DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

INTRODUCTION
Aspects of the present application provide processes for the purification of cabazitaxel.
BACKGROUND OF THE INVENTION
The drug compound known as “Cabazitaxel” has chemical names: (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxy carbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate; or 4-acetoxy-2a-benzoyloxy-5ß,20-epoxy-1ß-hydroxy,7ß,10ß-dimethoxy-9-oxo-11-taxen-13a-yl-(2R,3S)-3-t-butoxycarbonyl amino-3-phenyl-2-hydroxy propionate; or “7,10-dimethoxy docetaxel”. It has the structure of formula (I).

(I)
Cabazitaxel is an antineoplastic agent belonging to the taxane class. The commercial product sold as JEVTANA® Injection contains, as the active ingredient, an acetone solvate of cabazitaxel having the chemical name (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl} oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate-propan-2 -one(1:1).
U.S. Patent No. 5,847,170 discloses processes for the preparation of cabazitaxel and its intermediates. One of the processes for the preparation of cabazitaxel involves alkylation of the 7,10-hydroxy groups of 10-deacetylbaccatin III by a four step reaction sequence including silylation of 7,13-hydroxyl groups of 10-deacetylbaccatin III, alkylation of the 10-hydroxyl group, deprotection of silyl groups at 7,13 position, alkylation of the 7-hydroxyl group to give 7,10-dimethoxy-10-deacetylbaccatin III, which in subsequent steps is converted to cabazitaxel or its pharmaceutically acceptable salt. The other process for the preparation of cabazitaxel or its intermediate involves alkylation of the 7,10-hydroxy groups of 10-deacetylbaccatin III or its derivative by “Pummerer-type reaction”
U.S. Patent No. 5,962,705, describes a process for the direct alkylation of hydroxyl functions at the 7 and 10 position of a compound of formula:

wherein A represents hydrogen, a side chain of formula

wherein the alkylation is carried out in the presence of a alkylating agent selected from alkyl halide, an alkyl sulphate, or an oxonium and an anionization agent selected from a strong base, in organic medium which is inert under the reaction conditions, preferably ethers, polar aprotic solvents, aromatic solvents, and esters. However, according to the examples provided, it is observed that the alkylation process is not consistent and has drawbacks as it requires larger duration of time (for e.g., upto 24 hours) or has poor conversion rate (for e.g., 16.3%) or involves lower temperatures (for e.g., upto -78 °C).
China patent application No. CN 102060815 A describes a process for the preparation of cabazitaxel which involves direct O-alkylation of docetaxel.
U.S. Patent No. 7,241,907 discloses a process for the preparation of acetone solvate of 7,10-dimethoxy docetaxel which involves crystallization from a mixture of water and acetone.
U.S. Patent Application No. US2011/0144362 A1 describes different crystalline forms of 7,10-dimethoxy docetaxel. International application Publication No.WO2012/142117 A1 discloses various crystalline forms of cabazitaxel designated as Form I, Form II, Form III, Form IV and Form V. Further, it also discloses processes for the preparation of said forms which involves the use of solvent such as toluene, propanol, butanol and methyl t-butyl ether. Furthermore, it also discloses amorphous cabazitaxel in a powdery, non- foamy form and process for its preparation.
Chinese patent application No. CN 102,659,722 discloses a method for the preparation of amorphous cabazitaxel from an organic solvent and water.
Chinese patent application No. CN 1,02,675,257 discloses crystal forms of 7, 10-dimethoxy docetaxel and process for its preparation from acetone and water.
Chinese patent application No. CN 1,02,746,258 discloses crystalline forms of cabazitaxel designated as Form J, Form G and Form I. Further, it also discloses process for the preparation of crystalline Form J which involves crystallization from a C1-C6 ester; process for form G which involves crystallization from C1-C5 halogenated alkane or/and C1-C4 alcohol and process for form I which involves crystallization from .dichloromethane and cyclohexane.
PCT application publication Nos. WO2012/142117, WO2013/065070, WO2013/069027, WO2013/034979, WO2013/088335, WO 2013/080217; Chinese patent application No. CN 103044364, CN 103058960 also describes various processes for the preparation and purification of cabazitaxel.
Despite the existence of various processes for the preparation and purification of cabazitaxel, there remains a need for providing improved processes which provide consistent yield, purity and are suitable for industrial production.
SUMMARY OF THE INVENTION
An aspect of the present application relates to process for purification of cabazitaxel, which comprises:
a) obtaining a solution of cabazitaxel in an alcohol solvent;
b) crystallizing a solid from the solution of step a) by combining with solvent mixture of an ketone solvent, an ether solvent and an water;
c) isolating the obtained crystalline solid.
Another aspect of the present application relates to process for purification of cabazitaxel, which comprises:
a) obtaining a solution of cabazitaxel in an ketone solvent;
b) crystallizing a solid from the solution of step a) by combining with an solvent mixture consisting of an alcohol solvent, an ether solvent and an water;
c) isolating the obtained crystalline solid.
