WO2015087228A1

WO2015087228A1 - Process for the preparation of cabazitaxel and its solvates

Info

Publication number: WO2015087228A1
Application number: PCT/IB2014/066692
Authority: WO
Inventors: Madhuresh Kumar Sethi; Sanjay Mahajan; Bhairaiah Mara; Upendranath VEERA
Original assignee: Mylan Laboratories Ltd.
Priority date: 2013-12-10
Filing date: 2014-12-08
Publication date: 2015-06-18

Abstract

The present disclosure provides anisole and benzyl alcohol solvates of cabazitaxel and methods of their production. The solvates may be characterized by powder x-ray diffraction patterns. The present disclosure also provides methods for the synthesis of cabazitaxel.

Description

PROCESS FOR THE PREPARATION OF CABAZITAXEL AND ITS SOLVATES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application No. 5688/CHE/2013 filed on Dec 10, 2013.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present disclosure relates generally to the preparation of cabazitaxel, and more specifically to the preparation of anisole and benzyl alcohol solvates cabazitaxel.

DESCRD7TION OF THE BACKGROUND

Cabazitaxel, chemically known as (2a,5p,7p,10p,13a)-4-acetoxy-13-({(2R,3S)-3- [(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10- dimethoxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate - propan-2-one, has the structure shown as Formula-I. Cabazitaxel is a semi-synthetic taxoid derivative, marketed under the trade name JEVTANA® for the treatment of hormone-refractory prostate cancer.

Formula-I

Active pharmaceutical ingredients (APIs) are frequently administered in the solid state as part of an approved dosage type (e.g., tablets, capsules, injectable etc.). Solids provide a convenient, compact, and generally stable vehicle for an API or a drug product. APIs can exist in a variety of distinct solid forms, where each form may display unique physicochemical properties such as hygroscopicity, morphology, solubility, and bioavailability. Unfortunately, some potentially useful compounds with highly desirable molecular pharmacological properties may never realize their maximum potential because the materials into which they are incorporated for oral dosing interfere with these desirable characteristics.

The present invention provides an anisole solvate of cabazitaxel, a benzyl alcohol solvate of cabazitaxel, and processes for the preparation of each. Such solvates of cabazitaxel provide significant benefits to the art and provide useful forms of this pharmaceutically active compound.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of cabazitaxel or its solvates, which may include the following steps:

a) reacting Formula-II with a hydrogen fluoride-organic base complex to give Formula-Ill,

Formula-II Formula-Ill

wherein P is suitable hydroxy protecting group;

b) selectively methylating Formula-Ill to give Formula-IV.

converting Formula- VI to cabazitaxel of Formula-I.

Formula-I

Another aspect of the present invention is to provide a process for the preparation of an anisole solvate of cabazitaxel, which may include the following steps:

a) dissolving cabazitaxel in mixture of halogenated solvent and anisole,

b) removing the solvent from the reaction mixture,

c) optionally heating the reaction mixture,

d) cooling the reaction mixture, and

e) isolating anisole solvate of cabazitaxel. Another aspect of the present invention provides a benzyl alcohol solvate of cabazitaxel, which may be prepared by the following steps:

a) dissolving cabazitaxel in mixture of halogenated solvent and benzyl alcohol, b) removing the solvent from the reaction mixture,

c) optionally heating the reaction mixture,

d) cooling the reaction mixture, and

e) isolating benzyl alcohol solvate of cabazitaxel.

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure 1 shows a powder X-ray diffraction pattern of the anisole solvate of cabazitaxel; Figure 2 shows a differential scanning calorimetry (DSC) thermogram of the anisole solvate of cabazitaxel;

Figure 3 shows a thermogravimetric analysis (TGA) thermal curve of the anisole solvate of cabazitaxel; and

Figure 4 shows a powder X-ray diffraction pattern of the benzyl alcohol solvate of cabazitaxel.

DETAILED DESCRD7TION OF THE INVENTION

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present disclosure provides method for the preparation of cabazitaxel, as well as methods of preparation for the anisole and benzyl alcohol solvates of cabazitaxel.

One aspect of the present invention is to provide a process for the preparation of cabazitaxel or its solvates, which may include the following steps: a) reacting Formula-II with a hydrogen fluoride-organic base complex to give Formula-Ill;

Formula-II Formula-Ill

wherein P is suitable hydroxy protecting group;

b) selectively methylating Formula-Ill to give Formula-IV:

Formula-Ill Formula-IV

c) condensing Formula-IV with Formula-V to get Formula- VI; and

Formula-IV Formula-V Formula- VI d) converting Formula- VI to cabazitaxel of Formula-I.

Formula-I Within the context of the present invention, the hydroxy protecting group of Formula-II may be, as examples, alkyl, aryl, arylalkyl, trialkylsilyl, or diarylalkylsilyl. In some embodiments of the present invention, trialkylsilyl or diarylalkylsilyl were found to particularly useful protecting groups. Suitable trialkylsilyl protecting groups include, for example, tnmethylsilyl (TMS), tnethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tn- isopropylsilyloxymethyl (TOMS) and triisopropylsilyl (TIPS) group. A suitable diarylaklylsilyl groups may be, for example diphenyl(tert-butyl)silyl. In certain embodiments of the present invention, triethylsilyl (TES) was found to be a particularly useful protecting group.

