KR100868116B1 - Docetaxel·monopropyleneglycol clathrate and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a docetaxel monopropylene glycol inclusion compound (clathrate) and a method for producing the same, the docetaxel monopropylene glycol inclusion compound according to the present invention having a structure of formula (1) has a 7- epimer content Since it is very low and excellent in stability, it can be usefully used as a raw material for anti-tumor and anti-leukemia treatment.

<Formula 1>

Description

DOCETAXEL MONOPROPYLENEGLYCOL CLATHRATE AND METHOD FOR THE PREPARATION THEREOF}

1 is an X-ray diffraction analysis of docetaxel trihydrate (a), docetaxel hemihydrate (b) and docetaxel anhydride (c).

2 and 3 are X-ray diffraction analysis results and NMR spectrum analysis results of docetaxel-monopropylene glycol-containing compounds prepared according to the present invention, respectively.

The present invention relates to a docetaxel-monopropylene glycol-containing compound having a low 7-epimer content and excellent stability and a method for preparing the same.

Docetaxel is a compound having the structure of Formula 2 below, and is a cancer chemotherapy agent having a wide range of anti-tumor and anti-leukemic activity, which has already been recognized for its activity and is commercially available as a treatment for breast cancer and ovarian cancer.

Where

Ph denotes a phenyl radical, Ac denotes an acetyl radical, Bz denotes a benzoyl radical, and Boc denotes a t-butoxycarbonyl radical, which is used herein in the same sense hereinafter.

There are three types of docetaxel crystalline forms known so far: docetaxel trihydrate (a), docetaxel hemihydrate (b), and docetaxel anhydride (c). The X-ray diffraction analysis results thereof are shown in FIG. 5723635 and J. Phys. IV France 11, Pr10-221 (2001). Of these, docetaxel trihydrate is a substantial raw material of docetaxel in circulation.

For example, US Pat. No. 5,635,635 discloses a method for preparing docetaxel trihydrate using a mixed solvent of methyl isobutyl ketone, acetone and water. However, this method is difficult to apply industrially because it requires the use of a special apparatus called centrifugal partition chromatography.

On the other hand, US Patent No. 602985 dissolves docetaxel in ethanol, and then crystallizes by dropwise addition of water at 50 ° C, and then docetaxel crystals are dried for 48 hours under reduced pressure conditions of oven temperature 38 ℃, relative humidity 80%, 5.07 kPa to docetaxel A method of preparing trihydrate is disclosed, and US Pat. No. 6838569 dissolves docetaxel in acetonitrile, crystallizes water by dropwise addition at 68 ° C., and then crystallizes the docetaxel crystal at an oven temperature of 36 ° C. and 650 torr. A method of preparing docetaxel trihydrate by drying for 36 hours under reduced pressure is disclosed.

The difficulty in producing high purity docetaxel is to remove impurities and residual solvent.

However, when preparing docetaxel trihydrate by the methods disclosed in this patent, 7-epimer, i.e. 4-acetoxy-2α-benzoyloxy-5-β, 20-epoxy-1,7α, 10β The content of -trihydroxy-9-oxo-tax-11-ene-13-α-yl (2R, 3S) -3-t-butoxycarbonylamino-2'-hydroxy-3-phenylpropionate 0.4 to 0.8%, which is higher than the docetaxel raw material standard (0.5% or less). Therefore, in order to lower the 7-epimer content to 0.5% or less, there is a problem that a separate purification operation must be performed.

Therefore, the inventors of the present invention while studying a method for easily producing a high-purity docetaxel, in the case of the docetaxel monopropylene glycol inclusion compound 7-epimer content is obtained in a very low state of 0.1% or less. Rather, the present invention has been completed by finding that the stability is very excellent and non-hygroscopic.

Accordingly, an object of the present invention is to provide a docetaxel-monopropylene glycol-containing compound having a 7-epimer content of 0.1% or less, excellent stability and non-hygroscopic property, and a method for preparing the same.

