KR20020066808A - Synthesis of taxane derivaties by asymmetric aminohydroxylation - Google Patents

Abstract

PURPOSE: Provided is a synthesis method of taxane derivatives, which are used for manufacturing an anticancer agent, paclitaxel, by asymmetric aminohydroxylation. CONSTITUTION: Taxane derivative of the formula(I) is manufactured by reacting cinnamic taxane derivative of the formula(II) and N-haloarylamide or its metallic salt. In the formula(II), R1 is acetyl, hydrogen, 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethyl)propoxycarbonyl, and R2 is hydrogen, trialkylsilyl, haloacetyl, alkanoyl, alkoxycarbonyl, alkylaminocarbonyl alkyl or aralkyl. In the formula(I), R1 and R2 are as described in the formula(II), and R3 is alkyl, aryl or substituted aryl.

Description

Method for preparing taxane derivatives using asymmetric aminohydroxylation reaction {Synthesis of taxane derivaties by asymmetric aminohydroxylation}

The present invention relates to a method for the effective synthesis of taxane derivatives used for the preparation of paclitaxel.

The production of paclitaxel using synthetic methods is mainly achieved using a coupling reaction between protected 10-diacetyl baccatin III or protected bacatin III and side chains.

In this case, as the side chains used, side chains in an activated form, such as β-lactam, oxazoline, oxazolidine, oxazolidinone, and oxazinone, are used. However, in order to synthesize the activated side chains, not only a multi-step synthesis but also a process of separating pure chiral enantiomers requires difficulty in processing and yield reduction of paclitaxel.

One of the methods for preparing side chains with preferred conformations is Song et. al (Tetrahedron: Asymmetry 10, 671-674 (1999), Chem. Commum. 2435-2436 (1998)) and Sharpless et. There is an asymmetric aminohydroxylation performed by al (US Pat. Nos. 5,767,304, 5,859,281). Song et al. Report the synthesis of enantioselective phenylisoserine derivatives through asymmetric aminohydroxylation of esters of simple cinnamic acids such as isopropyl trans-cinnamic acid. It was.

However, in the case of phenylisoserine esters synthesized from simple cinnamic esters, effective coupling with the taxane moiety requires conversion to the activated form and requires a multi-step synthesis process.

In addition, European Patent Publication 253738 reports an asymmetric aminohydroxylation reaction between alkoxycarbamate and cinnamic ester of taxane using an osmium catalyst. However, synthesis of paclitaxel from the product of this reaction requires continued synthesis processes such as deprotection and benzoylation of amines at the 3'-N position.

There is no example where the synthesis of paclitaxel was directly performed by reacting a taxane derivative of cinnamic acid with a haloalkylamide or haloarylamide, or a metal salt thereof in a solution containing an osmium catalyst and a chiral ligand as in the present invention.

The present invention provides a method for preparing paclitaxel.

The present invention provides a method for preparing a paclitaxel precursor for preparing paclitaxel.

The present invention relates to a process for the preparation of a taxane derivative used in the preparation of paclitaxel. The method for producing a taxane derivative represented by formula (I) in the present invention comprises reacting a cinnamic acid taxane derivative of formula (II) with N-haloarylamide or a metal salt thereof.

Wherein R ₁ is acetyl, hydrogen, 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloromethyl) propoxycarbonyl, and R ₂ is hydrogen, trialkylsilyl, haloacetyl, alkanes Noyl, alkoxycarbonyl, alkylaminocarbonyl alkyl or aralkyl.

Wherein R ₁ and R ₂ are as defined in formula (II) and R ₃ is alkyl, aryl or substituted aryl.

Compounds of formula (I) include water, alcohols and dichloromethane comprising lithium hydroxide (LiOH) and osmium tetraoxide (OsO ₄ ) or potassium osmate dihydrate (K ₂ OsO ₄ 2H ₂ O) at 0 to 30 ° C. Reacting a compound of formula (II) with N-haloarylamide such as N-bromobenzamide, N-chlorobenzamide, or a metal salt thereof in a solution composed of a nonpolar organic solvent containing benzene, toluene, or xylene Can be synthesized. Reacting N-bromobenzamide with a compound of formula (II) yields a mixture of stereoisomers of formula (I), which provides a compound of formula (I) having a preferred conformation by chromatography or physicochemical methods. Can be separated.