According to the present disclosure, Formula-II may then be reacted with a hydrogen fluoride-organic base complex to provide Formula-Ill. The organic base that is complexed to the hydrogen fluoride may be, as examples, pyridine, dimethylaminopyridine, or an amine. Examples of suitable amines include, for example, triethylamine and diisopropylethylamine. In certain embodiments of the present invention, pyridine and triethylamine have been found to be particularly useful bases that complex to hydrogen fluoride where the resulting complex is useful in this particular reaction step. According to the present disclosure, methylation of Formula-Ill may be carried out in the presence of a methylating agent and a base to give Formula-IV. Suitable methylating agents include, as examples, a methyl halide, dimethyl sulfate, and trimethyl oxonium salt. Within the context of the present invention, examples of methyl halides include methyl iodide methyl bromide and methyl chloride. The base may be, as examples, alkali metal hydrides or alkali metal hydroxides. Examples of suitable alkali metal hydrides include sodium hydride, potassium hydride, lithium hydride, calcium hydride, and magnesium hydride. Examples of suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide. In certain embodiments of the present invention, sodium hydride and potassium hydroxide have been found to be particularly useful bases. According to the present disclosure, the condensation of Formula-IV with Formula-V may be carried out in presence of a suitable condensing agent. The condensing agent may be, as examples, di-2-pyridyl carbonate (DPC), or a carbodiimide. Examples of suitable carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIPC), and ethyl-(N-N'-dimethyl aminopropyl carbodiimide (EDC). In certain embodiments, N,N'-dicyclohexylcarbodiimide was found to be a particularly useful condensing agent. The condensation of Formula-IV with Formula-V may be optionally carried out in the presence of a catalyst. Examples of suitable catalysts include hydroxybenzotriazole and aminopyridines. Examples of suitable aminopyridines include dimethylaminopyridine and pyrrolidinopyridine.

According to the present disclosure, the obtained compound of Formula- VI may then be purified by suspending it in an ethereal solvent at a temperature of 20-30 °C. Examples of suitable ethereal solvents include diethyl ether, diisopropyl ether, methyl tert-butyl ether, and mixtures thereof. In some embodiments of the present invention, methyl tert- butyl ether was found to be a particularly useful ethereal solvent. The solution may then be heated to a temperature of 30-60 °C. It has been found, in some embodiments of the present invention, that a temperature of 40-50 °C is particularly useful for conducting this reaction step. The reaction mass may then be cooled to 10-30 °C. It has been found, in some embodiments of the present invention, that a temperature of 20-30 °C is particularly useful. The reaction mixture may be stirred to form a solid. The solid may then be filtered, washed with methyl tert-butyl ether, and dried to get a substantially pure compound of Formula- VI.

According to the present disclosure, Formula- VI may be converted to cabazitaxel by reacting Formula- VI with an inorganic acid or organic acid. Examples of suitable inorganic acids include hydrochloric acid, sulfuric acid, and nitric acid. In certain embodiments, hydrochloric acid was found to be a particularly useful inorganic acid. Examples of suitable organic acids include acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, and p-toluene sulphonic acid. Within the context of the present invention, the obtained cabazitaxel may be optionally further converted into solvate forms, for example, anisole, acetone, isopropyl acetate, or ethyl acetate. The anisole solvate of cabazitaxel, in certain embodiments, has been found to a particularly useful form. One embodiment of the present invention provides the anisole solvate of cabazitaxel, which may be prepared by the following steps:

a) dissolving cabazitaxel in mixture of halogenated solvent and anisole;

b) removing the solvent from the reaction mixture;

c) optionally heating the reaction mixture;

d) cooling the reaction mixture; and

e) isolating an anisole solvate of cabazitaxel.

According to the present disclosure, cabazitaxel may be dissolved in a mixture of halogenated solvent and anisole. Within the context of the present invention, useful halogenated solvents include, as examples, dichloromethane, dichloroethane, or chloroform. The reaction mixture may then be concentrated under vacuum. The reaction mixture may then be optionally heated to a temperature of 30-100 °C. In certain embodiments of the present invention, a temperature of 30-80 °C has been found to be particularly useful. The reaction mass may then be cooled to 0-30 °C to form a solid. In some embodiments of the present invention, a temperature of 0-10 °C was found to be particularly useful. The obtained solid may then be filtered, washed with anisole, and dried to obtain an anisole solvate of cabazitaxel.

Within the context of the present invention, the obtained cabazitaxel anisole solvate may be converted into the unsolvated form of cabazitaxel by column chromatography using eluent which includes dichloromethane, mixture of dichloromethane and methanol.