In order to achieve the above object, the present invention provides a docetaxel monopropylene glycol-containing compound of formula (1):

Where

Ph represents a phenyl radical, Ac represents an acetyl radical, Bz represents a benzoyl radical, and Boc represents a t-butoxycarbonyl radical.

In addition, the present invention comprises dissolving docetaxel of formula (2) in an organic solvent and propylene glycol, and then adding anti-solvent to recover the resulting crystals, docetaxel of formula (1) Provided is a method for producing a monopropylene glycol-containing compound.

<Formula 1>

<Formula 2>

Hereinafter, the present invention will be described in more detail.

The docetaxel-monopropylene glycol inclusion compound of Chemical Formula 1 according to the present invention is a inclusion compound in which propylene glycol is included in docetaxel, and 90.0 to 92.5 wt% of docetaxel with respect to the total content of the inclusion compound, propylene glycol It contains 7.6 to 9.6 weight%.

The docetaxel monopropylene glycol inclusion compound of the present invention is a 7-epimer, that is, 4-acetoxy-2α-benzoyloxy-5-β, 20-epoxy-1,7α, 10β-trihydroxy- The content of 9-oxo-tax-11-ene-13-α-yl (2R, 3S) -3-t-butoxycarbonylamino-2'-hydroxy-3-phenylpropionate is 0.1% or less. Very low, non-hygroscopic, and excellent in stability, it can be usefully used as a raw material for the treatment of anti-tumor and anti-leukemia.

The docetaxel monopropylene glycol inclusion compound of the formula (1) of the present invention is dissolved in docetaxel of formula (2) in an organic solvent and propylene glycol, and the resulting crystals are filtered and dried under reduced pressure to remove the solvent It can be easily obtained by removing.

<Formula 1>

<Formula 2>

Docetaxel of Formula 2 used as a starting material in the present invention can be prepared and used in the following manner: As shown in Scheme 2, 1) (2R, 3S) -Nt-butoxycarbonyl-4- The phenylisoserine methyl ester compound (Formula 3) is reacted with 1-dimethoxymethyl naphthalene in the presence of an acid catalyst in an organic solvent to prepare an oxazolidine methyl ester derivative (Formula 4), and the compound of Formula 4 is sequentially Hydrolysis under conditions to prepare an oxazolidine acid derivative (Formula 5); 2) an oxazolidine side chain-containing taxane (Formula 7) is prepared by coupling an oxazolidine acid derivative (Formula 5) with a protected 10-deacetylbacatin III (Formula 6) in the presence of a condensing agent in a solvent; ; 3) reacting an oxazolidine side chain containing taxane compound (Formula 7) in the presence of an acid in an organic solvent to prepare a docetaxel (Formula 8) in which a 7,10-hydroxy group is protected; 4) Docetaxel (Formula 2) may be prepared by removing the protecting group at the 7,10-position of docetaxel (Formula 8) in which the 7,10-hydroxy group is protected.

Organic solvents used to dissolve docetaxel in the present invention include dichloromethane, chloroform, ethyl acetate, methyl acetate, dimethyl carbonate, diethyl ether or acetone, etc., the amount used is 5 to 30 times by volume based on the weight of docetaxel It is preferable to use.

Propylene glycol used in the present invention is preferably used in the range of 1 to 50 equivalents relative to docetaxel.

According to the present invention, in order to separate and recover a docetaxel monopropylene glycol inclusion compound from a docetaxel solution dissolved in an organic solvent and propylene glycol, anti-solvent is added dropwise to the solution to form a crystal. In this case, C _5-7 alkanes such as pentane, hexane or heptane may be used as the anti-solvent. The anti-solvent is preferably used in an amount of 1 to 5 volume times based on the organic solvent.

After the crystals thus obtained were recovered through filtration, the obtained docetaxel-monopropylene glycol-containing compound contained a solvent and a semi-solvent, and thus the crystals were prepared at an oven temperature of 20 to 80 캜, 0.1 to Docetaxel-monopropylene glycol-containing compounds can be easily prepared by drying under a reduced pressure of 10 torr, for example, by removing the residual solvent to a level that satisfies the ICH (International Conference on Harmonization) Standard for Acceptable Residual Solvents. Can be.

