WO2013048169A2

WO2013048169A2 - Method for preparing taxane derivatives

Info

Publication number: WO2013048169A2
Application number: PCT/KR2012/007885
Authority: WO
Inventors: Young Min Kim; Seong Ho Kim; Jin Suk Cho; Moon Suk Kim; Jong Won Yoon; Ho Joon Choi; Jai Young Song
Original assignee: Samyang Genexbio Corporation
Priority date: 2011-09-30
Filing date: 2012-09-28
Publication date: 2013-04-04
Also published as: JP5870197B2; JP2014528408A; KR101379694B1; WO2013048169A3; KR20130035466A

Abstract

There is provided a method for preparing docetaxel that is a taxane derivative, and more specifically, a method for preparing docetaxel in which since the docetaxel having high purity can be prepared at a high yield through a simple production method including preparing an intermediate having a specific structure of a steric configuration that is the same type as the docetaxel that is a final product from a taxane compound having a specific structure and then semi-synthesizing the docetaxel using them, the method is very suitable for industrial manufacturing.

Description

METHOD FOR PREPARING TAXANE DERIVATIVES

The present invention relates to a method for preparing docetaxel that is a taxane derivative. More particularly, the present invention relates to a method for preparing docetaxel, in which since the docetaxel having high purity can be prepared at a high yield through a simple production method including preparing an intermediate that is a specific structure of a steric configuration having the same type as the docetaxel that is a final product from a taxane compound having a specific structure and then semi-synthesizing the docetaxel using them, the method is very suitable for industrial manufacturing.

Docetaxel (a compound represented by the following Chemical Formula 1) belongs to a taxoid group and is a drug for anti-tumor chemotherapy, having an extensive anti-tumor and anti-leukemic activity. Docetaxel is a semi-synthetic anti-cancer drug derived from a chemical modification of 10-deacetylbaccatin III extracted from the leaves and peels of the European or Indian yew tree and is a medicine that is widely available on the market for treatment of breast cancer, ovarian cancer and the like because the effectiveness of the drug has been recognized in various countries of the world including those in Europe:

[Chemical Formula 1]

Many researches are being carried out to develop a method for synthesizing docetaxel, including a practicable semi-synthetic route for preparing docetaxel and a method for preparing intermediates used for preparing the same so far. For example, International Patent Publication No. WO 92/009589 discloses a method for preparing a taxane derivative including docetaxel, with the following steps: a) a step of performing an esterification reaction by heating 7,10-ditroc-10-deacetylbaccatin III and a oxazolidine derivative at 80℃ in toluene; b) a step of ring-opening an oxazolidine ring using excess amount of formic acid; c) a step of introducing a protective group of Boc (t-butoxycarbonyl group) to an amine side chain; and d) a step of deprotecting 7,10-hydroxy protective group. However, in this case, there is a limit that in order to obtain a desired compound with a yield of approximately 85%, a concentration process that is technologically difficult and a complex extraction/purification process should be performed after carrying out a high-temperature condensation reaction and a complex extraction and purification reaction in step a) and a ring-opening reaction and a Boc-removing reaction at the same time in step b). In addition, in step d), since an excess of acetic acid and zinc powder are used in a deprotection reaction of 7,10-hydroxy protective group, heat is highly generated and there is a high risk of explosion so the method is not appropriate for large scale manufacturing.

International Patent Publication No. WO 94/007878 discloses a method for preparing docetaxel using an oxazolidine derivative, including a) a step of performing an esterification reaction of 7,10-ditroc-10-deacetylbaccatin III and an oxazolidine derivative [(2R,4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyloxazolidine-5- carboxylic acid] in the presence of toluene at 20℃; b) a step of opening an oxazolidine ring using a hydrochloric acid; and c) a step of deprotecting 7,10-hydroxy protective group. However, in this case, the toluene used in step a) is a material that belongs to Class 2 in ICH Guideline Q3C (Guideline Impurities: Guideline for Residual Solvents) and is generally defined as a harmful chemical substance (a hallucinogenic substance) causing an excitement, hallucination, or narcosism so that the use of the toluene is limited. In addition, the method has a disadvantage in that since different solvents are used for each of the steps, the time for removing the solvents becomes long and the cost of production is increased when performing large scale manufacturing.