Another embodiment of the present invention provides a benzyl alcohol solvate of cabazitaxel, which can be prepared by the following steps:

a) dissolving cabazitaxel in mixture of halogenated solvent and benzyl alcohol; b) removing the solvent from the reaction mixture;

c) optionally heating the reaction mixture;

d) cooling the reaction mixture; and

e) isolating benzyl alcohol solvate of cabazitaxel. According to the present disclosure, cabazitaxel may be dissolved in mixture of halogenated solvent and benzyl alcohol. Examples of halogenated solvents include dichloromethane, dichloroethane and chloroform. In certain embodiments of the present invention, dichloromethane was found to be particularly useful. The reaction mixture may then be concentrated under vacuum. The reaction mixture may then be optionally heated to a temperature of 30-60 °C. In certain embodiments, a temperature of 40-50 °C was found to be particularly useful. The reaction mass may then be cooled to 20-35 °C to form a solid. A temperature of 25-30 °C was found to be particularly useful in some embodiments of the present invention. The obtained solid may then be filtered, washed with benzyl alcohol, and dried to get a benzyl alcohol solvate of cabazitaxel.

Within the context of the present invention, the obtained cabazitaxel benzyl alcohol solvate may be converted into the unsolvated form of cabazitaxel by column chromatography using eluent which includes dichloromethane, mixture of dichloromethane and methanol.

In one more embodiment of the present invention, cabazitaxel used as an input material in the present disclosure is, but not limited to crystalline or any solvate.

The solvates of the present invention may be characterized by their X-ray powder diffraction patterns. Thus, X-ray diffraction patterns of the anisole and benzyl alcohol solvates of cabazitaxel were measured on BRUKER D-8 Discover powder diffractometer equipped with a goniometer of Θ/2Θ configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time. The anisole solvate of cabazitaxel may be characterized by a powder X-ray diffraction pattern having significant peaks at 7.91, 10.06, 13.84, 14.04, 17.31, 17.79, 20.28, 22.54 and 23.88 ± 0.2° 2-theta. The anisole solvate of cabazitaxel may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 1. The benzyl alcohol solvate of cabazitaxel may be characterized by a powder X-ray diffraction pattern having significant peaks at 7.96, 10.13, 13.99, 14.90, 15.97, 17.30, 19.79, 20.44, 22.63 and 23.98 ± 0.2° 2-theta. The benzyl alcohol solvate of cabazitaxel may be further characterized by a powder X-ray diffraction pattern as depicted in Figure 4.

The solvates of the present invention may also be characterized by differential scanning calorimetry (DSC). The DSC measurements were carried out on a TA Q1000 differential scanning calorimeter (TA Instruments). The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30-250 °C purging with nitrogen at a flow rate of 50 ml/min. Standard aluminum crucibles covered by lids with pin holes were used. The anisole solvate of cabazitaxel may be characterized by a DSC thermogram as depicted in Figure 2.

The solvates of the present invention may also be characterized by thermogravimetric analysis (TGA) or differential thermal analysis (DTA). TGA/DTA was recorded using a TA Q5000 Dynamic Vapor Sorption Instrument (TA Instruments). The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30 °C-300 °C purging with nitrogen at a flow rate of 25 ml/min. The anisole solvate of cabazitaxel may be characterized by a TGA thermal curve as depicted in Figure 3.

The cabazitaxel and solvates of cabazitaxel as synthesized by the methods disclosed herein may be useful in the treatment of individuals with hormone-refractory metastatic prostate cancer. In particular, they may be useful at treating those patients previously treated with a docetaxel-containing treatment regimen. In some embodiments, the cabazitaxel or solvates of the present invention may be included an injectable solution for intravenous delivery to a patient. One of skill in the art will recognize a wide variety of pharmaceutically acceptable excipients that may be included in the formulation or packaged separately for inclusion in the final prepared formulation immediately prior to intravenous delivery. Suitable excipients may include emulsifiers, such as polysorbate 80, surfactants, and diluents, such as ethanol.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1-A process for the preparation of 10-deacetyl-7-O-triethylsilyl baccatin- III

A mixture of 10-deacetyl baccatin III (20 g), dimethylformamide (60 ml), and imidazole (7.75 g) was stirred at 20-30 °C and cooled to 0-5 °C. To this, a triethylsilyl chloride solution (prepared by dissolving 9.96 g triethylsilyl chloride in 10 ml dimethylformamide) was added at the same temperature. To this mixture, ethyl acetate (200 ml) and water (100 ml) was added and the aqueous and organic layers were separated. Water was added again to the organic layer, and the layers were separated again. A mixture of ethyl acetate and tetrahydrofuran (1 : 1) was added to the organic layer, followed by water (100 ml). The separated organic layer was washed with a brine solution (Prepared by using 10 g sodium chloride dissolved in 100 ml Water) and concentrated under vacuum. Hexanes (200 ml) were then added to the concentrated mass and the mixture was stirred, producing a solid. The solid was filtered, washed with hexanes, and dried to yield 10-deacetyl-7-O-triethylsilyl baccatin-III. Example 2-A process for the preparation of 10-deacetyl-7-O-triethylsilyl baccatin- III

A mixture of 10-deacetyl baccatin III (20 g), dimethylformamide (60 ml), and imidazole (4.25 g) was stirred at 20-30 °C and cooled to 0-5 °C. To this, triethylsilyl chloride solution (prepared by dissolving 8.30 g triethylsilyl chloride in 10 ml dimethylformamide) was added and stirred at the same temperature. To this mixture, ethyl acetate (200 ml) and water (100 ml) was added and the organic and aqueous layers were separated. To the organic layer, water (100 ml) was added and layers were separated. A mixture of ethyl acetate and THF (1 : 1) was added to the organic layer. Next water (100 ml) was added and the organic and aqueous layer separated again. The separated organic layer was washed with brine solution (Prepared by using 10 g sodium chloride dissolved in 100 ml Water) and concentrated under vacuum. Hexanes (200 ml) were added to the concentrated mass and the mixture was stirred, producing a solid. The solid was filtered, washed with hexanes, and dried to yield 10-deacetyl-7-O-triethylsilyl baccatin-III.

