formula I

which comprises:
(i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel; (ii) dissolving the product of step (i) in methanol; (iii) removing the solvent to obtain cabazitaxel.
In another aspect, the present invention provides a process for the preparation of amorphous cabazitaxel, represented by the Formula I

which comprises:
(i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel; (ii) dissolving the product of step (i) in methanol;

(iii) removing the solvent to obtain amorphous cabazitaxel.
In yet another aspect, the present invention provides a process for the preparation of cabazitaxel represented by the formula I,

Formula I which process comprises:
(i) reactin g a compound of Formula II

with a compound of Formula III

in the presence of DCC, DMAP and DCM (dichloromethane). 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 dichloromethane; and (iii) purifying the compound obtained from step (ii) (iv) dissolving the product of step (iii) in methanol; (v) removing the solvent to obtain cabazitaxel.

which process comprises:
(i) reactin g a compound of Formula II

In a further aspect, the present invention provides a process for the preparation of amorphous cabazitaxel represented by the formula I.


with a compound of Formula III
in the presence of DCC. DMAP and DCM (dichloromethane). 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 dichloromethane; and (iii) purifying the compound obtained from step (ii) (iv) dissolving the product of step (ii) in methanol; (v) removing the solvent to obtain amorphous cabazitaxel.
In an aspect, the present invention provides a process for the preparation of amorphous cabazitaxel, which process comprises:
(i) convertin g the compound of formula (IV);


using hydrochloric acid in elhanol and dichloromethane; (ii) purifying the compound obtained from step (i); and (iii) converting the compound obtained in step (ii) into amorphous cabazitaxel.
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.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides a process for the preparation of cabazitaxel, represented by the Formula I

which comprises: (i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel; (ii) dissolving the product of step (i) in methanol; (iii) removing the solvent to obtain cabazitaxel.
In another embodiment, the present invention provides a process for the preparation of amorphous cabazitaxel. represented by the Formula I

which comprises: (i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel; (ii) dissolving the product of step (i) in methanol; (iii) removing the solvent to obtain amorphous cabazitaxel.
In yet another aspect, the present invention provides a process for the preparation of cabazitaxel represented by the formula I.


which process comprises:

with a compound of Formula III

(i) reacting a compound of Formula II
in the presence of DCC, DMAP and DCM (dichloromethane), 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 dichloromethane; and (iii) purifying the compound obtained from step (ii) by dissolving in ethyl acetate; (iv) dissolving the product of step (iii) in methanol; (v) removing the solvent to obtain cabazitaxel.

with a compound of Formula III

In an embodiment, the present invention provides a process for the preparation of amorphous cabazitaxel, which process comprises: (i) reactin g a compound of Formula II

Formula III in the presence of DCC, DMAP and DCM (dichloromethane), 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 dichloromethane; and (iii) purifying the compound obtained from step (ii) by dissolving in ethyl acetate; (iv) dissolving the product of step (iii) in methanol: (v) removing the solvent to obtain amorphous cabazitaxei.

to crude cabazitaxel of formula I
In a further embodiment, the present invention provides a process for the preparation of amorphous cabazitaxei, which process comprises: (i) convertin g the compound of formula (IV);


using hydrochloric acid in ethanol and dichloromethane; (ii) purifying the compound obtained from step (i); and (iii) converting the compound obtained in step (ii) into amorphous cabazitaxel.
The details of the above embodiment are as follows:
Step (i) involves the conversion of compound of formula (IV) to crude cabazitaxel of formula (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.
Step (ii) involves purifying the compound obtained from step (ii).
The purification step involves dissolving the product obtained from step (i) in a solvent selected from the group consisting of acetonitrile, ethyl acetate, and the like and their mixtures thereof. The amount of solvent that is used in step (ii) may be taken in appropriate quantities sufficient to dissolve crude cabazitaxel.
In an embodiment, the crude cabazitaxel obtained from step (i) is first subjected to a column chromatography on silica with dichloromethane-dichloromethane/ethyl acetate. The desired fractions are dried under vacuum for about 20-60°C. preferably at 40°C for 2 hours to get the dry mass. The material thus obtained is then dissolved in ethyl acetate to obtain pure cabazitaxel.
In another embodiment, the crude cabazitaxel obtained from step (i) is suspended in acetonitrile and filtered to get pure cabazitaxel.

In yet another embodiment, the crude cabazitaxel obtained from step (i) is purified from mixture of ethyl acetate and acetonitrile.
In an embodiment, the product obtained from step (ii), which is pure cabazitaxel is proceeded to step (iii) without drying.
Step (iii) involves converting the compound obtained in step (ii) into amorphous cabazitaxel. The conversion involves, dissolving the pure cabazitaxel obtained from step (ii) in methanol and recovering methanol under vacuum.
The genera] reaction scheme of the above embodiment of the instant invention can be schematically represented as scheme-A:


