KR101009467B1 - Taxan derivative useful for synthesizing docetaxel and a method for preparing the same - Google Patents

Abstract

The present invention relates to novel taxane derivatives represented by the following general formula (I), useful for the synthesis of docetaxel, a process for preparing the derivatives, and a process for preparing docetaxel. The novel taxane derivatives according to the invention have tribromoacetyl substituents at positions 7 and 10 of 10-deacetylbacatin III.

7,10-bis (tribromoacetyl) -10-deacetylbacatin III, docetaxel, tribromoacetyl bromide, 10-deacetylbacatin III

Description

Taxane derivative useful for synthesizing docetaxel and a method for preparing the same}

The present invention relates to a derivative of 10-deacetylbaccatin III which can be usefully used for the synthesis of docetaxel represented by the formula (II) and a method of preparing the derivative. More specifically, the present invention relates to derivatives in which the hydroxy groups 7 and 10 of 10-deacetylbaccatin III are protected by tribromoacetyl group so as to be useful in the synthesis of docetaxel, and a method of preparing the same.

Docetaxel (Docetaxel) is a well-known strong anticancer component having a wide range of anticancer efficacy and is represented by the following structural formula (II).

Pharmaceutical formulations containing such compounds are useful for the treatment of non-small cell lung cancer, ovarian cancer and breast cancer in women.

Docetaxel is prepared by a semisynthetic method starting from 10-deacetylbaccatin III represented by the following general formula (III) obtained from natural products.

To prepare docetaxel, a phenylisoserine derivative should be introduced at position 13 of the starting material 10-deacetylbaccatin III. However, there are four hydroxy groups in 10-deacetylbaccatin III, and among them, 7 and 10 hydroxy groups have better reactivity than 13 hydroxy groups, so in order to introduce phenylisoserine derivatives into 13 hydroxy groups, 7 and 10 hydroxyl groups should be protected. The protecting groups used to protect the 7 and 10 hydroxy groups of 10-deacetylbaccatin III include triethylsilyl group and 2,2,2-trichloroethoxycarbonyl group.

U.S. Patent 5,254,703 uses triethylsilyl groups as protecting groups for 10-deacetylbaccatin III. To remove this protecting group at the end of docetaxel synthesis, hydrochloric acid, a strong acid, is used and the yield is 90%. However, the reactivity with triethylsilyl chloride in the hydroxy groups of 10-deacetylbaccatin III is very difficult to selectively protect only the hydroxy groups 7 and 10 in the order of 7> 13> 10. In fact, the yield of 10-deacetylbaccatin III protected with 7 and 10 by reacting 10-deacetylbaccatin III with triethylsilyl chloride is only 14% (Tetrahedron 55 (1999) pp. 6567-6576).

Korean Patent Application No. 1987-0007752 has reacted 10-deacetylbaccatin III with 2,2,2-trichloroethylchloroformate, so that the hydroxy groups of Nos. 7 and 10 are 2,2,2-trichloroethoxycarbonyl groups. Protected 10-deacetylbaccatin III in 93% yield. In the final step of docetaxel synthesis, the reaction to remove the protecting group removes the protecting group in 90% yield by using acetic acid as a reaction solvent and reacting with zinc at 60 ° C. However, this method also has a problem of using a very violent strong acidic condition in the protecting group removal reaction, and these problems are difficult to purify the final compound and cause an unexpected byproduct. The fact that various byproducts are produced in the process of preparing docetaxel is well described in the prior art document (R. Vasu Dev et al., Jouranl of Pharmaceutical And Biomedical Analysis 40 (2006) pp. 614-622).

Accordingly, the present inventors solved the problems of the known technology as described above, and continued the research to develop a new protecting group of 10-deacetylbacatin III which is easier to use in the preparation of docetaxel. It was found that derivatives (formula I) protecting hydroxy groups 7 and 10 of the tribromoacetyl group may be useful for the synthesis of docetaxel.

That is, the present inventors have developed a novel derivative and its synthesis method to easily protect the 7 and 10 hydroxy groups of 10-deacetyl baccatin III, and mildly protecting group removal reaction conditions. In particular, the present inventors focused on finding a novel 10-deacetylbaccatin III derivative in which a protecting group removal reaction can be easily performed under almost neutral conditions, considering that taxane derivatives such as docetaxel are unstable in strong acids or basicity. It was.