Example 3-A process for the preparation of 10-β methoxy-lO-deacetoxy-7-O- triethylsilyl baccatin-ΠΙ (Formula II)

A first reaction mixture of 10-deacetyl-7-O-triethylsilyl baccatin-III (20 g), methyl iodide (100 ml), and THF (100 ml) was stirred for 30 min at room temperature and cooled to 0-5 °C. To the reaction mixture, 2 g of sodium hydride (~ 60% in liquid paraffin oil) was added and stirred. In a separate flask, a second reaction mixture of water (200 ml) and ammonium chloride (60 g) was prepared, to which ethyl acetate (560 ml) was then added. The first reaction mixture was then added to the second reaction mixture and stirred, creating an aqueous and an organic layer. Layers were separated. The organic layer was washed with water (100 ml) followed by brine solution (prepared by using 60 g Sodium chloride dissolved in 200 ml Water) and concentrated under vacuum. THF (60 ml) and heptanes (600 ml) were then added to the concentrated mass and stirred, producing a solid. The solid was filtered, washed with heptanes, and dried to yield 10-β methoxy-10- deacetoxy-7-O-triethylsilyl baccatin-II (one example of Formula-II). Example 4-A process for the preparation of ΙΟβ-methoxy-lO-deacetoxy baccatin-III (Formula III)

A mixture of 10-β methoxy-10-deacetoxy-7-O-triethylsilyl baccatin-III (20 g), pyridine (20 ml), and acetonitrile (50 ml) was stirred for 30 min at 20-30 °C and cooled to 0-5 °C. Hydrogen fluoride- pyridine complex (10 g hydrogen fluoride- pyridine complex in 50 ml acetonitrile) was then added slowly. The reaction mass temperature was raised to 20-30 °C and a pre-combined mixture of ethyl acetate (200 ml), THF (100 ml), and water (100 ml) was added. The aqueous and organic layers were separated, and water (100 ml) was added to the organic layer. The layers were again separated and water (60 ml) was again added to the organic layer. The pH of the reaction mixture was adjusted to 7-7.5 with a sodium bicarbonate solution. Layers were separated and the organic layer was then washed with brine solution (20 g Sodium chloride dissolved in 100 ml Water) and concentrated under vacuum. The obtained crude material was purified by column chromatography using a mixture of dichloromethane (350 ml) and ethyl acetate (150 ml) as an eluent. Ethyl acetate (80 ml) was then added to the concentrated mass and the mixture was stirred, producing a solid. The solid was filtered, washed with ethyl acetate, and dried to yield ΙΟβ-methoxy-lO-deacetoxy baccatin-III (Formula-Ill).

Example 5-A process for the preparation of ΙΟβ-methoxy-lO-deacetoxy baccatin-III (Formula ΠΙ)

A mixture of 10-β methoxy-10-deacetoxy-7-O-triethylsilyl baccatin-III (20 g), triethylamine (40 ml), and acetonitrile (50 ml) was stirred for 30 min at 20-30 °C and cooled to 0-5 °C. Hydrogen fluoride-pyridine complex (8 g hydrogen fluoride-pyridine in 50 ml acetonitrile) was then added slowly. The reaction mass temperature was raised to 20-30 °C, stirred at same temperature, then a pre-combined mixture of ethyl acetate (200 ml), THF (100 ml), and water (100 ml) was added. The organic and aqueous layers were separated and water (100 ml) was added to the organic layer. The organic and aqueous layers were again separated and water (60 ml) was added again to the organic layer. The pH of the reaction mixture was adjusted to 7-7.5 using sodium bicarbonate solution. Layers were separated and the organic layer was washed with brine solution (20 g Sodium chloride dissolved in 100 ml Water) and concentrated under vacuum. THF (60 ml) was added to the obtained residue, and the temperature of the reaction mass was raised to 45-55 °C. The reaction mixture was then stirred and cooled to 20-30 °C. Heptane (60 ml) was added to the reaction mixture at 20-30 °C and stirred at same temperature. The reaction mass was cooled to 0-5 °C and stirred, producing a solid. The solid was filtered, washed with heptane, and dried to yield ΙΟβ-methoxy-lO-deacetoxy baccatin-III (Formula-Ill).