In order to obtain the compound of formula (I) by the amino hydroxylation reaction of arylamide with respect to the cinnamic acid-taxene derivative of the present invention, it is preferable to appropriately control the reaction conditions such as the molar ratio of chiral ligand, solvent and reactant. need. Since two new chiral centers are generated as a result of the reaction, a total of four isomers can be generated, two positional isomers and two stereoisomers each, and a diol is generated by dehydroxylation. Can be. In particular, the asymmetric aminohydroxylation reaction between the benzamide and the cinnamic esters of the taxane derivatives is asymmetric between the alkoxycarbamate and the cinnamic esters of the taxanes because of the possibility of side reactions of Hoffman rearrangement in the benzamide. There is a need for optimized reaction conditions that differ from European Patent Publication No. 253738, which suggests aminohydroxylation reactions. In particular, further preparation of paclitaxel using the process of EP-A-253738 requires further deprotection and benzoylation processes. In addition, since the cinnamic esters of taxanes already have several chiral centers in the molecule itself, the aminohexilation reactions of benzamide to simple cinnamic acid esters, such as isopropyl trans-cinnamic acid, which do not have chiral centers. (Tetrahedraom: Asymmetry 671-674, 1999) require different reaction conditions.

The composition ratio of stereoisomers comprising the compound of formula (I) resulting from asymmetric aminohydroxylation can be controlled by selecting the appropriate chiral ligand. Chiral ligands include dihydroquinine, dihydroquinine acetate, dihydroquinine chlorobenzoate, dihydrodiquinine phthalazine ((DHQ)₂PHAL), dihydroquinine pyrazine ((DHQ)₂PYR), dihydroquinine anthraquinone ((DHQ)₂AQN), and dihydroquinidine and its derivatives can be used equivalently, preferably in catalytic amount Can be used. The catalytic amount is from several to several tens of mole percent of the reactants. An asymmetric ligand such as dihydroquinine acetate is better in the present invention than a symmetric ligand that exhibits optimal stereoselectivity in the aminohydroxylation of benzamide to esters of simple cinnamic acid, such as isopropyl trans-cinnamic acid. Stereoselectivity can be exhibited and osmium can be used in equivalent or preferably catalytic amounts.

N-bromobenzamide or metal salts thereof of the present invention are described in J. Am. Chem. Soc., 59, 121 (1937).

The ester of formula (II) is a bacca 7-OH-protected cinnamic acid using a condensing agent such as carbodiimide, for example dicyclohexylcarbodiimide, in anhydrous nonpolar solvents such as benzene and toluene at room temperature. Obtained by esterification with tin III. At this time, 7-OH of Bacatin III may be protected by ester, ether, silyl ether, carbonate and the like. As an example 13-cinnaylyl-7-triethylsilyl-bacatin III can be prepared using 7-triethylsilyl bacatin III.

The present invention also relates to a process for preparing paclitaxel from cinnamic acid taxane derivatives.

Paclitaxel of the synthesis method according to the invention is R_OneIs acetyl, R₂Is reacted with cinnamic acid taxane derivative of formula (II) which is triethylsilyl and N-halbenzamide or a metal salt thereof₃Phenyl Compounds of formula (I) can be prepared and paclitaxel can be prepared by deprotecting the 7-OH protecting group according to known methods. One example of deprotection is in the case of 7-triethylsilyl-paclitaxel, which can be reacted at room temperature by adding pyridine, acetonitrile and fluoric acid / pyridine to obtain paclitaxel.

Hereinafter, the present invention will be described in detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1. Preparation of 13-cinamoyl-7-triethylsilyl-bacatin III.