As a result, the present inventors reacted 10-deacetylbaccatin III represented by the formula (III) with tribromoacetyl chloride in the presence of a base to form a tribromo hydroxy group 7 and 10 represented by the formula (I). A 10-deacetylbaccatin III derivative protected by an acetyl group was prepared, and a new method was developed to remove the protecting group under mild or mild basic conditions in the protecting group removing step.

Therefore, according to the present invention, it was possible to develop a novel 10-deacetylbaccatin III derivative which can easily prepare docetaxel without using a strong acid used in the prior art or using a reagent that generates a toxic gas.

It is an object of the present invention to provide 7,10-bis (tribromoacetyl) -10-deacetylbacatin III, a new intermediate of docetaxel, which is a key component of promising anticancer agents, and to provide a new method for its preparation.

Another object of the present invention is to provide a new 7,10-bis (tribromoacetyl) -10-deacetylbaccatin III, which is simpler and more economically available for the preparation of docetaxel, and to provide a new method for its preparation. .

Another object of the present invention is to provide a new method for producing docetaxel.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention is to provide 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the following general formula (I) and a preparation method thereof.

7,10-bis (tribromoacetyl) -10-deacetylbacatin III (I) is reacted with tribromoacetyl chloride in the presence of a base 10-deacetylbacatin III represented by the formula (III) It is prepared by (Scheme 1).

By introducing a tribromoacetyl group into a new protecting group in 10-deacetylbaccatin III represented by the formula (III) as described above, it is possible to use neutral acid for the preparation of docetaxel without using a strong acid or a reagent that generates a toxic gas. However, a mildly basic mild condition can provide a method for easily removing the protecting group.
The present invention also provides a method for preparing docetaxel represented by the formula (II) by removing the 7 and 10 tribromoacetyl protecting groups of the taxane derivative represented by the formula (IV) under weakly basic or neutral conditions, respectively. (Scheme 2). 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromo) represented by formula (IV) Acetyl) -10-deacetylbacatin III is readily prepared according to techniques known in the art from 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) Can be.

Preferred embodiments of the invention are shown in Schemes 1 and 2 below.

7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I), wherein the hydroxy groups at positions 7 and 10 are protected with tribromoacetyl groups, is a new taxane derivative. The present invention aims to provide a novel taxane derivative represented by the formula (I). 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I) can be prepared by reacting with tribromoacetyl chloride in the presence of a base in a reaction solvent. It is also a subject of the present invention.

In the following, the present invention is described in more detail.

Scheme 1: 7,10- Vis ( Tribromoacetyl ) -10- Deacetylbacatin III Preparation of Formula (I): Introduction of Protecting Groups

7,10-bis (tribromoacetyl) -10 represented by formula (I) by reacting 10-deacetylbaccatin III represented by formula (III) with tribromoacetyl chloride in the presence of a base in a reaction solvent Prepare deacetylbacatin III.

Tribromoacetyl chloride is used in more than stoichiometric amount, preferably 1 to 1.5 equivalent times, relative to 10-deacetylbaccatin III represented by the formula (III).

Solvents usable for this reaction include ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether and dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, ethyl acetate and isopropyl Esters such as acetate and n-butyl acetate, aliphatic hydrocarbons such as pentane, hexane, heptane, chloride hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, One or more selected from amides such as dimethylacetamide and dimethylformamide, and basic solvents such as pyridine may be mentioned. When pyridine is used as the solvent, it can be directly reacted without adding a separate base. Further bases that can be used include organic bases such as pyridine, triethylamine, imidazole, DBU and diisopropylethylamine, alkoxides such as potassium t-butoxide and sodium ethoxide, n-butyllithium, phenyl lithium, Lithium diisopropylamide, sodium hydride, lithium bistrimethylsilylamide and the like. Reaction temperature is -20-60 degreeC, Preferably it is 10-30 degreeC. The reaction time is from immediately after the reaction to 12 hours, preferably 30 minutes to 2 hours.

7,10-bis (tribromoacetyl) -10-deacetylbacatin III (Formula I) obtained through the reaction as described above was concentrated under reduced pressure, extracted with ethyl acetate and water, and concentrated. After recrystallization with toluene or without extraction process can be recovered by column chromatography using ethyl acetate and hexane as eluent.