Example 6-A process for the preparation of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-ΙΠ (Formula- TV)

A first reaction mixture of ΙΟβ-methoxy-lO-deacetoxy baccatin-III (5 g), methyl iodide (50 ml), and dimethyl formamide (20 ml) was stirred for 30 min at 20-30 °C and cooled to 0-5 °C. To this mixture, 0.86 g of sodium hydride (~ 60% in liquid paraffin oil w/w) was added and the mixture was stirred. In another flask, a second reaction mixture of water (80 ml) and ammonium chloride (24 g) was prepared, to which ethyl acetate (500 ml) was added. The first reaction mixture was added to the second reaction mixture and the combined mixture was stirred. The aqueous and organic layers were separated and water (80 ml) was added to the organic layer. Layers were separated and the organic layer was washed with brine solution (prepared by using 24 g Sodium chloride dissolved in 80 ml water) and concentrated under vacuum. Methanol (20 ml) was then added to the concentrated mass, and the mixture was stirred, producing a solid. The solid was filtered, washed with methanol, and dried to yield 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (Formula-IV).

Example 7-A process for the preparation of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-ΙΠ (Formula- TV)

A first reaction mixture of ΙΟβ-methoxy-lO-Deacetoxy baccatin-III (10 g), dimethyl sulfoxide (50 ml), and toluene (50 ml) was stirred for 30 min at 20-30 °C and cooled to 0 to 5 °C. To this mixture, methyl iodide (100 ml) and potassium hydroxide (2.31 g) were added and stirred at same temperature. In another flask, a second reaction mixture of water (160 ml) and ammonium chloride (24 g) was prepared, to which a mixture of dichloromethane (500 ml) and ethyl acetate (500 ml) was added. The first reaction mixture was then added to the second reaction mixture and the combined mixture was stirred. The aqueous and organic layers were separated and mixture of ethyl acetate (50 ml) and dichloromethane (75 ml) was added to the aqueous layer. Again, the aqueous and organic layers were separated and the two separated organic layers were combined into one mixture. Water (160 ml) was then added to the mixture of organic layers. Layers were separated and the organic layer was then washed with brine solution (prepared by using 48.0 g Sodium chloride dissolved in 160 ml water) and concentrated under vacuum. The obtained material was purified using column chromatography using dichloromethane and methanol (99.5:0.5) as the eluent. The eluted product was then concentrated under vacuum. THF (50 ml) was added to the concentrated mass, and temperature was raised to 65-70 °C. The reaction mass was stirred, filtered, washed with toluene, and dried to yield 7β, Ι Οβ-dimethoxy-lO-deacetyl baccatin-III (Formula-IV).

Example 8-A process for the preparation of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (Formula-IV)

A first reaction mixture of ΙΟβ-methoxy-lO-deacetoxy baccatin-III (10 g), methyl iodide (100 ml), and dimethyl sulfoxide (50 ml) was stirred for 30 min at 20-30 °C and cooled to -10 to -15 °C. To this mixture, potassium hydroxide (2.31 g) was added and the temperature was raised to 0-5 °C. In another flask, a second reaction mixture of water (160 ml) and ammonium chloride (24 g) was prepared, to which a mixture of dichloromethane (500 ml) and ethyl acetate (500 ml) was added. The first reaction mixture was then added to the second reaction mixture and the combined mixture was stirred. The aqueous and organic layers were separated and a mixture of ethyl acetate (50 ml) and dichloromethane (75 ml) was added to the aqueous layer. Again, the layers were separated and the organic layers were combined. Water (160 ml) was then added to the mixture of organic layers. Layers were separated and the organic layer was then washed with brine solution (prepared by using 48.0 g Sodium chloride dissolved in 160 ml water) and concentrated under vacuum. THF (40 ml) was added to the concentrated mass, and the mixture was stirred, producing a solid. The solid was filtered, washed with isopropyl ether, and dried to yield 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (Formula-IV).

Example 9-Purification of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (Formula-IV)

A mixture of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (3 g) and THF (30 ml) was prepared at a temperature of 25-30 °C. Next, the temperature was raised to 60-70 °C. The reaction mass was stirred for 5 hours and cooled to 25-30 °C. The solid was filtered, washed with THF, and dried under vacuum. Toluene (30 ml) was then added to the solid. The toluene was then distilled out under vacuum and the remaining mass dried to yield 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III.

Example 10-A process for the preparation of 4a-acetoxy-2a-benzoyloxy-5p, 20- epoxy-ip-hydroxy, 7β, 10p-dimethoxy-9-oxo-ll-taxene-13a-yl (2R, 4S, 5R)-3-tert- butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l, 3-oxazolidine-5-carboxylate (Formula- VI)

(2R, 4S, 5R)-3-tert-butoxycabonyl -2-(4-methoxy phenyl)-4-phenyl-l-3-oxazolodine-5- carboxylic acid (6.1 g) was added to a mixture of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (4 g), toluene (200 ml), dimethylaminopyridine (0.925 g), and Ν,Ν'- dicyclohexylcarbodiimide (3.93 g) and stirred at a temperature of 20-30 °C. A hydrochloric acid solution (35% of 1.2 ml of aqueous hydrochloride acid in 20 ml of ethyl acetate) was added to this mixture and reaction mass was filtered through a Hyflo bed. A sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was added to the filtrate and the organic and aqueous layers were separated. A sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was again added to the organic layer and again, the layers were separated. Water (40 ml) was then added to the organic layer, and again, the layers were separated. The organic layer was washed with brine solution (Prepared by using 12 g Sodium chloride dissolved in 40 ml Water) and dried. Activated carbon (0.4 g) was added to the filtered solution and the mixture was stirred. The solution was filtered through a Hyflo bed with toluene to remove the carbon. The filtrate was concentrated under vacuum, after which a mixture of ethyl acetate (40 ml) and heptanes (200 ml) was added, producing a solid. The solid was filtered, washed with heptanes, and dried to yield 4a-acetoxy-2a-benzoyloxy-5p, 20- epoxy-ΐ β- hydroxy, 7β, 10P-dimethoxy-9-oxo-l l-taxene-13a-yl (2R, 4S, 5R)-3-tert- butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l , 3-oxazolidine-5-carboxylate (Formula- VI). Example 11-A process for the preparation of 4a-Acetoxy-2a-benzoyloxy-5p, 20- epoxy-iphydroxy, 7β, 10p-dimethoxy-9-oxo-ll-taxene-13a-yl (2R, 4S, 5R)-3-tert- butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l, 3-oxazolidine-5-carboxylate (Formula- VI)