Another aspect of the present application relates to process for purification of cabazitaxel, which comprises:
a) obtaining a solution of cabazitaxel in an ketone solvent;
b) crystallizing a solid from the solution of step a) by combining with an solvent mixture consisting of an alcohol solvent, an aliphatic hydrocarbon solvent and an water;
c) isolating the obtained crystalline solid.
Another aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) obtaining a solution of cabazitaxel in an C1-C6 ester solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
Another aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a ketone solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
Another aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a nitrile solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustrative example of a X-ray powder diffraction pattern of cabazitaxel, prepared according to Example 2.
Figure 2 is an illustrative example of a DSC pattern of cabazitaxel, prepared according to Example 2.
Figure 3 is an illustrative example of a TGA pattern of cabazitaxel, prepared according to Example 2.
Figure 4 is an illustrative example of a X-ray powder diffraction pattern of cabazitaxel, prepared according to Example 3.
Figure 5 is an illustrative example of a DSC pattern of cabazitaxel, prepared according to Example 3.
Figure 6 is an illustrative example of a TGA pattern of cabazitaxel, prepared according to Example 3.
Figure 7 is an illustrative example of an X-ray powder diffraction pattern of cabazitaxel, prepared according to Example 4.
Figure 8 is an illustrative example of a DSC pattern of cabazitaxel, prepared according to Example 4.
Figure 9 is an illustrative example of a TGA pattern of cabazitaxel, prepared according to Example 4.
DETAILED DESCRIPTION
An aspect of the present application relates to process for purification of cabazitaxel, which comprises:
a) obtaining a solution of cabazitaxel in an alcohol solvent;
b) crystallizing a solid from the solution of step a) by combining with solvent mixture of an ketone solvent, an ether solvent and an water;
c) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolution of cabazitaxel in a alcohol solvent, or may be obtained from a process by which the compound is prepared. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
Alcohol solvent that may be used in for obtaining the solution of Cabazitaxel include, but are not limited, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol. In embodiments, methanol is used.
The concentration of cabazitaxel in the solution is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
In an embodiment, the solution of Cabazitaxel in methanol may be stirred for about 4 hours to about 8 hours at 25-30°C for reducing the impurity at 1.12 RRT to desirable pharmaceutically acceptable limit or may be converting the impurity at 1.12 to Cabazitaxel.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
Step b) involves crystallizing a solid from the solution of step a) by combining with solvent mixture of an ketone solvent, an ether solvent and an water.
Adding the solution of step a) to solvent mixture of an ketone solvent, an ether solvent and an water., or adding solvent mixture of an ketone solvent, an ether solvent and an water to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Ketone solvent that may be used for crystallization of cabazitaxel include, but are not limited to, acetone, butanone, ethyl isopropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 3-pentanone. In embodiments, acetone is used.
Ether solvents that may be used for obtaining the solution of cabazitaxel include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
In an embodiment, step b) of crystallizing a solid from the solution of step a) involves combining with solvent mixture of acetone, diisopropyl ether and water.
The cabazitaxel solution can be combined with the desired solvent mixture at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
In an embodiment solvent used for washing is selected from, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
Another aspect of the present application relates to process for purification of cabazitaxel, which comprises:
a) obtaining a solution of cabazitaxel in an ketone solvent;
b) crystallizing a solid from the solution of step a) by combining with an solvent mixture consisting of an alcohol solvent, an ether solvent and an water;
c) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolution of cabazitaxel in a ketone solvent, or may be obtained from a process by which the compound is prepared. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
Ketone solvent that may be used in for obtaining the solution of Cabazitaxel include, but are not limited, acetone, butanone, ethyl isopropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 3-pentanone. In embodiments, acetone is used.
The concentration of cabazitaxel in the solution is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
Step b) involves crystallizing a solid from the solution of step a) by combining with solvent mixture of an alcohol solvent, an ether solvent and an water.
Adding the solution of step a) to solvent mixture of an alcohol solvent, an ether solvent and an water., or adding solvent mixture of an alcohol solvent, an ether solvent and an water to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Alcohol solvent that may be used for crystallization of cabazitaxel include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol. In embodiments, methanol is used.
Ether solvents that may be used for obtaining the solution of cabazitaxel include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
In an embodiment, step b) of crystallizing a solid from the solution of step a) involves combining with solvent mixture of methanol, diisopropyl ether and water.
The cabazitaxel solution can be combined with the desired solvent mixture at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
In an embodiment solvent used for washing is selected from, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
Another aspect of the present application relates to process for purification of cabazitaxel, which comprises:
obtaining a solution of cabazitaxel in an ketone solvent;
a) crystallizing a solid from the solution of step a) by combining with an solvent mixture consisting of an alcohol solvent, an alkane solvent and an water;
b) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolution of cabazitaxel in a ketone solvent, or may be obtained from a process by which the compound is prepared. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
Ketone solvent that may be used in for obtaining the solution of Cabazitaxel include, but are not limited, acetone, butanone, ethyl isopropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, 3-pentanone. In embodiments, acetone is used.