EXAMPLES:
The invention is further 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-2a-benzoyloxy-5p,20-epoxy-lp-hydroxy-7p,10p-dimethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate (compound of formula IV)
5 g of 4a-acetoxy-2α-benzoyloxy-5p.20-epoxy-lβ,13α-di hydroxy-7β,10β-dimethoxy-9-oxo-l 1-taxene is stirred in 45 ml of dry DCM (dichloromethane) at 20-25° C and then 5.92 g of (2R, 4S, 5R)-tert butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1.3-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, 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 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-n-taxen-13a-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate (compound of formula IV)
5 g of 4a-acetoxy-2α-benzoyloxy-5β;20-epoxy-lβ:13α-dihydroxy-7β,10β-dimethoxy-9-oxo-11-taxene is stirred in 45 ml 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 Dicyclohexylcarbodiimide (DCC) and 426 mg of Dimethylaminopyridine (DMAP) are charged. The reaction mixture is stirred at 20-25° C for 4-5 hrs. After completion of the reaction, Dicyclohexyl urea is removed by filtration, water is added to the filtrate and the DCM layer is separated. DCM is recovered. 210 ml of ethanol added and stirred at 40-45° C for 2 hrs then filtered to get the 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β, 10β-dimethoxy-9-

oxo-11-taxen-l3a-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate.
Example-3: Preparation 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-ylbenzoate (compound of formula I)
1.4 g of 4α-acetoxy-2α-benzoy loxy-5β.20-epoxy-1 p-hydroxy-7β, 10β-dimethoxy-9-oxo-11 -taxen-13α-yl(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 HC1 in ethanol and 17 ml of DCM. The mixture is stirred for 4-5 hours at 20° -25° C. After completion of the reaction, DCM and water is added, separated the DCM layer, concentrated and the crude product passed through column chromatography using DCM-Ethyl acetate as mobile phase. Yield > 75%.
Example-4: Preparation of amorphous Cabazitaxel (compound of formula I)
1.0 g of Cabazitaxel obtained in example 3 is suspended in 3 ml of ACN and the suspension stirred at 40° C for 30 min followed by agitation at 0° C for 2.0 hrs. The suspension is filtered and the solid washed with chilled ACN to obtain the pure product. The pure Cabazitaxel is dissolved in 10 ml of DCM at room temperature, passed over anhydrous sodium sulphate and the filtrate concentrated to get the solid. 5 ml of methanol is added to the residue and the methanol recovered to get the product. The methanol process is repeated twice, concentrated and finally dried under vacuum at 50° C to get the amorphous product.
Example-5: Preparation of amorphous Cabazitaxel (compound of formula I)
1.0 g of Cabazitaxel obtained in example 3 is suspended in 20 ml of Ethyl acetate, heated up to 40° C and added more ethyl acetate to get clarity at 40° C. The solution is stirred for 15 min, washed the ethyl acetate layer concentrated till thick slurry is obtained and stirred at 10-20° C for 2.0 hrs. The slurry is filtered and the solid washed with pre-cooled ethyl acetate to get the pure product. The pure cabazitaxel is dissolved in 20 ml of methanol at room temperature and concentrated on rotary evaporator to get the solid. 5 ml of methanol is added to the residue and

the methanol recovered to get the product. The methanol process is repeated twice, concentrated and finally dried under vacuum at 50° C to get the amorphous product.
Example-6: Preparation of amorphous Cabazitaxel (compound of formula I)
1.0 g of Cabazitaxel obtained in example 3 is suspended in 20 ml of Ethyl acetate heated up to 40° C and ACN added to get clarity at 40° C. The solution is stirred for 15 min the mixture of ethyl acetate and ACN is concentrated to get the thick slurry and stirred at 10-20° C for 2.0 hrs. The slurry is filtered and the solid washed with pre-cooled ethyl acetate to afford the pure product. The pure cabazitaxel is dissolved in 20 ml of Methanol at room temperature and concentrated on rotary evaporator to get the solid. 5 ml of methanol is added to the residue and the methanol recovered to get the product. The methanol process is repeated twice, concentrated and finally dried under vacuum at 50° C to get the amorphous product.

We claim:
1. A process for the preparation of cabazitaxel. represented by the Formula I

which comprises:
(i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel;
(ii) dissolving the product of step (i) in methanol;
(iii) removing the solvent to obtain cabazitaxel.
2. A process for the preparation of amorphous cabazitaxel. represented by the Formula I

which comprises:
(i) dissolving crude cabazitaxel in ethyl acetate to obtain pure cabazitaxel;
(ii) dissolving the product of step (i) in methanol;
(iii) removing the solvent to obtain amorphous cabazitaxel.
3. A process for the preparation of cabazitaxel represented by the formula I,

which process comprises:
(i) reactin g a compound of Formula II

with a compound of Formula III

in the presence of DCC, DMAP and DCM (dichioromethane). 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 dichloromethane: and (iii) purifying the compound obtained from step (ii) by dissolving in ethyl acetate; (iv) dissolving the product of step (iii) in methanol; (v) removing the solvent to obtain cabazitaxel.

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

with a compound of Formula III
4. A process for the preparation of amorphous cabazitaxel represented by the formula I,


in the presence of DCC. DMAP and DCM (dichloromethane). 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 dichloromethane; and (iii) purifying the compound obtained from step (ii) by dissolving in ethyl acetate; (iv) dissolving the product of step (ii) in methanol; (v) removing the solvent to obtain amorphous cabazitaxel.
5. A process for the preparation of amorphous cabazitaxel, which process comprises: (i) converting the compound of formula (IV);


to crude cabazitaxel of formula I

using hydrochloric acid in ethanol and dichloromethane; (ii) purifying the compound obtained from step (i); and (iii) converting the compound obtained in step (ii) into amorphous cabazitaxel.
6. A process according to claim 5, wherein step (ii) involves purifying the compound obtained in step (i) by dissolving in ethyl acetate.
7. A process according to claim 5, wherein step (iii) involves dissolving the compound obtained in step (ii) in methanol and removing the solvent to obtain amorphous cabazitaxel.
8. Amorphous cabazitaxel obtained according to the process of claim 5.