International Patent Publication No. WO 94/010169 discloses a method for preparing docetaxel with a low yield, which comprises a) a step of reacting an esterification of an oxazolidine derivatives [(2R,4S,5S)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylic acid] having S,S steric configuration of carbon atoms at the 4- and 5-positions and 7,10-ditroc-10-deacetylbaccatin III under an anhydride toluene solvent at 74℃ for 24 hours to obtain an epimer mixture; b) a step of deprotecting 7,10-hydroxy protective group and purifying the epimer mixture to isolate a desired target compound; and c) a step of purifying the oxazolidine ring after opening it using hydrochloric acid. However, in this case, the method is unsuitable for industrial manufacturing because a special process for isolating the epimer mixture is required and the method should be reacted for a long period of time―i.e., 24 hours at 74℃ using toluene, which is a harmful material.

In summary, the conventional techniques described above are inefficient for large scale manufacturing of docetaxel and thus do not suitably satisfy increased demand for docetaxel in the field of medicine and the like, and its application is also limited due to the use of a harmful chemical material and low productivity.

Therefore, the development of a technique to provide an effective method for large scale manufacturing of docetaxel with a high yield is urgently needed.

Cited Reference

Patent Documents

(Patent Document 1) International Patent Publication No. WO 92/009589

(Patent Document 2) International Patent Publication No. WO 94/007878

(Patent Document 3) International Patent Publication No. WO 94/010169

The present invention is intended to solve the problems of the conventional techniques as described above, and the technical object of the present invention is the provision of a method for preparing docetaxel with a high yield and high purity via simplified preparation processes.

In order to achieve the above-described technical object, the present invention provides a method for preparing docetaxel, the method including removing a protective group of a compound represented by the following Chemical Formula 3 through a deprotection reaction to prepare a compound represented by the following Chemical Formula 2 and preparing docetaxel represented by the following Chemical Formula 1 using the compound represented by the following Chemical Formula 2 obtained as an intermediate:

[Chemical Formula 3]

[Chemical Formula 2]

[Chemical Formula 1]

The preparation method according to the present invention can prepare docetaxel with a high yield through a simple process using an intermediate that is prepared to have a steric configuration that is the same form as that of the docetaxel, a final product thereby saving time and production cost. Accordingly, the method is very suitable for industrial mass production of docetaxel. In addition, since semi-synthetic docetaxel prepared according to the method of the present invention can be easily purified through a simple chromatography process or the like, docetaxel with high purity can be finally provided.

The present invention relates to a method for preparing docetaxel (Chemical Formula 1), the method including preparing a compound (Chemical Formula 2) of a specific structure having a steric configuration that is the same type as that of docetaxel through a deprotection reaction from an oxazolidine side chain-containing taxane compound (Chemical Formula 3) and preparing docetaxel (Chemical Formula 1) using the compound represented by the following Chemical Formula 2 obtained as an intermediate. For the present invention, the compound represented by Chemical Formula 2 is prepared from the compound represented by Chemical Formula 3, and preferably can be obtained through Chemical Formula 3 using Chemical Formula 4 as an initial material as described in the following Reaction Equation 1. Thus, according to a preferable embodiment of the present invention, a crude docetaxel is prepared by the method including (a) a step of preparing an oxazolidine side chain-containing taxane compound represented by Chemical Formula 3 through a condensation reaction of 10-deacetalbaccatin III with a protected 7,10-hydroxyl group represented by Chemical Formula 4 and an oxazolidine acid derivative represented by Chemical Formula 5; (b) a step of preparing 7,10-hydroxy taxane compound represented by Chemical Formula 2 by removing a protective group at the 7,10-position of the oxazolidine side chain-containing taxane compound obtained from the step of (a); and (c) a step of ring-opening 7,10-hydroxy taxane compound obtained from the step of (b) in the presence of an acidic medium.

The overall process to a specific example of a method for preparing docetaxel according to the present invention is schematically illustrated in the following Reaction Scheme 1:

[Reaction Scheme 1]

(For all of the Chemical Formulas and Reaction Schemes described herein, Troc represents 2,2,2-trichloroethoxycarbonyl, Ac represents acetyl, Bz represents benzoyl (C₆H₅-C(=O)-), Ph represents phenyl, Boc represents t-butoxycarbonyl, and Me represents methyl.)

Hereinafter, a preferable method for preparing docetaxel according to the present invention as mentioned above will be described in more detail step by step.

