KR20130035466A - Method for preparing taxane derivatives - Google Patents

Abstract

PURPOSE: A method for preparing a taxane derivative is provided to prepare high purity and high yield docetaxel by preparing an intermediate with a certain structure. CONSTITUTION: A method for preparing docetaxel comprises: a step of removing a protection group of a compound of chemical formula 3 through deprotection and preparing a compound of chemical formula 2; and a step of preparing doxetaxel of chemical formula 1 using the compound of chemical formula 2 as an intermediate. In the chemical formulas, Troc is 2,2,2-trichloroethoxycarbonyl; Ac is acetyl; Bz is benzoyl; Ph is phenyl; Boc is t-buthoxycarbonyl; and Me is methyl.

Description

Method for manufacturing taxane derivatives {METHOD FOR PREPARING TAXANE DERIVATIVES}

The present invention relates to a method for preparing docetaxel, which is a taxane derivative, and more particularly, to prepare an intermediate of a specific structure having a stereo configuration such as a docetaxel as a final product from a taxane compound having a specific structure, and then to use docetaxel. By semi-synthesis, it is possible to manufacture high yield and high purity docetaxel through a simple manufacturing process, and relates to a manufacturing method of docetaxel which is very suitable for industrial mass production.

Docetaxel (compound of formula 1) is a cancer chemotherapeutic agent that belongs to the taxoid family and has a wide range of anti-tumor and anti-leukemic activity. Docetaxel is a semi-synthetic anticancer agent derived from chemical modification of 10-deacetylbaccatin III extracted from the leaves and bark of European or Indian ancestors, and has been recognized for its efficacy in many countries around the world including Europe and in breast and ovarian cancers. It is widely marketed as a treatment for back:

[Formula 1]

To date, various studies have been conducted on the development of synthetic methods including viable semisynthetic routes for the preparation of docetaxel and methods of preparing the intermediates used to prepare the compounds. For example, WO 92/009589 discloses a process for a) esterifying a 7,10-Ditroc-10-deacetylbacatin III and an oxazolidine derivative by heating it to a temperature of 80 ° C. in a toluene solvent; b) ring opening of the oxazolidine ring with excess formic acid; c) introducing a Boc (t-butoxycarbonyl group) protecting group into the branched amine; And d) deprotecting the 7,10-hydroxy group protecting group. In this case, however, a high temperature condensation reaction and a complex extraction and purification process are carried out in step a), and Boc is removed at the same time as the ring opening reaction, followed by industrially difficult concentration process and complex extraction / purification process. There is a limit that the desired compound can be obtained with a yield of about 85% only. In addition, the deprotection reaction of the 7,10-hydroxy group protecting group in step d) uses an excess of acetic acid and powdered zinc, which causes excessive heat generation and high explosion risk, which is not suitable for mass production.

WO 94/007878 discloses a) 7,10-Ditroc-10-deacetylbacatin III and an oxazolidine derivative [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2 Esterifying-(4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylic acid] at 20 ° C. in a toluene solvent; b) ring opening of the oxazolidine ring with hydrochloric acid; And c) deprotecting a 7,10-hydroxy group protecting group, the method for producing docetaxel using an oxazolidine derivative. In this case, however, toluene used in step a) is a class 2 substance in the ICH guideline Q3C (Guideline Impurities: Guideline for residual solvents), which is a hazardous chemical (psychedelic substance) that generally causes an irritating, hallucinogenic or anesthetic effect. ), Its use is restricted. In addition, since a) to c) different solvents are used in each step, there is a problem in that the time for removing them in a mass production becomes long and the production cost increases.

International Patent Publication No. WO 94/010169 discloses a) oxazolidine derivatives in which the carbon atoms in the 4- and 5- positions have S, S conformations [(2R, 4S, 5S) -3- (tert-butoxycarbonyl ) -2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxylic acid] and 7,10-Ditroc-10-deacetylbaccatin III at 74 ° C. in anhydrous toluene solvent for 24 hours. Reacting to obtain an epimer mixture; b) deprotecting the 7,10-hydroxy group protecting group and separating the epimer mixture into the desired compound by purification; And c) ring opening an oxazolidine ring with hydrochloric acid followed by purification to produce docetaxel in low yield. However, in this case, a separate epimer mixture separation process is required, and toluene, which is a hazardous substance, needs to be reacted at 74 ° C. for a long time of 24 hours, which is unsuitable for industrial production.