The docetaxel-monopropylene glycol-containing compound prepared according to the present invention is 90 to 92.5% of docetaxel and 7.6 to 9.6% of propylene glycol when the docetaxel and the propylene glycol are respectively analyzed by the content analysis method. 7-epimer content is 0.1% or less and purity is 99.5% or more.

As such, the docetaxel-monopropylene glycol-containing compound according to the present invention is easily prepared in a state in which 7-epimer is reduced compared to docetaxel trihydrate and has excellent stability, and thus is useful as a raw material for treating anti-tumor and anti-leukemia. Can be used.

Hereinafter, the present invention will be described in more detail by the following Preparation Examples and Examples. However, the following Preparation Examples and Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example: Preparation of Docetaxel (Compound of Formula 2)

(1): (2R, 4S, 5R) -2- (1'-naphthyl) -3-t-butoxycarbonyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid methyl ester Preparation of (Compound of Formula 4)

295 g of (2R, 3S) -Nt-butoxycarbonyl-4-phenylisoserine methyl ester, 6 g of pyridinium p-toluenesulfonate and 222 g of 1-dimethoxymethylnaphthalene were added dropwise to 6 L of toluene, 3 L of toluene was removed by heating to reflux for 1 hour. After the reaction temperature was lowered to room temperature, the reaction solution was diluted with 3 L of ethyl acetate and neutralized with 1.5 L of saturated aqueous sodium bicarbonate solution. After separating the organic layer, the neutralized reaction solution was washed with 1.5 L of saturated brine aqueous solution, and then the organic layer was dried over anhydrous magnesium sulfate. After magnesium sulfate was separated by filtration, the organic solvent was distilled off under reduced pressure to obtain 520 g of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (d, J = 8.4 Hz, 1H), 7.89 (m, 2H, Ar), 7.42 (m, 10H, Ar), 5.60 (s, 1H), 4.58 ( d, J = 2.7 Hz, 1H), 3.11 (s, 3H), 1.06 (s, 9H).

(2): (2R, 4S, 5R) -2- (1'-naphthyl) -3-t-butoxycarbonyl-4-phenyl-1,3-oxazolidine-5-

Preparation of Carboxylic Acid (Compound of Formula 5)

The compound obtained in (1) was dissolved in 5 L of methanol, and 600 ml of 3N lithium hydroxide was slowly added dropwise while stirring at 0 ° C. After stirring for 2 hours, 2.5 L of methanol was removed by distillation under reduced pressure, and 2.5 L of water was added dropwise thereto. The water layer was washed twice with 1 L of ethyl acetate / hexane (1/10, v / v). The temperature of the mixed solution was maintained at 0 ° C. and neutralized by slowly dropwise adding 200 ml of 3N hydrochloric acid. 1 L of ethyl acetate was added dropwise to the mixed solution, and the aqueous layer was removed with a separatory funnel. The organic layer was washed with 1 L of saturated salt aqueous solution, the organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was separated by filtration, and the organic solvent was distilled off under reduced pressure to give 413 g (yield: 98.5%) of the title compound. Got it.

Melting point: 119 ° C .; [α] _D ²³ = +56.9。 (c = 1, CHCl ₃ )

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (d, J = 8.3 Hz, 1H), 7.91 (m, 2H, Ar), 7.46 (m, 10H, Ar), 5.60 (d, J = 3.1 Hz, 1H), 4.62 (d, J = 3.1 Hz, 1H), 1.04 (s, 9H)

(3): (2'R, 4'S, 5'R) -3'-t-butoxycarbonyl-2 '-(1' ''-naphthyl) -4'-phenyl-1 ', 3'- Preparation of oxazolidine-5'-carbonyl-7,10- (di-3 ", 5" -dinitrobenzoyl) -10-deacetylbacatin III (compound of formula 7)