The concentration of cabazitaxel in the solution is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
Step b) involves crystallizing a solid from the solution of step a) by combining with solvent mixture of an alcohol solvent, an aliphatic hydrocarbon solvent and an water.
Adding the solution of step a) to solvent mixture of an alcohol solvent, an aliphatic hydrocarbon solvent and an water., or adding solvent mixture of an alcohol solvent, an aliphatic hydrocarbon solvent and an water to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Alcohol solvent that may be used for crystallization of cabazitaxel include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol. In embodiments, methanol is used.
Alkane solvent that may be used for crystallization of cabazitaxel include, but are not limited to, n-pentane, n-hexane, n-heptane, n-octane. In embodiments, n-heptane is used.
In an embodiment, step b) of crystallizing a solid from the solution of step a) involves combining with solvent mixture of methanol, n-heptane and water.
The cabazitaxel solution can be combined with the desired solvent mixture at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
In an embodiment solvent used for washing is selected from, but are not limited to, n-pentane, n-hexane, n-heptane, n-pentane, water. In embodiments, n-heptane and water is used.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
An aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) obtaining a solution of cabazitaxel in a C1-C6 ester solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolution of cabazitaxel in a C1-C6 ester solvent, or may be obtained from a process by which the compound is prepared. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
C1-C6 ester solvent that may be used for obtaining the solution of cabazitaxel include, but are not limited to, ethylacetate, methylacetate, isopropyl acetate.
The concentration of cabazitaxel in the solution is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
Step b) involves crystallizing a solid from the solution of step a) by combining with an ether solvent.
Adding the solution of step a) to an ether solvent, or adding an ether solvent to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Ether solvents that may be used for obtaining the solution of cabazitaxel include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
The cabazitaxel solution can be combined with the desired ether solvent at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
Another aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a ketone solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolving cabazitaxel in a solvent mixture consisting of a ketone solvent and a halogenated hydrocarbon solvent. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
Ketone solvent that may be used for obtaining the solution of cabazitaxel include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone.
Halogenated hydrocarbon that may be used for obtaining the solution of cabazitaxel include, but are not limited to, dichloromethane, chloroform.
The concentration of cabazitaxel in the solution mixture is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent mixture chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
In an embodiment, a solution of cabazitaxel is obtained by dissolving cabazitaxel in a solvent mixture consisting of ketone and dichloromethane.
Step b) involves crystallizing a solid from the solution of step a) by combining with an ether solvent.
Adding the solution of step a) to an ether solvent, or adding an ether solvent to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Ether solvents that may be used for obtaining the solution of cabazitaxel include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
The cabazitaxel solution can be combined with the desired ether solvent at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
Another aspect of the present application relates to process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a nitrile solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
The solution of cabazitaxel may be obtained by the dissolving cabazitaxel in a solvent mixture consisting of a nitrile solvent and a halogenated hydrocarbon solvent. Any form of cabazitaxel, such as any crystalline or amorphous form of cabazitaxel, obtained by any method; is acceptable for providing the solution.
Nitrile solvent that may be used for obtaining the solution of cabazitaxel include, but are not limited to, acetonitrile, propionitrile and the like. In an embodiment, nitrile is acetonitrile.
Halogenated hydrocarbon that may be used for obtaining the solution of cabazitaxel include, but are not limited to, dichloromethane, chloroform.
The concentration of cabazitaxel in the solution mixture is not critical as long as sufficient solvent is employed to ensure total dissolution. The solution may be prepared by combining cabazitaxel with the solvent mixture chosen at room temperature, and optionally heating to the desired temperature of dissolution, or by adding cabazitaxel to a pre-heated solvent.
The solution may be prepared at temperatures ranging from about 25°C to the boiling point of the solvent chosen, depending on the solvent and quantity used.
The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization. Optionally the solution may be concentrated to the desired extent to decrease the solvent content.
In an embodiment, a solution of cabazitaxel is obtained by dissolving cabazitaxel in a solvent mixture consisting of acetonitrile and dichloromethane.
Step b) involves crystallizing a solid from the solution of step a) by combining with an ether solvent.
Adding the solution of step a) to an ether solvent, or adding an ether solvent to the solution of step a), to initiate crystallization process are both within the scope of the present application.
Ether solvents that may be used for obtaining the solution of cabazitaxel include, but are not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether. In embodiments, diisopropyl ether is used.
The cabazitaxel solution can be combined with the desired ether solvent at temperatures ranging from about 5°C to 40°C. The temperatures at which a solid precipitates depend on the solvents and their quantities used. Optionally, the suspension obtained may be cooled to the desired temperature and may then be stirred depending upon the desired extent of precipitation.