2.0 g (2.86 mmol) of 7-triethylsilyl bacatin III was dissolved in 30 ml of benzene by stirring at room temperature. To this solution was added 0.83 g (5.74 mmol) of trans-cinnamic acid and 1.18 g (5.74 mmol) of dicyclohexylcarbodiimide, together with 0.53 g (4.32 mmol) of dimethylaminopyridine. The reaction was stirred at rt for 18 h then filtered over benzene and concentrated in vacuo. The product was purified by silica column chromatography (hexane: ethyl acetate = 3: 1) to give 2.16 g of 13-cinamoyl-7-triethylsilyl-bacatin III.

Example 2. Preparation of Paclitaxel.

8.06 mg (0.1 mmol) of lithium hydroxide hydrate and 1.47 mg (0.004 mmol, 4 mol%) of potassium osmate dihydrate were added to 1 ml of water, followed by stirring at room temperature. 4.41 mg (0.012 mmol, 12 mol%) of dihydroquinine acetate and 1 ml of tert-butyl alcohol were added to the solution, followed by stirring at room temperature for 10 minutes. 84 mg (0.1 mmol) of 13-cinamoyl-7-triethylsilyl-bacatin III of Example 1 and 47.6 mg (0.2 mmol, 2 eq) of N-bromobenzamide were added at 4 ° C., and dichloromethane 2 ml was added and stirred below 5 ° C. for 12 h. 47.6 mg (0.2 mmol, 2 eq) of N-bromobenzamide is further added to the reaction solution, and the mixture is further stirred for 80 hours. After completion of the reaction, the mixture was washed twice with 2 ml of Na ₂ SO ₃ solution, and the washed solution was again extracted twice with 5 ml of ethyl acetate, combined, dried over anhydrous magnesium sulfate, filtered and concentrated. Chiral ligands were removed by passing through short silica and 7-triethylsilyl-paclitaxel was obtained as a mixture containing isomers. At this time, the content of 7-triethylsilyl-paclitaxel in the mixture was 37%.

To a mixture of stereoisomers comprising 7-triethylsilyl-paclitaxel, 1 ml of pyridine, 1 ml of acetonitrile and 1 ml of fluoric acid / pyridine (70 wt%) are added and stirred at room temperature for 6 hours.

After the reaction, the mixture was diluted with 25 ml of water, extracted twice with 25 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated by filtration. Separation by column chromatography on silica gel eluting with a mixture of n-hexane: ethyl acetate (1: 2 volume ratio) gave 26 mg of paclitaxel.

Example 3. Preparation of 7-triethylsilyl-paclitaxel.

8.06 mg (0.1 mmol) of lithium hydroxide hydrate and 1.02 mg (0.004 mmol, 4 mol%) of lithium hydroxide tetrahydrate were added to 1 ml of water, followed by stirring at room temperature. To this solution, 5.67 mg (0.012 mmol, 12 mol%) of dihydroquinine para-chlorobenzoate and 1 ml of tert-butyl alcohol were added and stirred at room temperature for 10 minutes. 84 mg (0.1 mmol) of 13-cinamoyl-7-triethylsilyl-bacatin III of Example 1 and 95.2 mg (0.4 mmol, 4 eq) of N-bromobenzamide were added at 4 ° C., and dichloromethane 2 ml was added and stirred at 5 ° C. or lower for 12 hours. After 12 hours, 47.6 mg (0.2 mmol, 2 eq) of N-bromobenzamide was added to the reaction solution, and the mixture was further stirred for 80 hours. The reaction solution was concentrated under reduced pressure and passed through a silica column to obtain 80 mg of a mixture containing 7-triethylsilyl-paclitaxel partially purified. The content of 7-triethylsilyl-paclitaxel included in this mixture was 34%. Purification using HPLC of the silica column (hexane: methanol: isopropyl alcohol = 96: 2: 2) gave 27 mg (yield: 23%) of pure 7-triethylsilyl-paclitaxel.

Example 4. Preparation of 7-triethylsilyl-paclitaxel.