(2R, 4S, 5R)-3-tert-butoxycabonyl -2-(4-methoxy phenyl)-4-phenyl-l-3-oxazolodine-5- carboxylic acid (6.1 g) was added to a mixture of 7β, ΙΟβ-dimethoxy-lO-deacetyl baccatin-III (4 g), toluene (200 ml), dimethylaminopyridine (0.925 g), and Ν,Ν'- dicyclohexylcarbodiimide (3.93 g) and stirred at a temperature of 20-30 °C. A hydrochloric acid solution (35 % of 1.2 ml of aqueous hydrochloric acid in 20 ml of ethyl acetate) was added to this mixture and reaction mass was filtered through a Hyflo bed. Sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was added to the filtrate and aqueous and organic layers were separated. Sodium bicarbonate solution (2.4 g sodium bicarbonate dissolved in 40 ml of water) was added to the organic layer and again, the layers were separated. Water (40 ml) was then added to the organic layer, and again, the layers were separated. The organic layer was washed with brine solution (Prepared by using 12 g Sodium chloride dissolved in 40 ml Water) and dried. Activated carbon (0.4 g) was added to the filtered solution and the mixture was stirred. The solution was filtered through a Hyflo bed with toluene to remove the carbon. The filtrate was concentrated under vacuum and tert-butyl methyl ether (40 ml) was added, producing a solid. The solid was filtered, washed with tert-butyl methyl ether, and dried to yield 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-ip-hydroxy, 7β, 10P-dimethoxy-9-oxo- l l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l, 3-oxazolidine-5-carboxylate.

Example 12-Purification of 4a-Acetoxy-2a-benzoyloxy-5p, 20-epoxy-ip-hydroxy, 7β, 10p-dimethoxy-9-oxo-ll-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4- methoxyphenyl)-4-phenyl-l, 3-oxazolidine-5-carboxylate (Formula- VI)

A mixture of 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-iphydroxy, 7β, 10P-dimethoxy-9- oxo-1 l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- phenyl-1, 3-oxazolidine-5-carboxylate (4 g) and tert-butyl methyl ether (40 ml) was prepared at a temperature of 20-30 °C. The temperature was raised to 40-50 °C. The reaction mass was stirred for 2 to 5 hours and then cooled to 20-30 °C, producing a solid. The solid was filtered, washed with tert-butyl methyl ether, and dried under vacuum to yield 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-iphydroxy, 7β, 10P-dimethoxy-9-oxo- 11 - taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-l, 3- oxazolidine- 5 - carboxy late.

Example 13-A process for the preparation of cabazitaxel

A mixture of 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-i p- hydroxy, 7β, 1 Οβ-dimethoxy- 9-oxo-l l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- phenyl-1, 3-oxazolidine-5-carboxylate (3.7 g) and ~ 0.2 N hydrochloric acid in ethanol (89 ml) was stirred under nitrogen atmosphere at a temperature of 0-5 °C. Dichloromethane (150 ml) and sodium bicarbonate solution (7.0 g sodium bicarbonate dissolved in 56 ml of water) was added to the reaction mass. The aqueous and organic layers were separated and a sodium bicarbonate solution (Prepared by using 7.0 g Sodium bicarbonate dissolve in 56 ml water) was added to the organic layer. Layers were separated and sodium bicarbonate solution (Prepared by using 7.0 g Sodium bicarbonate dissolve in 56 ml water) was added again to the organic layer and again, the layers were separated. This process was repeated once more, adding water to the organic layer water and then separating the two layers. The organic layer was washed with brine solution (Prepare by using 16.8 g Sodium chloride dissolved in 56 ml Water). The organic layer was concentrated under vacuum and crystallized from isopropyl acetate (19 ml) to yield cabazitaxel.