Step (a): Preparation of Oxazolidine Side Chain-containing Taxane Compound Represented by Chemical Formula 3

The present step is a step of preparing an oxazolidine side chain-containing taxane compound (the following Chemical Formula 3) having S, R steric configuration of carbon atoms at the 4- and 5-position by condensation (coupling) through an esterification reaction of 10-deacetylbaccatin III of which hydroxyl groups at the 7- and 10-position are protected with Troc group (the following Chemical Formula 4; 7,10-ditroc-10-deacetylbaccatin III) and an oxazolidine acid derivative that is introduced with a protective group as a side chain (the following Chemical Formula 5; [(2R,4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylic acid]):

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 3]

The compound represented by Chemical Formula 3 can be prepared by a condensation method (e.g., Steglich esterification) that is generally well known in the art using the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5.

The oxazolidine acid derivative represented by Chemical Formula 5 is preferably used in the amount of 1 to 2 equivalents and more preferably 1.2 to 1.5 equivalents relative to 1 equivalent of 10-deacetylbaccatin III represented by Chemical Formula 4. When it is used in the amount of less than 1 equivalent relative to 1 equivalent of 10-deacetylbaccatin III, the reaction may not be completed. When it is used in the amount of greater than 2 equivalents relative to 1 equivalent of 10-deacetylbaccatin III, it is not desirable in terms of economics because a great quantity of an expensive reagent is added.

For the condensation reaction in the step, at least one selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) may be used as a condensing agent, but the present invention is not limited thereto. Preferably, cheap dicyclohexylcarbodiimide is used. The condensing agent is preferably used in the amount of 1 to 4 equivalents and more preferably 1.7 to 2.2 equivalents relative to 1 equivalent of 10-deacetylbaccatin III. When it is used in the amount of less than 1 equivalent relative to an equivalent of 10-deacetylbaccatin III, the inconvenience of further adding the condensing agent will occur. When it is used in the amount of greater than 4 equivalents relative to an equivalent of 10-deacetylbaccatin III, the cost of the production may increase because of adding an excess of the reagent and a side product such as urea may be produced in a great amount thereby creating difficulty in the purifying process.

A solvent that can be used for the reaction in the step may include, but is not limited to, ethyl acetate, methyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran and the like. Preferably, an excellent environment-friendly ethyl acetate may be used.

An activating agent may be further added in the reaction of the step. The activating agent may include amines such as 4-dimethylaminopyrridine (DMAP) and pyridine alone or in combination of two or more, but the present invention is not limited thereto. Preferably, 4-dimethylaminopyrridine may be used. The activating agent may be preferably used in the amount of less than or equal to a stoichiometric equivalent, such as 0.3 to 0.5 equivalents relative to 10-deacetylbaccatin III. When it is used in the amount of less than 0.3 equivalent relative to an equivalent of 10-deacetylbaccatin III, the inconvenience of further adding the activating agent may occur because the reaction is not completed and when it is used in the amount of greater than 0.5 equivalent relative to an equivalent of 10-deacetylbaccatin III, the difficult may occur in the purifying process because a great quantity of side product is produced.

The reaction temperature in the step is preferably 0℃ to 60℃ and more preferably 20℃ to 30℃. When the reaction temperature is less than 0℃, the reaction does not proceed or the time of the reaction may be excessively longer. When the reaction temperature is greater than 60℃, the purity may be decreased due to an increase of side-product production during the reaction (such as a decrease of 5% to 10%).

The reaction time in the step is preferably 20 to 30 minutes. When the reaction time is less than 20 minutes, the desired compound may be insufficiently prepared. When the reaction time is greater than 30 minutes, the production of side product may be increased.

The production of side product may be minimized by properly controlling the amount of all kinds of reactants, additives, and solvent used, the reaction temperature, and the reaction time in the step of (a) as described above so that the resulting compound represented by Chemical Formula 3 can be directly used in the step of (b) that is the next step without a special isolation/purification process. Accordingly, the whole time for preparing docetaxel can be significantly decreased by the above-described continuous process.