Step c) involves isolating the obtained crystalline solid. The solid may be isolated by conventional techniques known in the art. For example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with a suitable solvent.
The isolated solid may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures about 25°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity and a constant weight.
In an aspect, the present application provides pharmaceutical compositions comprising Cabazitaxel prepared according to the above invention, together with one or more pharmaceutically acceptable excipients.
In an embodiment, the processes of the present application provides cabazitaxel having a purity greater than about 99.5% as determined using HPLC.
In another aspect, the present application provides cabazitaxel having purity greater than about 99.5%, preferably greater than 99.8% and less than about 0.01% of CBT-1A Impurity and less than 0.1% of CBT-2A Impurity as determined using HPLC.
In another aspect, the present application provides cabazitaxel having purity greater than about 99.9% and less than about 0.07% of amino alcohol Impurity as determined using HPLC.
In yet another aspect, the present application provides cabazitaxel having purity greater than about 99.8% and with less than about 0.1% of each of the compound given in the table below:

Code Structure
CBT-1A Impurity

CBT-2A Impurity

Amino Alcohol Impurity

Trimethoxy 10-DAB-III Impurity

N-Formyl Impurity

Di BOC Impurity

2’, 3’ Isomeric impurity

The purity of cabazitaxel and its related substances or impurities may be analyzed using various methods. A representative useful HPLC method is described below.
Column: YMC Pack ODS-A, 150 x 4.6 mm, 3 µm
Column temperature: 30 ± 2 °C
Injection volume: 15 µL
Diluent: Acetonitrile, Water, and Methanol (50:30:20 %v/v/v)
Run time: 85 min
Mobile Phase A: Mix methanol and acetonitrile in the ratio of 80:10:10(%v/v/v) filter and degass.
Mobile Phase B: Mix acetonitrile and water in the ratio of 90:10(%v/v), filter and degass.
Flow rate: 1.0 mL/min
Wavelength of detection: 230 & 210 nm
Program: Gradient
Gradient program:
Time (min) %A %B
0 75 25
5 75 25
35 50 50
65 15 85
75 15 85
76 75 25
85 75 25

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES
EXAMPLE 1: Preparation of (4S,5R)-5-((2aR,4S,4aS,6R,9S,11S,12S,12bS)-12b-acetoxy-12-(benzoyloxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4] benzo[1,2-b]oxet-9-yl)3-tert-butyl 2,2-dimethyl-4-phenyloxazolidine-3,5-dicarboxylate
(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid (75.6 g) and tetrahydrofuran (1080 mL) are charged into a round bottom flask at 25-30°C and the mixture is cooled to 10-15°C. 4-Dimethylamino pyridine (19.17 g), ethyl acetate (180 mL) are added to the reaction mixture and stirred for 5 minutes. N,N’-dicyclohexylcarbodiimide (97.2 g) and ethyl acetate (360 mL) are added and stirred the reaction mixture about 30 minutes. 7,10-dimethoxy-10-deacetylbaccatin III (90 g) and ethyl acetate (180 mL) are added to the reaction mixture, stirred at 10-15°C for 4 hours, filtered, and washed with ethyl acetate (200 mL). The filtrate obtained is charged into a round bottom flask, 1N hydrochloric acid (1800 mL) is added and stirred for 10 minutes. The organic layer is separated, charged into a round bottom flask, 7% saturated solution sodium bicarbonate solution (1800 mL) is added and stirred for 10 minutes. The organic layer is separated, charged into a round bottom flask, 10% saturated solution sodium chloride solution (1800 mL) is added and stirred for 10 minutes. The organic layer is separated, concentrated under vacuum to obtain about 450 mL of concentrated mass. N-heptane (1800 mL) is added to the concentrated mass, stirred for 60 minutes, filtered the obtained solid, washed with n-heptane, suction dried for 30 minutes and dried under vacuum at 48°C for 3 hours to give the title compound.
Yield: 134 g; Purity by HPLC: 96.06%
EXAMPLE 2: Preparation of cabazitaxel of formula (I)
(4S,5R)-5-((2aR,4S,4aS,6R,9S,11S,12S,12bS)-12b-acetoxy-12-(benzoyloxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca [3,4]benzo[1,2-b]oxet-9-yl) 3-tert-butyl 2,2-dimethyl-4-phenyloxazolidine-3,5-dicarboxylate (4 g) and formic acid (80 mL) are charged into the round bottom flask at 15-20°C and stirred the reaction mixture for 4 hours. Water (100 mL), 10% sodium chloride solution (100 mL) and ethyl acetate (100 mL) are added to the above reaction mixture at 25-30°C and stirred for 15 minutes. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layer is washed with saturated 10% sodium chloride solution (100 mL x 2) and organic layer is separated. The obtained organic layer and water (100 mL) are charged into round bottom flask at 15-20°C and the pH of the reaction mass is adjusted to 7.5-8.0 using sodium bicarbonate (32 g) at 15-20°C. The obtained reaction mass is stirred at 10-15°C for 60 minutes and bottom aqueous layer is separated. The reaction mass is washed with water (100 mL) and separated the bottom aqueous layer. Water (100 mL) is charged into the reaction mass and pH of the reaction mass is adjusted to 7.0 to 8.0 using sodium bicarbonate (8.0 g). Di-tert-butyl dicarbonate (1.88 mL) is added to the above reaction mixture at 15-20°C and stirred for 12 hours. The organic layer is separated, washed the organic layer with 10% sodium chloride solution (100 mL) and concentrated under vacuum to obtain 12 mL (3-5 volumes) of the concentrated mass. Diisopropyl ether (60 mL) is added to the reaction mass at 25-30°C and stirred for 1 hour. The obtained solid is filtered, washed with diisopropyl ether (8 mL), suction dried under vacuum completely for 15-30 minutes to give the title compound.