1.47 mg (0.004 mmol, 4 mol%) of potassium osmate dihydrate was added to 1 ml of water, followed by stirring at room temperature. To this solution was added 1.47 mg (0.004 mmol, 4 mol%) of dihydroquinine acetate and 1 ml of tert-butyl alcohol, and the mixture was stirred at room temperature for 10 minutes. 84 mg (0.1 mmol) of 13-cinamoyl-7-triethylsilyl-bacatin III of Example 1 and 52.1 mg (0.2 mmol, 2 eq) of N-bromobenzamide sodium salt at 4 ° C. were added, and dichloro 2 ml of methane were added and stirred for 40 hours. After the reaction, the reaction solution was washed twice with 2 ml of Na ₂ SO ₃ solution, and the washed solution was extracted twice again with 5 ml of ethyl acetate, and then mixed with the dichloromethane extract, dried over anhydrous sodium sulfate, and concentrated by filtration. A short silica column was used to remove chiral ligands and the like to obtain 7-triethylsilyl-paclitaxel in a mixture containing isomers and the content of 7-triethylsilyl-paclitaxel was 32%.

Example 5. Preparation of 7-triethylsilyl-paclitaxel.

1.47 mg (0.004 mmol, 4 mol%) of potassium osmate dihydrate was added to 1 ml of water, followed by stirring at room temperature. To this solution was added 3.11 mg (0.004 mmol, 4 mol%) of dihydroquinine phthalazine and 1 ml of tert-butyl alcohol, followed by stirring at room temperature for 10 minutes. 84 mg (0.1 mmol) of 13-cinamoyl-7-triethylsilyl-bacatin III of Example 1 and 52.1 mg (0.2 mmol, 2 eq) of N-bromobenzamide sodium salt at 4 ° C. were added, and dichloro 2 ml of methane were added and stirred for 40 hours. After the reaction, the mixture was washed twice with 2 ml of Na ₂ SO ₃ solution, and the washed solution was extracted twice again with 5 ml of ethyl acetate, and then mixed with the dichloromethane extract, dried over anhydrous sodium sulfate, and concentrated by filtration. By removing the chiral ligand and the like with a short silica column, 7-triethylsilyl-paclitaxel was obtained in a mixture containing isomers and the content of 7-triethylsilyl-paclitaxel was 19%.

From the cinnamic acid taxane derivative of the present invention, a paclitaxel precursor can be obtained stereoselectively through a single step reaction, and paclitaxel can be prepared from the anticancer agent.

Claims (7)

A process for producing a taxane derivative of formula (I), comprising reacting a cinnamic acid taxane derivative of formula (II) with N-haloarylamide or a metal salt thereof. Wherein R ₁ is acetyl, hydrogen, 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloromethyl) propoxycarbonyl, and R ₂ is hydrogen, trialkylsilyl, haloacetyl, alkanes Noyl, alkoxycarbonyl, alkylaminocarbonyl, alkyl or aralkyl and R ₃ is alkyl, aryl or substituted aryl. Wherein R ₁ and R ₂ are as defined in formula (I). The compound of claim 1, wherein R ₁ is acetyl, R ₂ is triethylsilyl, 2,2,2-trichloroethoxycarbonyl, 2- (2-trichloromethyl) propoxycarbonyl, t-butoxy Carbonyl or benzyl, R ₃ is phenyl. The process according to claim 1, wherein the reaction is carried out in the presence of at least one catalyst of osmium tetraoxide or potassium osmate dihydrate and a chiral ligand. 4. The method of claim 3 wherein the chiral ligand is dihydroquinine, dihydroquinine acetate, dihydroquinine chlorobenzoate, dihydroquinine phthalazine, dihydroquinine pyrazine, dihydroquinine anthraquinone, dihydroquinidine, di A hydroquinidine acetate, dihydroquinidine chlorobenzoate, dihydroquinidine phthalazine, dihydroquinidine pyrazine, and dihydroquinidine anthraquinone. The process according to claim 1, wherein the reaction is carried out in a solvent selected from the group consisting of water, alcohols and nonpolar organic solvents. The method of claim 5, wherein the nonpolar organic solvent is methylene chloride, chloroform, benzene, toluene or xylene. The method of claim 1, wherein the N-haloarylamide is N-bromobenzamide or N-chlorobenzamide, and the metal salt is a sodium salt or a potassium salt.