Step (b): Preparation of 7,10-Hydroxy Taxane Compound Represented by Chemical Formula 2

The present step is a step of preparing 7,10-hydroxy taxane compound (the following Chemical Formula 2) by removing a protective group (i.e., Troc group) at the 7- and 10-position of the oxazolidine side chain-containing taxane compound (the above Chemical Formula 3) obtained from the step of (a) through a deprotection reaction:

[Chemical Formula 2]

In an embodiment of the present invention, the deprotection reaction of the step may be performed by reacting the compound represented by Chemical Formula 3 with zinc in the presence of a proper reaction solvent―for example, acetic acid. In this case, acetic acid is preferably used in the amount of 0.2 to 5 times in the weight ratio relative to the compound represented by Chemical Formula 3 (provided 100% of the compound represented by Chemical Formula 3 is produced) and more preferably in the amount of 0.3 to 0.6 times. When it is used in the amount of less than 0.2 times relative to the weight of the compound represented by Chemical Formula 3, the reaction may not be completed. When it is used in the amount of greater than 5 times relative to the weight of the compound represented by Chemical Formula 3, there may be a problem in that a great quantity of acetic acid remains in the extraction and purification process. In addition, zinc may be preferably used in the amount of 0.3 to 1 time in the weight ratio relative to the compound represented by Chemical Formula 3 and more preferably in the amount of 0.4 to 0.6 times. When it is used in the amount of less than 0.3 times relative to the weight of the compound represented by Chemical Formula 3, the reaction may not be completed. When it is used in the amount of greater than 1 time relative to the weight of the compound represented by Chemical Formula 3, a further purification process may be required due to an increase of impurities.

Ethyl acetate, methanol, or the combination thereof may be used as a solvent that can be used in the reaction of the step, but the present invention is not limited thereto.

Celite may be further added to the reaction of the step in order to improve and solve an agglomeration problem of zinc during the reaction. Celite may be preferably used in the amount of 0.3 to 1 time in the weight ratio relative to the compound represented by Chemical Formula 3 and more preferably in the amount of 0.4 to 0.8 times. When it is used in the amount of less than 0.3 times relative to the compound represented by Chemical Formula 3, it may be less effective in an improvement of the phenomenon of agglomeration of zinc. When it is used in the amount of greater than 1 time relative to the compound represented by Chemical Formula 3, there may be a problem that a great quantity of celite remains in the extraction and purification process.

The reaction temperature in the step is preferably 40℃ to 70℃ and more preferably 45℃ to 65℃. When the reaction temperature is less than 40℃, the productivity is decreased so that the time of the reaction may be excessively longer and a momentary explosion may occur by heat during the reaction. When the reaction temperature is greater than 70℃, a further purification process may be required due to an increase of side product.

The reaction time in the step is preferably within 10 minutes, more specifically 5 to 10 minutes. When the reaction time is greater than 10 minutes, a further purification process may be required due to an increase of impurities.

The production of the side product may be minimized by properly controlling the use amount (especially, the use amount of zinc and acetic acid) of all kinds of reactants, additives, and solvent, and the reaction temperature and the reaction time in the step of (b) as described above so that the resulting compound represented by Chemical Formula 2 can be directly used in the step of (c) which is the next step without a special isolation/purification process. Accordingly, the whole time for preparing a docetaxel can be significantly decreased by the above-described continuous process.

Step (c): Preparation of Crude Product of Docetaxel

The present step is a step of finally preparing a crude product of docetaxel (the following Chemical Formula 1) by opening an oxazolidine ring through a ring-opening reaction in the presence of an acidic medium using the oxazolidine side chain-containing 7,10-hydroxy taxane compound (the above Chemical Formula 2) obtained from the step of (b) as an intermediate.

[Chemical Formula 1]

An example of the acidic medium that can be used for the ring-opening reaction in the step may include hydrochloric acid, sulfuric acid, acetic acid, methane sulfonic acid, and the like, but the present invention is not limited thereto. Hydrochloric acid is preferably used. The acidic medium is preferably used in the amount of 2% to 5% (v/v) based on the total volume of the reactant in the step of (c). When the use amount is less than 2% based on the total volume of the reactant, the reaction may not be completed and the reaction time may be longer. When the use amount is greater than 5% based on the total volume of the reactant, the side product may be increased and a further purification process may be required in order to remove acid during the extraction process.

An example of the reaction solvent that can be used in the step may include methanol, ethanol, isopropyl alcohol, ethyl acetate, or a mixture thereof, but the present invention is not limited thereto.

The reaction temperature in the step is preferably 0℃ to 40℃ and more preferably 20℃ to 30℃. When the reaction temperature is less than 0℃, the reaction may not be preceded or the time of the reaction may be excessively longer. When the reaction temperature is greater than 40℃, the production of the side product may be increased.