In short, the prior art as described above is inefficient in mass production of docetaxel, which does not adequately meet the increased demand for docetaxel in the pharmaceutical field, and its application is also limited due to the use of harmful chemicals and low productivity.

Therefore, the development of a technology for an efficient manufacturing method capable of mass production of docetaxel in high yield is urgently required.

International Patent Publication No. WO 92/009589 International Patent Publication WO 94/007878 International Patent Publication WO 94/010169

The present invention is to solve the problems of the prior art as described above, to provide a method for producing docetaxel which can be produced in high yield and high purity docetaxel through a simple manufacturing process as a technical problem.

In order to achieve the above technical problem, the present invention provides a compound represented by the following Chemical Formula 2 by removing the protecting group of the compound represented by the following Chemical Formula 3 through a deprotection reaction, and the compound represented by the following Chemical Formula 2 obtained as an intermediate Provided is a method for preparing docetaxel represented by the following Chemical Formula 1.

(3)

[Formula 2]

[Formula 1]

The production method according to the present invention can produce a high yield of docetaxel through a simple process using an intermediate prepared to have a stereoscopic batch of the same type as docetaxel as a final product, reducing the production time and manufacturing cost of the docetaxel It is very suitable for industrial mass production. In addition, the semi-synthetic docetaxel prepared according to the present invention can be easily purified through a simple chromatography process, it can finally provide a high purity docetaxel.

The present invention is to prepare a compound having a specific structure (Formula 2) having a stereostructure of the same form as docetaxel through a deprotection reaction from an oxazolidine side chain-containing taxane compound having a specific structure (Formula 3), and then obtained It relates to a method for preparing docetaxel (Formula 1) using the compound of as an intermediate. In the present invention, the compound of formula (2) is prepared from the compound of formula (3). Preferably, the compound of formula (2) can be obtained through formula (3) using formula (4) as a starting material as shown in Scheme 1 below. Therefore, according to one preferred embodiment of the present invention, (a) condensation reaction of 10-deacetylbaccatin III protected with 7,10-hydroxy group represented by the formula (4) with an oxazolidine acid derivative represented by the formula (5) Preparing an oxazolidine side chain-containing taxane compound represented by 3; (b) preparing a 7,10-hydroxy taxane compound represented by Chemical Formula 2 by removing the protecting group at the 7,10-position of the oxazolidine side chain-containing taxane compound obtained in step (a); And (c) ring-opening the 7,10-hydroxy taxane compound obtained in step (b) in the presence of an acidic medium to prepare a docetaxel crude product.

The overall procedure for this embodiment of the docetaxel preparation method of the present invention is schematically shown in Scheme 1:

[Reaction Scheme 1]

(In all formulas and schemes described herein, Troc is 2,2,2-trichloroethoxycarbonyl, Ac is acetyl, Bz is benzoyl (C ₆ H ₅ -C (= 0)-), Ph is Phenyl, Boc is t-butoxycarbonyl, and Me is methyl.)

Hereinafter, the preferred method for producing docetaxel of the present invention as described above in more detail step by step.

(a) step: preparing an oxazolidine side chain-containing taxane compound represented by formula (3)

This step comprises 10-deacetylbaccatin III (Formula 4; 7,10-Ditroc-10-deacetylbaccatin III) in which the hydroxyl groups at the 7- and 10-positions are protected by Troc groups, and the oxa having the protecting group introduced as a side chain. Zolidine acid derivatives (Formula 5; [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyloxazolidine-5-carboxyl Acid]) is condensed (coupling) through an esterification reaction to prepare an oxazolidine side chain-containing taxane compound having the S and R stereopositions of 4- and 5-positions of carbon elements (Formula 3) :

[Formula 4]

[Chemical Formula 5]

(3)

Compounds of Formula 3 may be prepared by condensation methods commonly known in the art (eg, Steglich Esterification) using compounds of Formula 4 and compounds of Formula 5.

The oxazolidine acid derivative of formula (5) is preferably used in an amount of 1 to 2 equivalents, more preferably 1.2 to 1.5 equivalents, relative to 1 equivalent of 10-deacetylbaccatin III of formula (4). If the amount is less than 1 equivalent to 10-deacetylbaccatin equivalent, the reaction may be terminated. If the amount is more than 2 equivalents to 10-deacetylbaccatin equivalent, the reagent is more than necessary for the reaction. It is not preferable from an economic point of view because of over addition.