92 g of the compound obtained in the above (2), 93 g of 7,10- (di-3 ', 5'-dinitrobenzoyl) -10-deacetylbaccatin III, and 610 mg of 4- (dimethylamino) pyridine were ethyl It was dissolved in 1.8 L of acetate. Stirring was carried out while maintaining the temperature in the reaction vessel at 25 ℃. After adding 52 g of dicyclohexylcarbodiimide at 25 ° C. and stirring for 2 hours, the formed dicyclohexylurea was separated by filtration. The cake was washed with 200 ml of ethyl acetate and the combined organic phases were washed with 300 ml of 1N hydrochloric acid. The organic layer was washed with 300 ml of saturated aqueous sodium bicarbonate solution, and then the organic layer was dried over anhydrous magnesium sulfate. After magnesium sulfate was separated by filtration, the organic solvent was distilled off under reduced pressure. 800 ml of acetonitrile were added to the residue, followed by stirring for 1 hour. Then, 800 ml of water was slowly added dropwise, followed by stirring for 2 hours. The solid was filtered, 800 ml of acetonitrile was added thereto, and stirred for 1 hour. Then, 800 ml of water was slowly added dropwise, followed by further stirring for 2 hours. The solid was filtered to give 134 g (yield: 100%) of the title compound.

Melting point: 202 ° C .; [a] _D ²³ = 16.1。 (c = 1, CHCl ₃ ); IR (KBr, cm ^-1 ) 3560, 3446, 3102, 2977, 2939, 2897, 1740, 1718, 1628, 1548, 1547, 1344, 1268, 1162, 1069, 978, 919, 729, 718.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.27 (m, 1H), 9.20 (m, 1H), 9.04 (m, 2H), 8.76 (m, 2H), 8.11 (d, J = 7.5 Hz, 2H) , 8.02 (m, 2H), 7.62 (m, 2H), 7.53 7.43 (m, 13H), 6.30 (s, 1H), 5.95 (t, J = 8.3 Hz, 1H), 5.68 5.58 (m, 3H), 4.93 (d, J = 8.0 Hz), 4.68 (d, J = 4.3 Hz), 4.32 (d, J = 8.6 Hz, 1H), 4.14 (d, J = 8.6 Hz, 1H), 3.79 (d, J = 7.1 Hz, 1H), 2.83 2.79 (m, 1H), 2.20 1.98 (m, 6H), 1.90 (s, 3H), 1.56 (s, 3H), 1.25 (s, 3H), 1.19 (s, 3H), 0.86 (s, 12 H).

(4): 13-[(2'R, 3'S) -3'-t-butoxycarbonylamino-3'-phenyl-2'-hydroxypropionyl] -7,10- (di-3 ", Preparation of 5 "-dinitrobenzoyl) -10-deacetylbacatin III (compound of formula 8)

134 g of the compound obtained in (3) was dissolved in 670 ml of chloroform and 130 ml of methanol, and 19.2 g of p-toluenesulfonic acid monohydrate was added dropwise thereto, and the reaction mixture was stirred at room temperature for 3 hours. The organic layer was washed with 1.4 L of water containing 13 g of sodium bicarbonate and dried over anhydrous magnesium sulfate. After magnesium sulfate was separated by filtration, the organic solvent was distilled off under reduced pressure to obtain a solid. After dissolving in 1.2 L of diethyl ether to the obtained solid, 2.4 L of hexane was slowly added dropwise. After stirring for 3 hours at room temperature, the solid was separated by filtration, and then the obtained solid was dissolved in 330 ml of acetonitrile, and 770 ml of water was slowly added dropwise. The reaction was stirred at room temperature for 3 hours, and then the solvent was removed by filtration to give 109 g (yield: 91%) of the title compound.