The reaction time in the step is 1 to 2 hours. When the reaction time is within 1 hour, the reaction may not be completed so that there is a problem in that hydrochloric acid should be further added. When the reaction time is greater than 2 hours, the production of the side product may be increased.

For the crude product of the docetaxel obtained from the steps of (a) to (c) as described above, the reaction solvent may be filtered and concentrated, and further purified according to the general method in the art. A method of purifying the crude product of the docetaxel may include, but is not particularly limited to, a method that is generally used in the art, such as column chromatography and the like. The semi-synthetic docetaxel prepared according to the present invention may be easily purified through a simple chromatography process so that highly pure docetaxel can be finally provided.

Hereinafter, the present invention will be described in detail with reference to the Examples. The Examples are only to facilitate the understanding of the present invention, but the range of the present invention is not limited to the Examples.

EXAMPLES

Example 1: Preparation of Compound Represented by Chemical Formula 3

0.3 L of ethyl acetate was added into a reactor, and then 29 g of the compound represented by Chemical Formula 5 (at least 98% of HPLC purity, (2R,4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylic acid), 3 g of 4-dimethylaminopyrridine (DMAP), and 50 g of the compound represented by Chemical Formula 4 (at least 98% of HPLC purity) were added into the reactor. After adding 21 g of dicyclohexylcarbodiimide (DCC) at 20℃, a yellow suspension was stirred for 30 minutes. After completing the reaction, the reactant was filtered through a celite pad; then a filtrate was washed with an aqueous solution of sodium carbonate; and the resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum to obtain a desired yellow compound. For further purification, while 0.05 L of ethyl acetate was added and stirred at room temperature, 1 L of hexane was added dropwise for crystallization. After stirring for 1 hour at room temperature, a precipitate was filtered and then vacuum-dried at 40℃ to obtain a desired white compound (68 g, 95% of yield) (97% of HPLC purity).

A condition for a high performance liquid chromatography (HPLC) analysis and a method thereof are as follows.

Table 1

Table 2

Example 2: Preparation of Compound Represented by Chemical Formula 2

0.25 L of methanol was added to a reactor, 0.034 L of acetic acid, 50 g of celite, and 33 g of zinc (Zn dust, less than 10 micrometers) were added at 50℃ to 55℃, and then stirred for 10 minutes. 68 g of the compound represented by Chemical Formula 3 obtained from Example 1 as described above which was dissolved in 0.25 L of methanol was added to the reaction solution and then stirred at 50℃ to 60℃ for 10 minutes. After completing the reaction, the reactant in a hot state was filtered through a celite pad and then the celite pad was washed with 0.25 L of methanol. The resulting filtrate was then used in a next step without further purification (85% of HPLC purity of the filtrate).

- A condition for HPLC analysis and a method thereof are the same as that of Example 1 as described above.

Example 3: Preparation of Compound Represented by Chemical Formula 3

After adding the filtrate obtained from Example 2 as described above to a reactor, 0.027 L of a conc. hydrochloric acid was added to the mixture at 20℃. While the reaction solution was maintained at 20℃ to 25℃, the reaction solution was stirred for 90 minutes and then 0.5 L of dichloromethane and 0.5 L of purified water were added to the reaction solution and extracted. The resulting organic layer was dried over anhydride magnesium sulfate, filtered, concentrated under vacuum, and then vacuum-dried at 45℃ to obtain a desired yellow compound (52.5 g, 122% of two steps yield) [65% of the content measured by EP analysis method (European Pharmacopoeia 6.6. 01-2010: 2449)].

Example 4: Preparation of Compound Represented by Chemical Formula 1 through Continuous Process

(a) 2.5 L of ethyl acetate was added to a reactor, and then 290 g of the compound represented by Chemical Formula 5 (99% of HPLC purity), 30 g of 4-dimethylaminopyrridine (DMAP), and 500 g of the compound represented by Chemical Formula 4 (98% of HPLC purity) were added to the reactor. After adding 230 g of dicyclohexylcarbodiimide (DCC) at 20℃, a resulting yellow reactant was stirred for 30 minutes. After completing the reaction, the reactant was filtered through a celite pad; a filtrate was washed with an aqueous solution of sodium carbonate; and the organic layer obtained above was dried over an anhydride magnesium sulfate, filtered, and concentrated under vacuum to obtain a desired yellow compound (93% of HPLC purity of the filtrate).