In the condensation reaction of this step, the condensing agent is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). One or more species may be used, but is not necessarily limited thereto. Preferably, dicyclohexylcarbodiimide is used which is inexpensive. The condensing agent is preferably used in an amount of 1 to 4 equivalents, more preferably 1.7 to 2.2 equivalents, relative to 1 equivalent of 10-deacetylbaccatin III. If the amount is less than 1 equivalent to 10-deacetyl baccatin equivalents, the reaction may not be terminated, resulting in the inconvenience of adding an additional condensate, and the amount is more than 4 equivalents to 10-deacetylbaccatin equivalents. When the reagent is over-added, the manufacturing cost increases and a large amount of by-products such as urea are generated, which may cause difficulty in the purification process.

Solvents usable in this step include, but are not limited to, ethyl acetate, methyl acetate, dichloromethane, toluene, xylene, tetrahydrofuran, and the like. Preferably, ethyl acetate is used which is highly environmentally friendly.

An activator may be further added to the reaction of this step. As the activating agent, amines such as 4-dimethylaminopyridine (DMAP) and pyridine may be used alone or in combination of two or more thereof. However, the activator is not necessarily limited thereto, and 4-dimethylaminopyridine is preferably used. The activator is preferably used in an amount of less than stoichiometric equivalent to 10-deacetylbaccatin III, such as in an amount of 0.3 to 0.5 equivalent times. If the amount is less than 0.3 equivalent to 10-deacetyl baccatin equivalent, the reaction may not be terminated, which may cause inconvenience to additionally add an activator, and the amount is more than 0.5 equivalent to 10-deacetylbaccatin equivalent. If a large amount of by-products are generated may cause difficulties in the purification process.

Preferred reaction temperature in this step is 0 to 60 ° C, more preferably 20 to 30 ° C. If the reaction temperature is less than 0 ℃ the reaction may not proceed or the reaction time is too long, if the reaction temperature exceeds 60 ℃ by-product generation during the reaction may increase the purity (for example, 5 to 10% lower) .

The preferred reaction time of this step is 20-30 minutes. If the reaction time is less than 20 minutes, the target compound may not be sufficiently prepared, and if the reaction time exceeds 30 minutes, by-products may be increased.

Properly adjusting the amount of use of the various reactants, additives and solvents, reaction temperature and reaction time in step (a) as described above minimizes the generation of by-products, and the obtained compound of formula 3 is the next step without separate separation / purification process. It can be used immediately in step (b), the overall manufacturing time of docetaxel is significantly shortened by this continuous process.

(b) step: preparing a 7,10-hydroxy taxane compound represented by formula (2)

This step is carried out by the deprotection reaction to remove the protecting groups (ie, the Troc group) in the 7- and 10- positions of the oxazolidine side chain-containing taxane compound obtained in step (a) (Formula 3), 7,10- To prepare a hydroxy taxane compound (Formula 2):

[Formula 2]

In one embodiment, the deprotection reaction of this step can be carried out by reacting the compound of formula 3 with zinc in the presence of a suitable reaction solvent such as acetic acid. In this case, acetic acid is preferably used in an amount of 0.2 to 5 multiples, more preferably 0.3 to 0.6 multiples by weight relative to the compound of formula 3 (assuming 100% of the compound of formula 3 is produced). If the amount is less than 0.2 times the weight of the compound of Formula 3, the reaction may be terminated. If the amount is more than 5 times the weight of the compound of Formula 3, excess acetic acid may remain during extraction and purification. have. In addition, zinc is preferably used in an amount of 0.3 to 1 multiple, more preferably 0.4 to 0.6 multiple by weight relative to the compound of formula (3). If the amount is less than 0.3 times the weight of the compound of Formula 3, the reaction may not be terminated. If the amount is more than 1 times the weight of the compound of Formula 3, additional purification may be required as the impurity increases.

Solvents usable in the reaction of this step include, but are not limited to, ethyl acetate, methanol or mixtures thereof.

Celite may be further added to the reaction of this step to improve and eliminate zinc agglomeration during the reaction. Celite is preferably used in an amount of 0.3 to 1 multiple, more preferably 0.4 to 0.8 multiple by weight relative to the compound of formula (3). If the amount is less than 0.3 times the weight of the compound of Formula 3, the effect of improving the agglomeration of zinc may be insignificant. If the amount is more than 1 time of the weight of the compound of Formula 3, excess celite remains during extraction and purification. You may have a problem.