PXRD: Figure 1; DSC: Figure 2; TGA: Figure 3;
Residual solvents: Ethyl acetate: 5.9%, Diisopropyl ether: 5.8%
EXAMPLE 3: Purification of cabazitaxel using methanol/acetone/diisopropyl ether/Water
Cabazitaxel (obtained above) and methanol (12 mL) are charged into the round bottom flask at 25-30°C and stirred for 5-8 hours. Acetone (12 mL), Diisopropyl ether (50 mL) and Water (50 mL) are charged into the above solution at 25-30°C and stirred for 14-18 hours. The obtained solid is filtered, washed with diisopropyl ether (10 mL) and suck dried under vacuum completely. (Residual solvents: acetone: 0.4%, diisopropyl ether: 4.7%, ethyl acetate: 0.06%).The obtained compound and acetone (13.6 mL) are charged into a round bottom flask at 25-30°C, stirred for 15-30 minutes and filtered. The obtained filtrate is charged into the round bottom flask at 25-30°C. Methanol (13.6 mL), diisopropyl ether (42.5 mL) and water (42.5 mL) are charged into the above filtrate at 25-30°C and stirred for 14-16 hours. The obtained solid is filtered, washed with diisopropyl ether (8.5 mL), suck dried under vacuum and dried under vacuum below 50°C to give the pure Cabazitaxel.
Yield: 1.45 g (38%); Water Content (KF): 0.22; PXRD: Figure 4; DSC: Figure 5
TGA: Figure 6;
Residual solvents: Acetone: 1.0%, Diisopropyl ether: 9.1%, Ethyl acetate: 0.05%
EXAMPLE 4: Purification of cabazitaxel using acetone/methanol /n-heptane/Water
Cabazitaxel (11 g) and acetone (66 mL) are charged into the round bottom flask at 25-30°C and stirred for 10-15 minutes. The obtained solution is filtered and filtrate is charged into the round bottom flask at 25-30°C. Methanol (66 mL), n-heptane (275 mL) and water (275 mL) are charged into the round bottom flask at 25-30°C and stirred for 16-18 hours. The obtained precipitate is filtered, washed with n-heptane (55 mL) followed by water (55 mL), suck dried and dried at 70°C under vacuum to give the pure Cabazitaxel.
Yield: 9.5 g (86.3%); Purity by HPLC: 99.69%; Water Content (KF): 0.85%
PXRD: Figure 7; DSC: Figure 8; TGA: Figure 9
Residual solvents: acetone: 0.02%; n-heptane: 0.06%.
EXAMPLE 5: Purification of cabazitaxel using acetone/methanol /n-heptane/Water
Cabazitaxel (11 g) and acetone (66 mL) are charged into the round bottom flask at 25-30°C and stirred for 10-15 minutes. The obtained solution is filtered and filtrate is charged into the round bottom flask at 25-30°C. Methanol (66 mL), n-heptane (275 mL) and water (275 mL) are charged into the round bottom flask at 25-30°C and stirred for 16-18 hours. The obtained precipitate is filtered, washed with water (55 mL) followed by n-heptane (55 mL), suck dried and dried at 70°C under vacuum to give the pure Cabazitaxel.
Yield: 9.45 g (85.9%); Purity by HPLC: 99.66%; Water Content (KF): 0.78%
Residual solvents: n-heptane: 0.05%.
EXAMPLE 6: Purification of cabazitaxel using methanol/acetone/diisopropyl ether/Water
Cabazitaxel crude (10 g) and methanol (60 mL) are charged into the round bottom flask at 25-30°C and stirred for 5-8 hours. Acetone (60 mL), Diisopropyl ether (250 mL) and Water (250 mL) are charged into the above solution at 25-30°C and stirred for 14-18 hours. The obtained solid is filtered, washed with diisopropyl ether (50 mL) and suck dried under vacuum completely. (Residual solvents: acetone: 0.4%, diisopropyl ether: 4.7%, ethyl acetate: 0.06%).The obtained compound is dried under vacuum for 4 hours. (Residual solvents: Acetone: 0.9%, diisopropyl ether: 9.0%, ethyl acetate: 0.1%).
