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Semi-synthetic conversion of paclitaxel to docetaxel

Inactive Publication Date: 2007-02-01
INNOVATIONAL HLDG LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a simple process for converting paclitaxel or a paclitaxel-containing material to its synthetic analog, docetaxel, using a protected paclitaxel intermediate. The process involves protecting hydroxy groups at the C-2', C-7, and C-10 positions of the taxane, and introducing a t-Boc group at the nitrogen of the amide group at the C-3' position. The resulting protected paclitaxel derivative can then be converted to docetaxel by removing the protecting groups. The process is efficient and can be carried out in a one-pot reaction. The invention also provides a method for preparing a taxane mixture containing paclitaxel and other taxanes, and converting it to docetaxel."

Problems solved by technology

However, the above methods thus far developed involve subjects such as reaction under the conditions of extremely low temperatures, generation of diastereomers, use of asymmetry controlling agents, and the reaction under strongly alkaline conditions, which cause problems upon the industrialization thereof.

Method used

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  • Semi-synthetic conversion of paclitaxel to docetaxel
  • Semi-synthetic conversion of paclitaxel to docetaxel
  • Semi-synthetic conversion of paclitaxel to docetaxel

Examples

Experimental program
Comparison scheme
Effect test

example 1

Protection of C-7, C-2′ and / or C-10 Hydroxy Groups in a One Pot Reaction

[0135] As shown in FIG. 1, to a stirred solution of paclitaxel or paclitaxel containing material, in an organic solvent, such as THF, at around low to room temperature under an argon atmosphere was treated with a hydroxy-protecting agent, such as Boc2O, dichloroacetyl chloride, acetyl chloride, TESCl or like reagents in the presence of a base, such as 4-(N,N-dimethylamino)pyridine or n-BuLi or a mixture of n-BuLi / Li-t-OBu or like bases. The reaction was stirred at this temperature for a period between 30 minutes to 2 hours until complete consumption of the starting materials, as evidenced by TLC.

[0136] Alternatively, to a stirred solution of paclitaxel or paclitaxel containing material, in an organic solvent, such as THF, at around low to room temperature under an argon atmosphere can be treated with a hydroxy-protecting agent such as ethyl vinyl ether, in the presence of a catalytic amount of p-toluenesulfoni...

example 2

Synthesis of Docetaxel

[0141] As further shown in FIG. 1, C-2′, C-7 and C-10 protected docetaxel was hydrolyzed using formic acid to remove the C-7 and / or C-10 t-Boc protecting group and then with a mixture of NaHCO3 / Na2CO3 / H2O2 to deprotect the C-2′ and / or C-10 acetate groups to yield docetaxel. In the event that the C-2′ protecting group is ethoxyethyl, the deprotection is carried out under acidic condition, such as in the presence of acetic acid. Detailed description of deprotection at the C-2′, C-7 and C-10 positions are described in U.S. patent application Ser. No. 10 / 790,622, which application is assigned to the assignee of the present invention and is incorporated herein by reference in its entirety.

example 3

Synthesis of the Primary Amine Derivative of Paclitaxel

Nitrosation

[0142] To a solution of paclitaxel (0.76 mmol) or a paclitaxel containing material in glacial acetic acid (2.5 ml) and acetic anhydride (5 ml) at 0° C. is added NaNO2 (7.6 mmol). The resulting solution can be stirred under argon at 0° C. for 16 h and then poured over ice and extracted with diethyl ether. The combined organic extracts can be washed with water, 5% Na2CO3, water and saturated NaCl and dried over MgSO4. The dry extracts can be filtered and then concentrated in vacuo, and the crude product is purified by column chromatography using mixtures of hexane-ethyl acetate to afford the pure product.

Hydrolysis

[0143] To the above solution in tetrahydrofuran is added a 1.0 N solution of lithium hydroxide. The solution was stirred for 12 h at room temperature. After the removal of tetrahydrofuran in vacuo, the basic aqueous residue can be acidified by the addition of 10% acetic acid and extracted with ether. Dry...

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Abstract

A process is provided for the semi-synthesis of taxane derivatives useful in the preparation of docetaxel, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction of protecting the C-2′, C-7 and C-10 and introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position in paclitaxel and subsequently conversion to docetaxel, and derivatives used therein.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 881,711 filed Jun. 29, 2004, now pending, which application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to a semi-synthesis of taxane derivatives useful in the preparation of docetaxel, from pure or crude paclitaxel or related taxane starting material, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction and its conversion to docetaxel. [0004] 2. Description of the Related Art [0005] The taxane family of terpenes has received much attention in the scientific and medical community because the members of this family have demonstrated broad spectrum anti-leukemic and tumor-inhibitory activity. Docetaxel (1, Taxotere), a semi-synthetic analog, and paclitaxel (2, Taxol), a complex diterpene isolated from the bark of the Pacific yew...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D305/12C07D305/14
CPCC07D305/14
Inventor NAIDU, RAGINAFOO, SAMUEL SIANG KIANGXUE, BAO YUFAN, BO
Owner INNOVATIONAL HLDG LLC
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