Scheme 2: Formula ( IV The protecting group of the compound represented by

13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromo) represented by formula (IV) Tribromoacetyl protecting groups at positions 7 and 10 of acetyl) -10-deacetylbacatin III can be easily removed with ammonia or a salt of ammonia with a weak acid. At this time, ammonia water of 5 to 40% concentration or ammonia-organic solvent solution of the same concentration is used as the ammonia, and the amount of ammonia is in stoichiometric amount or higher relative to the compound of formula (IV), preferably 1 to 5 equivalents Use as a ship range. When a salt of ammonia and a weak acid is used, it is used in a range of 1 to 5 equivalents based on the compound represented by the formula (IV), wherein a weak acid capable of forming a salt with ammonia is selected from formic acid, acetic acid, propionic acid, and the like. Can be. Examples of the reaction solvent include alcohols such as methanol, ethanol and isopropyl alcohol, esters such as tetrahydrofuran and n-butyl acetate, chloride hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, benzene, toluene, At least one selected from aromatic hydrocarbons such as xylene, amides such as dimethylacetamide and dimethylformamide may be used, and the reaction is preferably performed at a temperature range of 0 to 60 ° C.

By providing a novel taxane derivative through the present invention, the taxane derivatives provided in the present invention are ammonia solution or so far compared to conventionally required very strong acidic conditions to remove the protecting groups at positions 7 and 10 of the taxane. Protecting groups can be removed very easily in weakly basic or neutral conditions using salts of ammonia and weak acids.

Docetaxel represented by the formula (II) obtained through the reaction as described above was concentrated by depressurizing the solvent, extracted with ethyl acetate and water, concentrated and recrystallized with toluene, or immediately without ethyl acetate and hexane Can be recovered by column chromatography used as eluent.

As described above, according to the present invention, the 7,10-bis represented by the formula (I) by reacting 10-deacetylbaccatin III represented by the formula (III) with tribromoacetyl chloride in the presence of a base in the reaction solvent (Tribromoacetyl) -10-deacetylbaccatin III was prepared and a new method was developed to easily remove the protecting group in mild to neutral or mild basic conditions in the protecting group removing step. 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) is represented by formula (IV) according to techniques known in the art to prepare docetaxel. -[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetylbacca It can be prepared as Tin III.

As described above, the 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I) provided in the present invention not only facilitates the synthesis process but also prior art in the protecting group removal step. Unlike them, the bulk synthesis process of docetaxel is easier because the protecting group can be easily removed under very mild conditions.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Example 1 Preparation of 7,10-bis (tribromoacetyl) -10-deacetylbacatin III (Formula I)

5.0 g (9.18 mmol) of 10-deacetylbacatin III was dissolved in 225 ml of chloroform, and then 22.3 ml (30 eq.) Of pyridine was added dropwise and stirred for 10 minutes. 6.66 g (21.11 mmol) tribromoacetyl chloride was slowly added thereto and stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 mL of toluene, cooled to 0 ° C., the resulting white solid was filtered and washed with 30 mL of hexane to give 9.31 g (yield 92%) of the title compound.

¹ H NMR (CDCl ₃ ) δ = 1.12 (s, 3H), 1.23 (s, 3H), 1.93 (s, 3H), 2.05 (m, 1H), 2.25 (s, 3H), 2.33 (m, 2H) , 2.33 (s, 3H), 2.74 (m, 1H), 4.03 (d, J = 6.4Hz, 1H), 4.18 (d, J = 8.4Hz, 1H), 4.37 (d, J = 8.4Hz, 1H) , 4.94 (m, 1H), 5.00 (d, J = 9.5 Hz, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.74 (m, 1H), 6.54 (s, 1H), 7.50 (t, J = 7.4Hz, 2H), 7.64 (t, J = 7.4Hz, 1H), 8.12 (d, J = 7.1Hz, 2H)

Example  2: 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10- Deacetylbacatin III Formula IV Protector removal

13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetyl 4.0 g (2.93 mmol) of Bacatin III was dissolved in 20 ml of a methanol: tetrahydrofuran (3/1, v / v) mixed solvent, and 2.0 M ammonia (2.93 ml, 5.86 mmol) dissolved in methanol was added dropwise. After stirring for 1 hour at room temperature, the reaction solvent was removed by distillation under reduced pressure. 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 ml of toluene, cooled to 0 ° C. and the resulting white solid was filtered and washed with 30 ml of hexane to obtain pure 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2. 2.21 g (yield 93%) of -hydroxy-3-isobutyl-propanoyl] -10-deacetylbacatin III (docetaxel) were obtained.