The above obtained compound (5.0 g) and acetone (40 mL) are charged into a round bottom flask at 25-30°C, stirred for 15-30 minutes and filtered. The obtained filtrate is charged into the round bottom flask at 25-30°C. Methanol (40 mL), diisopropyl ether (125 mL) and water (125 mL) are charged into the above filtrate at 25-30°C and stirred for 14-16 hours. The obtained solid is filtered, washed with diisopropyl ether (25 mL), suck dried under vacuum (Residual solvents: acetone: 0.8%, diisopropyl ether: 7.5%, ethyl acetate:0.02%) and dried under vacuum below 50°C to give the pure Cabazitaxel.
Purity by HPLC:99.67%; DSC: 157.25; TGA: 9.9; Moisture content: 0.22%
Residual Solvent: Acetone: 1.1%, diisopropyl ether: 9.7%, ethyl acetate: 0.05%
EXAMPLE 7: Purification of cabazitaxel using methanol/acetone/diisopropyl ether/Water
Cabazitaxel crude (10 g) and methanol (60 mL) are charged into the round bottom flask at 25-30°C and stirred for 5-8 hours. Acetone (60 mL), Diisopropyl ether (250 mL) and Water (250 mL) are charged into the above solution at 25-30°C and stirred for 14-18 hours. The obtained solid is filtered, washed with diisopropyl ether (50 mL) and suck dried under vacuum completely. (Residual solvents: acetone: 0.4%, diisopropyl ether: 4.6%, ethyl acetate: 0.07%).The obtained compound is dried under vacuum for 4 hours. (Residual solvents: Acetone: 1.0%, diisopropyl ether: 9.6%, ethyl acetate: 0.1%).
The above obtained compound (5.0 g) and acetone (40 mL) are charged into a round bottom flask at 25-30°C, stirred for 15-30 minutes and filtered. The obtained filtrate is charged into the round bottom flask at 25-30°C. Methanol (40 mL), diisopropyl ether (125 mL) and water (125 mL) are charged into the above filtrate at 25-30°C and stirred for 14-16 hours. The obtained solid is filtered, washed with diisopropyl ether (25 mL), suck dried under vacuum (Residual solvents: acetone: 0.9%, diisopropyl ether: 8.3%, ethyl acetate:0.04%) and dried under vacuum below 50°C to give the pure Cabazitaxel.
Purity by HPLC: 99.65%; DSC: 157.33; TGA: 9.2; Moisture content: 0.16%
Residual Solvent: Acetone: 1.1%, diisopropyl ether: 9.1%, ethyl acetate: 0.05%
EXAMPLE 8: Purification of cabazitaxel using acetone and n-heptane.
Cabazitaxel (17.6 g, Purity: 99.13%) and acetone (70 ml) are charged into the round bottom flask at 25-30°C and stirred to obtain a clear solution. The reaction mixture is filtered and charged to a second round bottom flask. N-heptane (140 mL) is slowly added for about 30 minutes and the obtained reaction mixture is stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with n-heptane (25 mL) and suction dried for 30 minutes to give cabazitaxel.
Yield: 14.2 g; Purity by HPLC: 99.45%.
EXAMPLE 9: Purification of cabazitaxel using acetone and diisopropyl ether.
Cabazitaxel (13.5 g, Purity: 99.45%) and acetone (81 ml) are charged into the round bottom flask at 25-30°C and stirred to obtain a clear solution. Diisopropyl ether (270 mL) is added to the reaction mixture and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (54 mL) and suction dried for 15 minutes to give cabazitaxel.
Yield: 11.4 g; Purity by HPLC: 99.71%.
EXAMPLE 10: Purification of cabazitaxel using acetone and n-heptane.
Cabazitaxel (22 g, Purity: 97.14%) and acetone (88 ml) are charged into the round bottom flask at 25-30°C and stirred to obtain a clear solution. N-heptane (220 mL) is added to the reaction mixture and stirred at 25-30°C for about 1 hour. The solid obtained is filtered, washed with n-heptane (20 mL) and suction dried for 30-45 minutes to give cabazitaxel.
Yield: 17.9 g; Purity by HPLC: 99.13%.
EXAMPLE 11: Purification of cabazitaxel using acetonitrile and diisopropyl ether.
Cabazitaxel (35 g, Purity: 99.59%) and acetonitrile (700 ml) are charged into the round bottom flask at 25-30°C, stirred to obtain a solution and filtered. The filtrate is charged into a round bottom flask, diisopropyl ether (2800 mL) is added and stirred at 25-30°C for about 6 hours. The solid obtained is filtered, and suction dried to give cabazitaxel.
Yield: 13.7 g; Purity by HPLC: 99.82%.
EXAMPLE 12: Preparation of cabazitaxel of formula (I).