Example 14-process for the preparation of cabazitaxel

A mixture of 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-i p- hydroxy, 7β, 1 Οβ-dimethoxy- 9-oxo-l l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- phenyl-1, 3-oxazolidine-5-carboxylate (3.7 g) and ~ 0.2 N hydrochloric acid in ethanol (89 ml) was stirred under nitrogen atmosphere at a temperature of 0-5 °C. Dichloromethane (150 ml) and sodium bicarbonate solution (7.0 g sodium bicarbonate dissolved in 56 ml of water) was added to the reaction mass. The aqueous and organic layers were separated and sodium bicarbonate solution (7.0 g sodium bicarbonate dissolved in 56 ml of water) was added to the organic layer. Layers were separated and sodium bicarbonate solution was added again to the organic layer and again, the layers were separated. Water (56 ml) was then added to the organic layer and once again, the aqueous and organic layers were separated. The organic layer was then washed with brine solution (Prepared by using 16.8 g Sodium chloride dissolved in 56 ml Water). The organic layer was concentrated under vacuum and anisole (30 ml) was added. The solid was filtered, washed with anisole, and dried to yield cabazitaxel.

Example 15-Process for the preparation of cabazitaxel

A mixture of 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-i p- hydroxy, 7β, 1 Οβ-dimethoxy- 9-oxo-l l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- phenyl-1, 3-oxazolidine-5-carboxylate (1 g) and ~ 0.2 N hydrochloric acid in ethanol (24 ml) was stirred under nitrogen atmosphere at a temperature of 0-5 °C. Dichloromethane (40 ml) and sodium bicarbonate solution (1.9 g sodium bicarbonate dissolved in 15 ml of water) was added to the reaction mass. The organic and aqueous layers were separated and a sodium bicarbonate solution was added again to the organic layer. This process was repeated yet again, and the aqueous and organic layers were separated. Water (56 ml) was added to the organic layer and again, the layers were separated. The organic layer was washed with brine solution. The organic layer was concentrated under vacuum and a mixture of dichloromethane and benzyl alcohol (1 : 1) was added The solid was filtered, washed with benzyl alcohol, and dried to yield cabazitaxel

Example 16-Purification of cabazitaxel

A mixture of cabazitaxel (6.5 g) and ethyl acetate (49 ml) was prepared at a temperature of 20-30 °C. The temperature was then raised to 50-80 °C. The reaction mixture was stirred and cooled to 20-30 °C. The solid was filtered, washed with ethyl acetate, and dried to yield cabazitaxel.

Example 17-Process for the preparation of cabazitaxel anisole solvate

A mixture of 4a-acetoxy-2a-benzoyloxy-5P, 20-epoxy-i p- hydroxy, 7β, 1 Οβ-dimethoxy- 9-oxo-l l-taxene-13a-yl (2R, 4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4- phenyl-1, 3-oxazolidine-5-carboxylate (3.7 g) and ~ 0.2 N hydrochloric acid in ethanol (89 ml) was stirred under nitrogen atmosphere at a temperature of 0-5 °C. Dichloromethane (150 ml) and sodium bicarbonate solution (7.0 g sodium bicarbonate dissolved in 56 ml of water) was added to the reaction mass. The aqueous and organic layers were separated and sodium bicarbonate solution (7.0 g sodium bicarbonate dissolved in 56 ml of water) was added to the organic layer. Layers were separated and sodium bicarbonate solution was added again the organic layer and again, the layers were separated. Water (56 ml) was added to the organic layer water and layers were again separated. The organic layer was washed with brine solution. The organic layer was concentrated under vacuum and anisole (30 ml) was added, producing a solid. The solid was filtered and washed with anisole (8 ml). Wet solid was dissolved into a mixture of anisole (16 ml) and p-methoxy benzaldehyde (3 ml). The temperature of the reaction mass was raised to 75-85 °C, stirred, then cooled to 20-30 °C, filtered, then washed with anisole. Wet solid was dissolved in dichloromethane (20 ml) and the reaction mass was filtered. Anisole (5 ml) was added to the filtrate which was then concentrated under vacuum to remove the dichloromethane. Anisole (20 ml) was added to the concentrate and the temperature was raised to 75-85 °C. The reaction mass was stirred and then cooled to 20-30 °C. The reaction mass was filtered, washed with anisole, and dried to yield cabazitaxel anisole solvate. Example 18-A process for the preparation of cabazitaxel anisole solvate

Cabazitaxel (1.0 g) was dissolved in a mixture of dichloromethane (5 ml) and anisole (5 ml). The reaction mass was concentrated under reduced pressure at < 40°C and then the temperature of the reaction mass was raised to 30-82 °C. The reaction mixture was stirred and cooled to 0-5 °C, producing a solid. The solid was filtered, washed with anisole, and dried to yield cabazitaxel anisole solvate.

Example 19-A process for the preparation of cabazitaxel from cabazitaxel anisole solvate

Cabazitaxel anisole solvate (0.28 g) was dissolved in dichloromethane (10 ml) and purified by using column chromatography (eluent: dichloromethane and methanol). After collecting the product fraction, the product in eluent was filtered and concentrated under pressure to yield cabazitaxel. Example 20-A process for the preparation of cabazitaxel benzyl alcohol solvate

Cabazitaxel (1.3 g) was dissolved in a mixture of dichloromethane (15 ml) and benzyl alcohol (10 ml). The reaction mass was concentrated under reduced pressure at < 45°C and the temperature of the reaction mass was raised to 45-50 °C. The reaction mixture was stirred and cooled to 25-30 °C, producing a solid. The solid was filtered, washed with benzyl alcohol, and dried to yield cabazitaxel benzyl alcohol solvate.