¹ H NMR (CDCl ₃ ) δ = 1.12 (s, 3H), 1.24 (s, 3H), 1.35 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 2.28 (m, 2H) , 2.58 (m, 1H), 3.91 (d, J = 7 Hz, 1H), 4.19 (d, J = 9 Hz, 2H), 4.32 (d, J = 9 Hz, 2H), 4.26 (m, 1H), 4.62 ( d, J = 2 Hz, 1H), 4.94 (d, J = 9 Hz, 1H), 5.22 (s, 1H), 5.26 (dd, J = 9 Hz and J = 3 Hz, 1H), 5.46 (d, J = 9 Hz, 1H), 5.68 (d, J = 7 Hz, 1H), 6.22 (t, J = 9 Hz, 1H), 7.38 (5H), 7.50, 7.60, and 8.12 (5H)

Example  3: 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10- Deacetylbacatin III Protector removal

13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetyl 4.0 g (2.93 mmol) of Bacatin III was dissolved in 30 ml of a methanol: tetrahydrofuran (3/1, v / v) mixed solvent, and 0.84 g (10.90 mmol) of ammonium acetate was added thereto. After stirring for 3 hours at room temperature, the reaction solvent was removed by distillation under reduced pressure. 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 ml of toluene, cooled to 0 ° C. and the resulting white solid was filtered and washed with 30 ml of hexane to obtain pure 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2. 2.18 g (yield 92%) of -hydroxy-3-isobutyl-propanoyl] -10-deacetylbacatin III (docetaxel) were obtained.

¹ H NMR (CDCl ₃ ) δ = 1.12 (s, 3H), 1.24 (s, 3H), 1.35 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 2.28 (m, 2H) , 2.58 (m, 1H), 3.91 (d, J = 7 Hz, 1H), 4.19 (d, J = 9 Hz, 2H), 4.32 (d, J = 9 Hz, 2H), 4.26 (m, 1H), 4.62 ( d, J = 2 Hz, 1H), 4.94 (d, J = 9 Hz, 1H), 5.22 (s, 1H), 5.26 (dd, J = 9 Hz and J = 3 Hz, 1H), 5.46 (d, J = 9 Hz, 1H), 5.68 (d, J = 7 Hz, 1H), 6.22 (t, J = 9 Hz, 1H), 7.38 (5H), 7.50, 7.60, and 8.12 (5H)

The present invention relates to 7,10-bis (tribromoacetyl) -10-deacetyl, which is easily prepared from 10-deacetylbaccatin III represented by formula (I) and represented by formula (I) that is easy to remove protecting groups. It has the effect of providing Bacatin III and its preparation.

In the prior art in which the protecting group of 10-deacetylbaccatin III represented by the formula (III) is introduced, the process of selectively protecting positions 7 and 10 is obtained in very low yield or requires an excessive amount of reagent, There is a problem that a very strong acidic condition is required during the removal of the protecting group. However, the present invention has an advantage that the protecting group can be easily introduced, and the protecting groups can be easily removed in a weakly basic or neutral condition using an ammonia solution or a salt of ammonia and a weak acid in the protecting group removing step.

Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (7)

7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) below.

7, represented by formula (I) according to claim 1, characterized in that 10-deacetylbaccatin III represented by formula (III) is reacted with tribromoacetyl chloride in the presence of a base in a reaction solvent. A process for preparing 10-bis (tribromoacetyl) -10-deacetylbacatin III.

The solvent used in the reaction according to claim 2, wherein the solvent used for the reaction is tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, At least one selected from dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, dimethylacetamide, dimethylformamide. The base used in the reaction according to claim 2, wherein the base used for the reaction is pyridine, triethylamine, imidazole, DBU, diisopropylethylamine, potassium t-butoxide, sodium ethoxide, n-butyllithium, phenyllithium, lithium di At least one selected from isopropylamide, sodium hydride, and lithium bistrimethylsilylamide. Using a salt of one a weak acid selected from the group consisting of ammonia or ammonia and acetic acid, formic acid and propionic acid, the tribromoacetyl protecting groups 7 and 10 of the taxane derivative represented by the following formula (IV) are respectively removed A process for producing docetaxel represented by the formula (II).

The method according to claim 5, wherein 5 to 40% of ammonia is added in an amount of 1 to 5 equivalents to the taxane derivative represented by the formula (IV) to remove the tribromoacetyl protecting group. The salt of one weak acid selected from the group consisting of ammonia and acetic acid, formic acid and propionic acid is added in an amount of 1 to 5 equivalents to the taxane derivative represented by the formula (IV) to remove the tribromoacetyl protecting group. The manufacturing method characterized by the above-mentioned.