WO2009040829A1

WO2009040829A1 - A novel process for the preparation of docetaxel

Info

Publication number: WO2009040829A1
Application number: PCT/IN2008/000048
Authority: WO
Inventors: Vikas Sadvilkar; Kannan Vishwanath; Vishwanathan Kashi
Original assignee: Benzochem Lifescience (P) Limited
Priority date: 2007-09-27
Filing date: 2008-01-24
Publication date: 2009-04-02

Abstract

A novel process is outlined for the synthesis or preparation of docetaxel with the help of novel alloy for the deprotection of the protected docetaxel and its conversion into docetaxel.

Description

Title: - A novel process for the preparation of docetaxel,

Field of the invention: -

The present invention relates to a novel process for the preparation of docetaxel, with the help of novel alloy for the deprotection of the protected docetaxel and its conversion into docetaxel,

Back Ground and prior art: -

U.S. Patent No. 288521, which teaches a process for converting paclitaxel or paclitaxel containing material to docetaxel by protecting one or more hydroxyl groups at the C-2, C-7, and C-IO position of the taxane , and by introdcing a t-BOC group at the nitrogen of the amide group at the C-3, position.

Protecting one or more hydroxyl groups at the C-2,C-7, and C-10, position is carried out in the presence of base , are selected from DMAP, pyridine, TEA,LiOH,n-Buli,Lih.

U.S. Patent No. 4814470, taxotere has been found to have very good antitumor activity and better bioavailability than paclitaxel, docetaxel and paclitaxel may be prepared semi-syntheticaly from 10-deacetyl baccatinl l l or baccatin 111 as set forth,

U.S. paten No. 4924011, 4924012, by the reaction of a [beta]-lactam and a suitably protected 10-deacetyl baccatin 111 or baccatin 111 derivative as set forth in U.S. patent No.5175315, by a method using oxazoline and international patent Kokai No.Hei.7-504444by a method using thioester.

Patent Kokai No.hei.10-50530 by a method using cinnamic acid,

CA 2549951 an improvement has been provided in the preparation od docetaxel. The improvement process involves the convenrsion of 9-dihydro- 13-acetyl baccatin 111 to docetaxel by the steps of removing the docetaxel protective side chain from 7-o- triethylsilyl-9, 10-diketodocataxel, where in the deprotection step is carried out using Lithium aluminum hydride,

More recently, Holton et al. disclosed in U.S. Patent No. 6,191 , 287 that the relative reactivity toward acetic anhydride as between C (7) and C (10) is different in the presence of a Lewis acid than it is in the presence of base. Holton et al. described processes for the selective derivatization of the C (7) or the C (10) hydroxy group of 10-DAB and other taxanes, wherein the C (10) hydroxy group may be protected or derivatized prior to the C (7) hydroxy group. Specifically, Holton et al. described a process for acylating or silylating the C (10) hydroxy group prior to acylating, silylating, or ketalizing the C (7) hydroxy group.

Therefore none of the above cited prior art acknowledged the reactants used and parameters mentioned in the alleged invention, therefore the alleged invention is novel and inventive.

Objects: -

Very important object of the present invention is that easy conversion of the two reactants into docetaxel, which is industrially feasible and convenient.

Summer of the Invention: -

DETAILED DESCRIPTION: -

The present invention relates to a novel process for the preparation of docetaxel with the help of novel alloy for the deprotection of the protected and its conversion into docetaxel, more specifically. The present invention relates to a process for the preparation of docetaxel, in the embodiment of the present invention the deprotection of the C (7) and the C (10) hydroxyl groups of 10-deacetyl baccatin 111 (10 DAB) using a novel alloy as a protecting group. 10 DAB, which is extracted from the needless of the English yew taxus baccata L.), is key starting material in the production of taxol (also known as paclitaxel) and docetaxel (taxotere, both of which are potent anti cancer agents. Conversion of 10-DAB to a cytotoxically active taxane requires selective derivatization of the C (13) hydroxy group to form a C (13) ester side chain. Because 10-DAB is a polyol and because each of these hydroxy groups is not equally reactive under a defined set of conditions, preparation of taxol or docetaxel from 10-DAB typically requires selective protection and/or derivatization of the C (7) and the C (10) hydroxy groups before the C (13) side chain is attached.