Melting point: 173 ° C .; [a] _D ²³ = 8.9 ° (c = 1, CHCl ₃ ); IR (KBr, cm ^-1 ) 3543, 3432, 3101, 2978, 2900, 1736, 1628, 1548, 1494, 1455, 1368, 1345, 1269, 1163, 1095, 1070, 978, 920, 730, 718.

¹ H NMR (CDCl ₃ , 300 MHz): δ 9.27 (m, 1H), 9.21 (m, 1H), 9.03 (m, 2H), 8.87 (m, 2H), 8.15 (d, J = 7.5 Hz, 2H) , 7.65 (m, 1H), 7.54 (m, 2H), 7.40 7.43 (m, 5H), 6.63 (s, 1H), 6.27 (m, 1H), 5.88 (m, 1H), 5.80 (d, J = 6.9 Hz, 1H), 5.38 (d, J = 9.4 Hz, 1H), 5.28 (m, 1H), 5.03 (d, J = 8.1 Hz, 1H), 4.67 (d, J = 3.1 Hz, 1H), 4.41 (d, J = 8.6Hz, 1H), 4.26 (d, J = 8.6Hz, 1H), 4.07 (d, J = 6.7Hz, 1H), 3.34 (d, J = 5.3Hz, 1H), 2.87 (m , 1H), 2.46 (s, 3H), 2.42 (m, 2H), 2.01 2.05 (m, 3H), 2.01 (s, 3H), 1.87 (s, 1H), 1.59 (s, 3H), 1.39 (s , 3H), 1.36 (s, 9H), 1.32 (s, 3H).

(5): Preparation of docetaxel (compound of formula 2)

13-[(2'R, 3'S) -3'-t-butoxycarbonylamino-3'-phenyl-2'-hydroxypropionyl] -7,10- (di-3 obtained in the above (4). 60 g of ", 5" -dinitrobenzoyl) -10-deacetylbaccatin III was added to a mixed solution of 300 ml of methanol and 60 ml of morpholine, and stirred at room temperature for 3 hours. 500 ml of ethyl acetate was added dropwise to the reaction solution, and 700 ml of 1N hydrochloric acid was slowly added dropwise at 0 ^° C. The organic layer was separated and dried over anhydrous magnesium sulfate. After magnesium sulfate was separated by filtration, the organic solvent was distilled off under reduced pressure. The residue was purified by silica column chromatography to give 35 g of the title compound (yield: 87%, HPLC purity: 99.0%) as a white solid.

Example 1 Preparation of Docetaxel Monopropylene Glycol Inclusion Compound

10 g of docetaxel (HPLC purity: 99.0%) obtained in the same manner as in Preparation Example was dissolved in 150 ml of dichloromethane and 15 ml of propylene glycol at room temperature, and then 200 ml of n-hexane was slowly added dropwise thereto. The mixed solution was stirred at room temperature for 12 hours, and after filtration, the obtained solid was dried for 24 hours under an oven temperature of 60 ° C. under a reduced pressure of 0.1 torr, and the X-ray diffraction analysis as shown in FIG. 2 and the NMR as shown in FIG. 10.1 g (yield: 92%) of the docetaxel-monopropylene glycol-containing compound having a spectrum was obtained.

HPLC purity: 99.7%

7-Epimer: 0.03%

Docetaxel content: 91.2%

Melting Point: 208-214 ℃

Propylene glycol 8.4%;

Residual solvent dichloromethane: 20 ppm or less, n-hexane: 5 ppm or less

Example 2 Preparation of Docetaxel Monopropylene Glycol Inclusion Compound

9.8 g of docetaxel-monopropylene glycol-containing compound having the same X-ray diffraction value and NMR spectrum as in Example 1, except that ethyl acetate was used instead of dichloromethane as an organic solvent. Yield: 90%).

HPLC purity: 99.8%

7-Epimer: 0.04%

Docetaxel content: 91.0%

Melting Point: 210-215 ℃

Propylene glycol 8.7%;

Residual solvent ethyl acetate: 113 ppm, n-hexane: 5 ppm or less

Test Example: Stability Test of Docetaxel Monopropylene Glycol Containing Compound

The docetaxel monopropylene glycol inclusion compound prepared in Example 1 and the docetaxel trihydrate (comparative example) prepared by the method disclosed in U.S. Patent No. 6022985 were compared.