The preferred reaction temperature in this step is 40 to 70 ° C, more preferably 45 to 65 ° C. If the reaction temperature is less than 40 ℃, the reaction time is too long, the reaction time may be too long, the instantaneous explosion may occur due to the exotherm during the reaction, if the reaction temperature exceeds 70 ℃ may require additional purification process as the by-products increase .

The preferred reaction time of this step is within 10 minutes, more specifically 5 to 10 minutes. If the reaction time exceeds 10 minutes, further purification may be required due to an increase in impurities.

Properly adjusting the amount of various reactants, additives and solvents (particularly, amounts of zinc and acetic acid), reaction temperature and reaction time in step (b) as described above minimizes the generation of by-products, and separately separates the obtained compound of Formula 2 Can be used immediately in the next step (c) without the separation / purification of the bar, by this continuous process the overall manufacturing time of the docetaxel is significantly reduced.

(c) step: preparation of the docetaxel crude product

This step is to use the oxazolidine side chain-containing 7,10-hydroxy taxane compound (formula 2) obtained in the step (b) as an intermediate to ring-open the oxazolidine ring through a ring opening in the presence of an acidic medium Finally, to prepare a docetaxel (Formula 1) crude product:

[Formula 1]

Acidic media that can be used for the ring opening in this step include, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid and methanesulfonic acid, preferably hydrochloric acid. The acidic medium is preferably used in an amount of 2-5% (v / v) based on the total volume of the reactants in step (c). If the amount is less than 2% based on the total volume of the reactants, the reaction may be unterminated or the reaction time may be too long. If the amount is greater than 5% based on the total volume of the reactants, the by-products are increased and the acid is removed from the extraction process. Additional purification may be required.

Reaction solvents usable in this step include, but are not limited to, methanol, ethanol, isopropyl alcohol, ethyl acetate or mixtures thereof.

Preferred reaction temperature in this step is 0 to 40 ° C, more preferably 20 to 30 ° C. If the reaction temperature is less than 0 ℃ may not proceed or the reaction time is too long, and if the reaction temperature exceeds 40 ℃ by-products can be increased.

The preferred reaction time of this step is 1 to 2 hours. If the reaction time is less than 1 hour, the reaction is not terminated and additional hydrochloric acid may cause a problem. If the reaction time exceeds 2 hours, by-products may be increased.

The docetaxel crude product obtained through the above steps (a) to (c) may be filtered and concentrated and further purified according to a conventional method in the art. The method for purifying the docetaxel crude product is not particularly limited, and may be purified through methods commonly used in the art, such as column chromatography. Semisynthetic docetaxel prepared according to the present invention can be easily purified through a simple chromatographic process, can finally provide a high purity docetaxel.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are provided only for the understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.

Example 1 Preparation of a Compound of Formula 3

0.3 L of ethyl acetate was added to the reactor, and 29 g of a compound represented by Chemical Formula 5 (HPLC purity of 98% or more, (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl ) -4-phenyloxazolidine-5-carboxylic acid), 3 g of 4-dimethylaminopyridine (DMAP) and 50 g of a compound of Formula 4 (at least 98% HPLC purity) were added thereto. 21 g of dicyclohexylcarbodiimide (DCC) was added at 20 ° C, and the yellow reactant was stirred for 30 minutes. After completion of the reaction, the reaction product was filtered through a pad of celite, the filtrate was washed with an aqueous sodium carbonate solution, and the obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow target compound. 0.05 L of ethyl acetate was added at room temperature for further purification, and 1 L of hexane was added dropwise while stirring to crystallize. After stirring at room temperature for 1 hour, the precipitate was filtered and then dried in vacuo at 40 ° C. to give a white desired compound (68 g, yield 95%). (HPLC purity 97%)

High performance liquid chromatography (HPLC) analysis conditions and assays were as follows.