4-acetoxy-2a-benzoyloxy-5ß-20-epoxy-1-hydroxy-9-oxo-7ß,10ß-dimethoxy-11-taxen-13ayl-(45,5R)-3-tert-butylcarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidine carboxylate (30 g) and formic acid (600 mL) are charged into the round bottom flask at 15-20°C and stirred the reaction mixture for 2-3 hours. Ethyl acetate (750 mL), water (750 mL) and 10% sodium chloride solution (750 mL) are added to the above reaction mixture at 15-20°C and stirred for 10 minutes. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (750 mL). The combined organic layer is washed with saturated 10% sodium chloride solution (2x750 mL) and organic layer is separated. The obtained organic layer and water (750 mL) are charged into round bottom flask at 25-30°C and the pH of the reaction mass is adjusted to 7.5-80 using sodium bicarbonate (240 g). Di-tert-butyl dicarbonate (14.16 mL) is added to the above reaction mixture and stirred for 3 hours. The organic layer is separated, washed the organic layer with 10% sodium chloride solution (750 mL) and concentrated under vacuum upto 4-5 volumes of organic layer. Diisopropyl ether (450 mL) is added to the reaction mass at 25-30°C and stirred for 1 hour. The obtained solid is filtered, washed with diisopropyl ether (90 mL), suction dried for 15 minutes to give the title compound.
Purity by HPLC: 92.05%, Amino Alcohol Impurity: 0.85%, CBT-1A Impurity: 0.2%, CBT-2A Impurity: 2.2%.
Cabazitaxel obtained above (10 g, Purity: 92.05%), dichloromethane (80 mL) and acetone (80 mL) are charged into a round bottom flask at 25-30°C, stirred to obtain a solution and filtered. The filtrate is charged into a round bottom flask, diisopropyl ether (320 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (50 mL) and suction dried to give cabazitaxel.
Purity by HPLC: 97.91%, Amino Alcohol Impurity: 0.33%, CBT-1A Impurity: 0.05%, CBT-2A Impurity: 0.71%.
Cabazitaxel obtained above (8.5 g, Purity: 97.91%), acetone (42.5 mL) and dichloromethane (42.5 mL) are charged into a round bottom flask at 25-30°C, stirred to obtain a clear solution. Diisopropyl ether (170 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (42 mL) and suction dried to give pure cabazitaxel.
Purity by HPLC: 99.3%, Amino Alcohol Impurity: 0.1%, CBT-1A Impurity: 0.01%, CBT-2A Impurity: 0.2%.
EXAMPLE 13: Purification of Cabazitaxel using Acetonitrile/Dichloromethane/ Diisopropyl ether.
Cabazitaxel (1g, Purity: 92.91%), dichloromethane (5 mL) and acetonitrile (5 mL) are charged into a round bottom flask at 25-30°C, stirred to obtain a solution and filtered. Diisopropyl ether (20 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (10 mL) and suction dried to give pure cabazitaxel.
Purity by HPLC: 98.09%, Amino Alcohol Impurity: 0.3%, CBT-2A Impurity: 0.6%.
EXAMPLE 14: Purification of Cabazitaxel using Acetone/Dichloromethane/ Diisopropyl ether
Cabazitaxel (1g, Purity: 92.07%), acetone (5 mL) and dichloromethane (5 mL) are charged into a round bottom flask at 25-30°C and stirred for 3-5 minutes. Diisopropyl ether (20 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (5 mL) and suction dried to give pure cabazitaxel.
Purity by HPLC: 98.83%, Amino Alcohol Impurity: 0.16%, CBT-2A Impurity: 0.45%.
EXAMPLE 15: Purification of Cabazitaxel using Acetone/Dichloromethane/ Diisopropyl ether
Cabazitaxel (1g, Purity: 92.07%) and dichloromethane (5 mL) are charged into a round bottom flask at 25-30°C, stirred and filtered. The filtrate is charged into a round bottom flask, acetone (5 mL) and diisopropyl ether (25 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (5 mL) and suction dried to give pure cabazitaxel.
Purity by HPLC: 98.04%, Amino Alcohol Impurity: 0.29%, CBT-2A Impurity: 0.59%.
EXAMPLE 16: Purification of Cabazitaxel using Acetone/Dichloromethane/ Diisopropyl ether
Cabazitaxel (1g, Purity: 92.07%) and dichloromethane (6 mL) are charged into a round bottom flask at 25-30°C, stirred and filtered. The filtrate is charged into a round bottom flask, acetone (3 mL) and diisopropyl ether (20 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (5 mL) and suction dried to give pure cabazitaxel.
Purity by HPLC: 97.92%, Amino Alcohol Impurity: 0.35%, CBT-2A Impurity: 0.71%.
EXAMPLE 17: Purification of Cabazitaxel using Acetone/Dichloromethane/ Diisopropyl ether
Cabazitaxel (3.7g, Purity: 97.29%), acetone (18.5 mL) and dichloromethane (18.5 mL) are charged into a round bottom flask at 25-30°C and stirred for 3-5 minutes. Diisopropyl ether (74 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (11.1 mL) and suction dried to give cabazitaxel.