Example 21-A process for the preparation of cabazitaxel from cabazitaxel benzyl alcohol solvate

Cabazitaxel benzyl alcohol solvate (0.9 g) was dissolved in dichloromethane (10 ml) and purified by using column chromatography (eluent: Dichloromethane and methanol). After collecting the product fraction, the eluent was filtered and concentrated under reduced pressure to yield cabazitaxel.

Example 22-A process for the preparation of cabazitaxel acetone solvate A mixture of cabazitaxel (5 g), water (22.5 ml), and acetone (47.5 ml) was prepared at a temperature of 25-30 °C and stirred. Water (25 ml) was then added and stirring continued to produce a solid. The solid was filtered, washed with acetone, and dried to yield cabazitaxel acetone solvate. Example 23-A process for the preparation of cabazitaxel from cabazitaxel anisole solvate

Cabazitaxel anisole solvate (10 g) was dissolved in dichloromethane (50 ml) and silica gel (10 g) was added. The slurry was concentrated under vacuum to get a mixture of silica gel and Cabazitaxel anisole solvate. Column was loaded with silica gel (70 g) by using dichloromethane (100 ml) and obtained mixture of silica gel and Cabazitaxel anisole solvate. Column was eluted with dichloromethane (500 ml), mixture of dichloromethane and methanol (99.5:0.5) followed by mixture of dichloromethane (900 ml) and methanol (100 ml). Product fractions are collected and concentrated under vacuum to yield cabazitaxel.

Claims

WE CLAIM:

A cabazitaxel anisole solvate.

The cabazitaxel anisole solvate of claim 1 , which has a powder X-ray diffraction pattern having significant peaks at 2-theta angles of about 7.91, 10.06, 13.84, 14.04, 17.31, 17.79, 20.28, 22.54, and 23.88 ± 0.2°

The cabazitaxel anisole solvate of claim 1 , which has a powder X-ray diffraction pattern as depicted in Figure 1.

A cabazitxel benzyl alcohol solvate.

The cabazitaxel benzyl alcohol solvate of claim 4, which has a powder X-ray diffraction pattern having significant peaks at 2-theta angles of about 7.96, 10.13, 13.99, 14.90, 15.97, 17.30, 19.79, 20.44, 22.63, and 23.98 ± 0.2°.

The cabazitaxel benzyl alcohol solvate of claim 4, which has a powder X-ray diffraction pattern as depicted in Figure 4.

A process for the preparation of cabazitaxel or its solvates comprising the steps of:

reacting Formula-II with a hydrogen fluoride/organic base compl give Formula-Ill;

Formula-II Formula-Ill wherein P is suitable hydroxy protecting group;

b. selectively methylating Formula-Ill in the presence of a methylating agent and a second base to give Formula-IV;

Fonnula-III Formula-IV c. condensing Formula-IV with Formula-V to get Formula- VI with a suitable condensing agent; and

Formula-IV Formula- VI converting Formula- VI to cabazitaxel of Formula-I in the presence of inorganic acid or an organic acid.

8. The process according to claim 7, wherein the hydrogen fluoride/organic base complex includes a base selected form the group consisting of pyridine, dimethylaminopyridine, and an amine.

9. The process according to claim 8, wherein the amine is selected from the group consisting of triethylamine and diisopropylethylamine.

10. The process according to claim 7, wherein P is selected from the group consisting of an alkyl group, aryl group, arylalkyl group, trialkylsilyls group, or diarylalkylsilyl group.

11. The process according to claim 10, wherein the triaklylsilyl group is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOMS), and triisopropylsilyl (TIPS).

12. The process according to claim 10, wherein the diarylaklylsilyl group is diphenyl(tert-butyl)silyl.

13. The process according to claim 7, wherein the second base used in step b is selected from the group consisting of alkali metal hydrides and alkali metal hydroxides.

14. The process according to claim 10, wherein the alkali metal hydride is selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, calcium hydride, and magnesium hydride.

15. The process according to claim 10, wherein the alkali metal hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide.

16. The process according to claim 7, wherein the methylating agent is selected from the group consisting of dimethyl sulfate, trimethyl oxonium salt, or a methyl halide.

17. The process according to claim 13, wherein the methyl halide is selected from the group consisting of methyl iodide, methyl bromide, methyl fluoride, and methyl chloride.

18. The process according to claim 7, wherein the condensing agent used in step c is selected from the group consisting of di-2-pyridyl carbonate (DPC) and a carbodiimide.

19. The process according to claim 15, wherein the carbodiimide is selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIPC), and ethyl-(N-N'-dimethyl aminopropyl carbodiimide (EDC).

20. The process according to claim 15, wherein the condensation reaction is carried out in the presence of a catalyst.

21. The process according to claim 20, wherein the catalyst is selected from the group consisting of hydroxybenzotriazole and an aminopyridine.

22. The process according to claim 21, where in the aminopyridine is selected from the group consisting of dimethylaminopyridine and pyrrolidinopyridine.

23. The process according to claim 7, wherein the inorganic acid used in step d, is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid.

24. The process according to claim 7, wherein the organic acid used in step d, is selected from the group consisting of acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, and p-toluenesulphonic acid.