TABLE 1 HPLC Analysis Conditions

Table 2 HPLC Analysis (Unit: v / v%)

Example 2: Preparation of Compound of Formula 2

0.25 L of methanol was added to the reactor, 0.034 L of acetic acid, 50 g of celite and 33 g of zinc (Zn dust, 10 micrometers or less) were added at 50 to 55 ° C, followed by stirring for 10 minutes. 68 g of the compound of formula 3 obtained in Example 1 dissolved in 0.25 L of methanol was added to the reaction solution, and stirred at 50 to 60 ° C for 10 minutes. After completion of the reaction, the reaction mixture was filtered through a pad of celite in a hot state, and after washing and filtering the pad of celite with 0.25 L of methanol, the filtrate was used for the next reaction without further purification. (85% HPLC Purity of Filtrate)

HPLC analysis conditions and methods are the same as in Example 1 above.

Example 3: Preparation of Compound of Formula 1

After introducing the filtrate obtained in Example 2 into the reactor, 0.027 L of concentrated hydrochloric acid was added at 20 ° C. After the reaction solution was stirred at 20 to 25 ° C. for 90 minutes, 0.5 L of dichloromethane and 0.5 L of purified water were added to the reaction solution, followed by extraction. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then dried in vacuo at 45 ° C. to give a yellow target compound (52.5 g, 122% yield in two steps). (Content 65% by EP assay (European Pharmacopoeia 6.6. 01-2010: 2449))

Example 4: Preparation of Compound of Formula 1 through Continuous Process

(a) 2.5 L of ethyl acetate was added to a reactor, and 290 g of a compound of Formula 5 (99% purity of HPLC), 30 g of 4-dimethylaminopyridine (DMAP) and 500 g of a compound of Formula 4 (98% purity of HPLC) were added thereto. Input. 230 g of dicyclohexylcarbodiimide (DCC) was added at 20 ° C, and the yellow reactant was stirred for 30 minutes. After completion of the reaction, the reaction product was filtered through a pad of celite, the filtrate was washed with an aqueous sodium carbonate solution, and the obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow target compound. (HPLC purity 93% of the filtrate)

(b) The filtrate containing the obtained compound of Formula 3 was added to a reactor, and 0.35 L of acetic acid and 500 g of celite were added at 55 ° C. 330 g of zinc (Zn dust, 10 micrometers or less) was slowly added to the reaction solution, stirred for 10 minutes, and the reaction product was filtered through a celite pad in a hot state. After additionally washing and filtering the celite pad with 2 L of ethyl acetate, the filtrate was used for the next reaction without further purification. (HPLC purity 82% of the filtrate)

(c) The filtrate containing the obtained compound of formula (2) was added to a reactor, and 0.35 L of concentrated hydrochloric acid was added at 20 ° C. After the reaction solution was stirred at 20 to 25 ° C. for 90 minutes, the reaction solution was washed twice with 5 L of purified water. The organic layer was dehydrated with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo at 45 ° C. to give a yellow target compound (482 g, 3 steps overall yield 107%). (Content 65% by EP method)

Example 5 Preparation of Compound of Formula 1 Through Continuous Process

(a) 2.5 L of ethyl acetate was added to a reactor, and 290 g of a compound of Formula 5 (99% purity of HPLC), 30 g of 4-dimethylaminopyridine (DMAP) and 500 g of a compound of Formula 4 (98% purity of HPLC) were added thereto. Input. 230 g of dicyclohexylcarbodiimide (DCC) was added at 20 ° C, and the yellow reactant was stirred for 30 minutes. After completion of the reaction, the reaction mixture was filtered through a pad of celite, the filtrate was washed with an aqueous sodium carbonate solution, the obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a total volume of about 0.8-1 L.

(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, 10 micrometers or less) were added and stirred for 10 minutes at 50 ° C. The filtrate containing the obtained compound of Formula 3 was dissolved in 2.5 L of methanol, introduced into the reactor, stirred for 10 minutes, and the reaction was filtered through a pad of celite in a hot state. After additionally washing and filtering the pad of celite with 2 L of methanol, the filtrate was used for the next reaction without further purification. (83% HPLC Purity of Filtrate)

(c) The filtrate containing the obtained compound of formula (2) was added to a reactor, followed by addition of 0.28 L of concentrated hydrochloric acid at 20 ° C. After the reaction solution was stirred at 20 to 25 ° C. for 90 minutes, 7.5 L of dichloromethane and 5 L of purified water were added to the reaction solution. The obtained organic layer was dehydrated with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo at 45 ° C. to obtain a yellow target compound (488 g, 108% yield in 3 steps). (Content 71% by the EP method)

