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One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel

a technology of paclitaxel and docetaxel, which is applied in the field of semisynthesis of taxane derivatives, can solve problems such as structural complexity of taxanes

Inactive Publication Date: 2005-12-29
CONOR MEDSYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] In brief, the present invention relates to the semi-synthesis of taxane intermediates useful in the preparation of paclita

Problems solved by technology

Taxanes are structurally complicated molecules, and the development of commercially viable synthetic methods to make taxanes has been a challenge.

Method used

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  • One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel
  • One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel
  • One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel

Examples

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example 1

Protection of C-7, 10 Hydroxy Groups and Attachment of a Beta-Lactam Side Chain in a One Pot Reaction

[0116] As shown in FIG. 1, to a stirred solution of 10-deacetylbaccatin III (10-DAB), in an organic solvent, such as THF, at around room temperature under an argon atmosphere was treated with a hydroxy-protecting agent, such as Boc2O, 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. 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.

[0117] To this first solution of the C-7,10 protected 10-deacetylbaccatin III derivative in an organic solvent, such as the freshly distilled THF, under argon atmosphere at low temperature most preferably at −40 to −50° C., was added drop wise a solution of a base, such as n-BuLi, in hexanes or a mixture of n-BuLi / Li-t-OBu. After stirring for 30 min to 1 hr at this temperature, a soluti...

example 2

Synthesis of Docetaxel

[0118] As further shown in FIG. 1, the C-13 beta-lactam protected taxane intermediate, was hydrolyzed using formic acid to remove the C-7 and / or C-10 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, as 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.

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Abstract

A process is provided for the semi-synthesis of taxane intermediates useful in the preparation of paclitaxel and docetaxel, in particular, the semi-synthesis of protected taxane intermediate in a one pot reaction of protecting the C-7, 10 and attaching a side chain at C-13 position and subsequently deprotecting the group to form paclitaxel or docetaxel, and intermediates used therein.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to the semi-synthesis of taxane derivatives useful in the preparation of paclitaxel and docetaxel, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction. [0003] 2. Description of the Related Art [0004] The taxane family of terpenes has received much attention in the scientific and medical community because members of this family have demonstrated broad spectrum anti-leukemic and tumor-inhibitory activity. A well-known member of this family is paclitaxel (1, Taxol). [0005] Paclitaxel was first isolated from the bark of the pacific yew tree (Taxus brevifolia) in 1971, and has proved to be a potent natural anticancer agent. For example, paclitaxel has been found to have activity against different forms of leukemia and against solid tumors in the breast, ovary, brain, and lung in humans. [0006] This activity has stimulated an intense research effort over r...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor NAIDU, RAGINA
Owner CONOR MEDSYST
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