Specifically, each of the docetaxel monopropylene glycol inclusion compound and docetaxel trihydrate prepared in Example 1 was left for 8 weeks under accelerated conditions (60 ± 2 ℃, humidity 75 ± 5%), 1, After week, 2, 4 and 8 weeks the chemical purity of each compound was determined by liquid chromatography. The results are shown in Table 1 below.

As shown in Table 1, the docetaxel-monopropylene glycol-containing compound prepared in Example according to the present invention was stably present without change in purity of the main component up to 8 weeks under the accelerated conditions, while the docetaxel trihydrate as a comparative example. Purity decreased by about 0.7% in four weeks. From this result, it was confirmed that the docetaxel monopropylene glycol inclusion compound of the present invention is a much more stable compound than docetaxel trihydrate.

In addition, the docetaxel-monopropylene glycol-containing compound prepared in Example 1 was left for one week at a relative humidity of 25% and 50% and an external temperature of 40 ° C., and then analyzed for purity and content by HPLC. There was no change in the content of propylene glycol inclusion compounds and the amount of impurities.

In addition, the docetaxel-monopropylene glycol-containing compound prepared in Example 1 was left at a relative humidity of 90% and an external temperature of 30 ° C. for 72 hours to change the crystal form due to moisture absorption and deoxidation of propylene glycol to X-ray diffraction. Observations using analysis and NMR showed no change in crystalline form and no degradation of propylene glycol. This means that the docetaxel monopropylene glycol inclusion compound is a very stable compound that does not hygroscopically proceed to hydrate.

As described above, the docetaxel-monopropylene glycol-containing compound of formula 1 of the present invention is not only obtained with a 7-epimer content of 0.1% or less, but also has excellent stability as a raw material for anti-tumor and anti-leukemia treatment. It can be usefully used.

Claims (10)

Docetaxel-monopropylene glycol-containing compound of formula (I): <Formula 1>

Where Ph represents a phenyl radical, Ac represents an acetyl radical, Bz represents a benzoyl radical, and Boc represents a t-butoxycarbonyl radical. The method of claim 1, A docetaxel monopropylene glycol containing compound, characterized by containing 90 to 92.5% by weight of docetaxel and 7.6 to 9.6% by weight of propylene glycol, based on the total content of the docetaxel and monopropylene glycol inclusion compound. The method of claim 1, A docetaxel monopropylene glycol inclusion compound, characterized by containing 7% or less of 7-epimer. Docetaxel mono of formula (1) comprising dissolving docetaxel of formula (2) in an organic solvent and propylene glycol selected from the group consisting of dichloromethane and ethyl acetate, and then adding hexane to recover the resulting crystals Process for preparing propylene glycol inclusion compound: <Formula 1>

<Formula 2>

Where Ph represents a phenyl radical, Ac represents an acetyl radical, Bz represents a benzoyl radical, and Boc represents a t-butoxycarbonyl radical. The method of claim 4, wherein The method for producing a docetaxel monopropylene glycol inclusion compound, characterized in that the recovery step comprises the step of filtering the resulting crystals and drying under reduced pressure of 0.1 to 10 torr at a temperature of 20 to 80 ℃. . delete The method of claim 4, wherein A method for producing a docetaxel monopropylene glycol-containing compound, wherein the organic solvent is used in an amount of 5 to 30 times by volume based on the weight of docetaxel. The method of claim 4, wherein A method for producing a docetaxel monopropylene glycol inclusion compound, wherein the propylene glycol is used in an amount ranging from 1 to 50 equivalents relative to docetaxel. delete The method of claim 4, wherein A method for producing a docetaxel monopropylene glycol inclusion compound, wherein the hexane is used in an amount of 1 to 5 times by volume based on the volume of the organic solvent.

Images