Purification of Semisynthetic Docetaxel (Compound of Formula 1)

450 g of the semisynthetic docetaxel obtained in Example 5 was completely dissolved in 2.5 L of methanol, and then crystallized by dropwise addition to 13 L of purified water. The resulting white crystals were stirred at 30 to 35 ° C. for 30 minutes, then filtered through a filter paper, and the white crystals were washed with 2.5 L of purified water. The obtained wet white crystalline compound was dried in vacuo at 65 ° C. to obtain a white desired compound (415 g). (84% content by EP assay)

Separation and purification were performed by liquid chromatography on a column (25 90 cm) filled with silica gel (60-100 micrometer, Timely, Japan). Mobile phase was equilibrated with a flow rate of 3.4 L / min using a 2.5% methanol / 97.5% dichloromethane solution, and 300 g of the sample was dissolved in dichloromethane and all injected. The mobile phase solvent was continued to flow and the corresponding peak was collected using a UV detector, and then concentrated under reduced pressure. Drying in vacuo at 40 ° C. afforded the desired compound as a white solid (227 g, 99.5% HPLC purity, 0.1% or less of an individual analog). The following analysis was performed about the obtained docetaxel.

1. Specific optical rotation [α] (based on the method EP pharmacopeia method)

[α] ²³ _D = -40.01 ° (c = 0.1, MeOH)

2.NMR 400 MHz (CDCl ₃ )

3. High Resolution Mass Spectroscopy (HRMS) (device name-Shimadzu LCMS-IT-TOF, Kyoto, Japan)

Claims (14)

To remove the protecting group of the compound represented by the formula (3) through a deprotection reaction to prepare a compound represented by the formula (2),
To obtain a docetaxel represented by the following formula (1) using the compound represented by the formula (2) as an intermediate,
Method for preparing docetaxel represented by Formula 1 below:
(3)

(2)

[Formula 1]

In the above, 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 of claim 1,
(a) an oxazolidine side chain represented by the following formula (3) by condensation reaction of a 10-deacetylbaccatin III protected with a 7,10-hydroxy group represented by the following formula (4) with an oxazolidine acid derivative represented by the following formula (5) Preparing a containing taxane compound;
(b) preparing a 7,10-hydroxy taxane compound represented by the following Chemical Formula 2 by removing the protecting group at the 7,10-position of the oxazolidine side chain-containing taxane compound obtained in step (a); And
(c) ring-opening the 7,10-hydroxy taxane compound obtained in step (b) in the presence of an acidic medium to prepare a docetaxel crude product.
Method for preparing docetaxel represented by Formula 1 below:
[Chemical Formula 4]

[Chemical Formula 5]

(3)

(2)

[Formula 1]

In the above, 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 according to claim 2, wherein in step (a), the oxazolidine acid derivative represented by Formula 5 is used in an amount of 1 to 2 equivalents based on 1 equivalent of 10-deacetylbaccatin III represented by Formula 4. Method for preparing docetaxel. The method of claim 2, wherein in step (a), the condensation reaction is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-3- (3-dimethylaminopropyl) carbodiimide ( A process for producing docetaxel, characterized in that in the presence of at least one condensation agent selected from EDC). The method of claim 2, wherein in step (a), 4-dimethylaminopyridine, pyridine or a mixture thereof is added as an activator. The method for preparing docetaxel according to claim 2, wherein the oxazolidine side chain-containing taxane compound represented by the formula (3) obtained in step (a) is used directly in step (b) without separate purification. The method of claim 2, wherein in step (b), acetic acid and zinc are used to remove the protecting group at the 7,10-position. 8. The method for producing docetaxel according to claim 7, wherein 0.2 to 5 multiples of acetic acid and 0.3 to 1 multiples of zinc are used relative to the weight of the oxazolidine side chain-containing taxane compound represented by the formula (3). 8. The method of claim 7, wherein in step (b), celite is added. The method of claim 2, wherein in step (b), the reaction temperature is 40 to 70 ℃, the reaction time is within 10 minutes. 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 used directly in step (c) without separately separating and purifying. The method of claim 2, wherein in step (c), the acidic medium is at least one selected from hydrochloric acid, sulfuric acid, acetic acid, and methanesulfonic acid. The method of 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 the reactants. The method of claim 2, further comprising the step of purifying the docetaxel crude product prepared in step (c).