(b) The filtrate including the resulting compound represented by Chemical Formula 3 was added to the reactor, and then 0.35 L of acetic acid and 500 g of celite were added to the reactor at 55℃. 330 g of zinc (Zn dust of less than 10 micrometers) were slowly added to the reaction solution, stirred for 10 minutes, and the reactant in a hot state was then filtered through a celite pad. After washing and filtering the celite pad using a further 2 L of ethyl acetate, the filtrate was used in the next reaction without a further purification (82% of HPLC purity of the filtrate).

(c) After adding the filtrate including the compound represented by Chemical Formula 2 obtained above to the reactor, 0.35 L of strong hydrochloric acid was added to the reactor at 20℃. While the reaction solution was maintained at 20℃ to 25℃, the reaction solution was stirred for 90 minutes and was then washed twice using 5 L of purified water. The organic layer was dried over anhydride magnesium sulfate, filtered, concentrated under vacuum and then vacuum-dried at 45℃ to obtain a desired yellow compound (482 g having 107% of the whole yield for 3 steps) (the content measured by EP analysis method was 65%).

Example 5: Preparation of Compound Represented by Chemical Formula 1 through Continuous Process

(a) 2.5 L of ethyl acetate was added to a reactor, and 290 g of the compound represented by Chemical Formula 5 (99% of HPLC purity), 30 g of 4-dimethylaminopyrridine (DMAP), and 500 g of the compound represented by Chemical Formula 4 (98% of HPLC purity) were added to the reactor. After adding 230 g of dicyclohexylcarbodiimide (DCC) at 20℃, a yellow reactant was stirred for 30 minutes. After completing the reaction, the reactant was filtered through a celite pad, a filtrate was washed with an aqueous solution of sodium carbonate, the resulting organic layer was dried over anhydride of magnesium sulfate and then concentrated under vacuum to be approximately 0.8 L to 1 L of the total volume.

(b) 2.5 L of methanol was added to the reactor, 0.35 L of acetic acid, 500 g of celite, and 350 g of zinc (Zn dust of less than 10 micrometers) were added to the reactor at 50℃ and then stirred for 10 minutes. A filtrate containing the resulting compound represented by Chemical Formula 3 was dissolved in 2.5 L of methanol and then added to the reactor. After stirring for 10 minutes, the reactant in a hot state was filtered through a celite pad. The celite pad was washed and filtered using an additional 2 L methanol and then the filtrate was used in the next reaction without further purification (83% of HPLC purity of the filtrate).

(c) After adding the filtrate including the compound represented by Chemical Formula 2 obtained above to the reactor, 0.28 L of a conc. hydrochloric acid was added to the reactor at 20℃. While the reaction solution was maintained at 20℃ to 25℃, the reaction solution was stirred for 90 minutes, then 7.5 L of dichloromethane and 5 L of purified water were added to the reaction solution and then extracted. The resulting organic layer was dried over an anhydride magnesium sulfate, filtered, concentrated under vacuum and then vacuum-dried at 45℃ to obtain a desired yellow compound (488 g having 108% of the whole yield for 3 steps) (the content measured by EP analysis method was 71%).

Purification of Semi-Synthetic Docetaxel (Compound Represented by Chemical Formula 1)

450 g of the semi-synthetic docetaxel obtained from Example 5 as described above was completely dissolved in 2.5 L of methanol and then added dropwise to 13 L of purified water for crystallization. The resulting white crystals were stirred at 30℃ to 35℃ for 30 minutes and then filtered through a filter paper, and the white crystals were washed with 2.5 L of purified water. The resulting wet white crystal compound was vacuum-dried at 65℃ to obtain a desired white compound (415 g) (the content measured by EP analysis method was 84%).

Isolation and purification were performed by liquid chromatography with a column (25 × 90 cm) filled with silica gel (60 micrometers to 100 micrometers, Timely, Japan). The column was equilibrated in the velocity of flow of 3.4 L/min using 2.5% methanol/97.5% dichloromethane solution as a mobile phase. 300 g of sample was dissolved in dichloromethane and then all of it was injected. While continuously flowing with a mobile phase-solvent, a relevant peak was fractioned using a UV detector and then pressure-concentrated. It was vacuum-dried at 40℃ to obtain a desired compound in a white solid (227 g, HPLC purity was 99.5%, and individual related compound was less than or equal to 0.1%). The following analyses were performed with the resulting docetaxel.