Purity by HPLC: 97.29%, CBT-1A Impurity: 0.06%, CBT-2A Impurity: 0.85%, Amino Alcohol Impurity: 0.42%, Trimethoxy 10-DAB III Impurity: 0.02%, N-Formyl Impurity: 0.09%, Di Boc Impurity: not detected, 2’,3’-Isomer: not detected.
Cabazitaxel obtained above (2.25 g, Purity: 97.29%), acetone (11.25 mL) and dichloromethane (11.25 mL) are charged into a round bottom flask at 25-30°C and stirred for 3-5 minutes. Diisopropyl ether (45 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (11.25 mL) and suction dried to give cabazitaxel.
Purity by HPLC: 99.67%, CBT-1A Impurity: not detected, CBT-2A Impurity: 0.12%, Amino Alcohol Impurity: 0.11%, Trimethoxy 10-DAB III Impurity: not detected, N-Formyl Impurity: 0.02%, Di Boc Impurity: not detected, 2’,3’-Isomer: not detected.
EXAMPLE 18: Purification of Cabazitaxel using Acetone/Dichloromethane/ Diisopropyl ether
Cabazitaxel (3.5g, Purity: 96.83%), acetone (17.5 mL) and dichloromethane (17.5 mL) are charged into a round bottom flask at 25-30°C and stirred for 3-5 minutes. Diisopropyl ether (70 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (10.5 mL) and suction dried to give cabazitaxel.
Purity by HPLC: 96.83%, CBT-1A Impurity: 0.07%, CBT-2A Impurity: 1.1%, Amino Alcohol Impurity: 0.48%, Trimethoxy 10-DAB III Impurity: 0.02%, N-Formyl Impurity: 0.12%, Di Boc Impurity: not detected, 2’,3’-Isomer: not detected.
Cabazitaxel obtained above (2.1 g, Purity: 96.83%), acetone (10.5 mL) and dichloromethane (10.5 mL) are charged into a round bottom flask at 25-30°C and stirred for 3-5 minutes. Diisopropyl ether (42 mL) is added and stirred at 25-30°C for about 2 hours. The solid obtained is filtered, washed with diisopropyl ether (10.5 mL) and suction dried to give cabazitaxel.
Purity by HPLC: 99.69%, CBT-1A Impurity: 0.02, CBT-2A Impurity: 0.12%, Amino Alcohol Impurity: 0.07%, Trimethoxy 10-DAB III Impurity: not detected, N-Formyl Impurity: not detected, Di Boc Impurity: not detected, 2’,3’-Isomer: not detected.
,CLAIMS:We claim:
1. A process for purification of cabazitaxel, comprising:
a) obtaining a solution of cabazitaxel in an alcohol solvent;
b) crystallizing a solid from the solution of step a) by combining with solvent mixture of an ketone solvent, an ether solvent and water;
c) isolating the obtained crystalline solid.
2. The process of claim 1, wherein the alcohol solvent is methanol; ketone solvent is acetone and ether solvent is diisopropyl ether.
3. A process for purification of cabazitaxel, comprising:
a) obtaining a solution of cabazitaxel in a ketone solvent;
b) crystallizing a solid from the solution of step a) by combining with a solvent selected from an alcohol solvent, an ether solvent, an aliphatic hydrocarbon solvent or the mixtures thereof and water;
c) isolating the obtained crystalline solid.
4. The process of claim 3, wherein the ketone solvent is acetone; alcohol solvent is methanol; ether solvent is diisopropyl ether, and aliphatic hydrocarbon is n-heptane.
5. A process for the purification of Cabazitaxel, comprising:
a) obtaining a solution of cabazitaxel in a C1-C6 ester solvent;
b) crystallizing a solid from the solution of step a) by combining with a ether solvent; and
c) isolating the obtained crystalline solid.
6. The process of claim 5, wherein the ester solvent is ethyl acetate, methyl acetate and isopropyl acetate; ether solvent is diisopropyl ether.
7. A process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a ketone solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with a ether solvent; and
c) isolating the obtained crystalline solid.
8. The process of claim 7, wherein the ketone solvent is selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; halogenated hydrocarbon is selected from dichloromethane and chloroform; ether solvent is diisopropyl ether.

9. A process for the purification of Cabazitaxel, which process comprises the steps of:
a) dissolving cabazitaxel in a solvent mixture consisting of a nitrile solvent and a halogenated hydrocarbon solvent;
b) crystallizing a solid from the solution of step a) by combining with an ether solvent; and
c) isolating the obtained crystalline solid.
10. The process of claim 9, wherein the nitrile solvent is acetonitrile; halogenated hydrocarbon is selected from dichloromethane and chloroform; ether solvent is diisopropyl ether.