1. Specific Optical Rotation [α] (According to Analysis Method EP Pharmacopoeia)

[α]²³ _D = -40.01°(c = 0.1, MeOH)

2. NMR 400 MHz (CDCl₃)

3. High Resolution Mass Spectroscopy (HRMS) (Apparatus Name ― Shimadzu LCMS-IT-TOF, Kyoto, Japan)

Claims

A method for preparing docetaxel represented by the following Chemical Formula 1, the method comprising the steps of:

removing a protective group of a compound represented by the following Chemical Formula 3 through a deprotection reaction to prepare a compound represented by the following Chemical Formula 2; and

preparing docetaxel represented by the following Chemical Formula 1 by using the obtained compound represented by the following Chemical Formula 2 as an intermediate:

[Chemical Formula 3]

[Chemical Formula 2]

[Chemical Formula 1]

wherein,

Troc represents 2,2,2-trichloroethoxycarbonyl;

Ac represents acetyl;

Bz represents benzoyl;

Ph represents phenyl;

Boc represents t-butoxycarbonyl; and

Me represents methyl.
The method for preparing docetaxel represented by the following Chemical Formula 1 according to claim 1, the method comprising the steps of:

(a) performing a condensation reaction of 7,10-hydroxy-protected 10-deacetylbaccatin III represented by the following Chemical Formula 4 and an oxazolidine acid derivative represented by the following Chemical Formula 5 to prepare an oxazolidine side chain-containing taxane compound represented by the following Chemical Formula 3;

(b) removing the protecting groups at the 7- and 10-positions of the oxazolidine side chain-containing taxane compound obtained in step (a) above to prepare 7,10-hydroxy taxane compound represented by the following Chemical Formula 2; and

(c) performing a ring-opening reaction of the 7,10-hydroxy taxane compound obtained in step (b) above in the presence of an acidic medium to prepare a crude docetaxel:

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 3]

[Chemical Formula 2]

[Chemical Formula 1]

wherein,

Troc represents 2,2,2-trichloroethoxycarbonyl;

Ac represents acetyl;

Bz represents benzoyl;

Ph represents phenyl;

Boc represents t-butoxycarbonyl; and

Me represents methyl.
The method for preparing docetaxel according to claim 2, wherein in step (a), the oxazolidine acid derivative represented by Chemical Formula 5 is used in an amount of 1 to 2 equivalents relative to 1 equivalent of the 10-deacetylbaccatin III represented by Chemical Formula 4.
The method for preparing docetaxel according to claim 2, wherein in step (a), the condensation reaction is performed in the presence of one or more condensation agents selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
The method for preparing docetaxel according to claim 2, wherein in step (a), 4-dimethylaminopyridine, pyridine or a mixture thereof is added as an activating agent.
The method for preparing docetaxel according to claim 2, wherein the oxazolidine side chain-containing taxane compound represented by Chemical Formula 3 obtained in step (a) is directly used in step (b) without further isolation or purification.
The method for preparing docetaxel according to claim 2, wherein in step (b), the protecting groups at the 7- and 10-positions are removed by using acetic acid and zinc.
The method for preparing docetaxel according to claim 7, wherein the acetic acid is used in an amount of 0.2 to 5 times and the zinc is used in an amount of 0.3 to 1 time, relative to the weight of the oxazolidine side chain-containing taxane compound represented by Chemical Formula 3.
The method for preparing docetaxel according to claim 7, wherein in step (b), celite is added.
The method for preparing docetaxel according to claim 2, wherein in step (b), the reaction temperature is 40℃ to 70℃ and the reaction time is 10 minutes or less.
The method for preparing docetaxel according to claim 2, wherein the 7,10-hydroxy taxane compound represented by Chemical Formula 2 obtained in step (b) is directly used in step (c) without further isolation or purification.
The method for preparing docetaxel according to claim 2, wherein in step (c), the acidic medium is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid and methanesulfonic acid.
The method for preparing docetaxel according to claim 2, wherein in step (c), the acidic medium is used in an amount of 2% to 5%(v/v) based on the total volume of reactants.
The method for preparing docetaxel according to claim 2, further comprising a step of purifying the crude product of docetaxel prepared in step (c).