Early strategies for the preparation of taxol, docetaxel and other taxanes from 10-DAB were based on the observation of Senilh et al. {C.R. Acad. Sci. Paris, IT, 1981 , 293, 501 ) that the relative reactivity of the four hydroxy groups of 10-DAB toward acetic anhydride in pyridine is C (7)-OH>C (10)-OH>C (13)-OH>C (I )-OH. Denis et al. reported {J. Am. Chem. Soc, 1988, 110, 5917) selective silylation of the C (7) hydroxy group of 10-DAB with triethylsilyl chloride in pyridine to give 7-triethylsilyl-10-deacetyl baccatin (III) in 85% yield.

The alleged invention relates to the condensation of protected 10- DAB III with 3-[N-(BOC) amino]-3-phenyl-2-hydroxy propanoic acid by esterification of the hydroxyl group at the C-13 position of the protected 10-DAB III with the COOH group of the N-protected amino acid. Finally the deprotection of the protected Docetaxel into Docetaxel by the use of a novel zinc-nickel alloy to afford high yielding and purer Docetaxel.

Various parameters such as temperature of the reaction, speed of stirring, solvents, catalyst loading and Resin particle size were studied to determine the efficacy of the process.

The advantage of this process is the easy conversion of the two reactants into Docetaxel.

The typical specifications of the novel alloy catalyst are as follows:

Nickel-zinc alloy with nickel content of upto 2.5%.

Zinc (CAS No:7440-66-6) >97.5% + Nickel (CAS No:7442-02-0) upto

2.5%

Mesh size:250-350,

The present invention relates to a process of preparing docetaxel using alloy catalyst comprising the following steps, taking a required quantity of preteted docetxel dissolved in acetic acid and methanol, added activated alloy powder along with HCI are added to the above solution, further water is added and allowed to heat between 30 -90C and reaction being monitered by TLC after completion of reaction the solution is filtered to remove solid. Said solution is further concentrated and re-dissolved with ethylacetate, allowed to wash using NaHCo3, water and Nacl finally dried and concentrated to get crude docetaxel in high yield with purity of more than 98%. The crude docetaxel is purified using a silica column in a mixture of ethyl and petroleum ether to obtain pure docetaxel having HPLC purity 99.6%

The silent feature of this invention is enhanced purity of docetaxel with ease of operation and the use of Zinc-nickel alloy to afford selective deprotection in the final step of the synthesis.

Example 1

400g protected Docetaxel are dissolved in 4L acetic acid and 4L methanol. Activated 750g Zn powder with 5% HCI, are added to the above solution. 2L water are added and reacted at 40-8O⁰C, the reaction being monitored by TLC. After the reactant is consumed, the solution is filtered to remove solid. The solution is concentrated and re-dissolved with ethylacetate, washing by NaHCOS, water and NaCI, finally dried and concentrated to get crude Docetaxel, 300g with a purity of 98%.

The crude Docetaxel is purified on a silica column in a mixture of ethyl acetate and petroleum ether to obtain purified Docetaxel 280g having an HPLC purity of 99.6%.

Example 2

400g protected Docetaxel are dissolved in 4L acetic acid and 4L methanol. Activated 500g Zn powder with 5% HCI, are added to the above solution. 2L water are added and reacted at 40-80°C, the reaction being monitored by TLC. After the reactant is consumed, the solution is filtered to remove solid. The solution is concentrated and re-dissolved with ethylacetate, washing by NaHCO3, water and NaCI, finally dried and concentrated to get crude Docetaxel, 255g with a purity of 98%.

The crude Docetaxel is purified on a silica column in a mixture of ethyl acetate and petroleum ether to obtain purified Docetaxel 220g having an HPLC purity of 99.5%.

Example 3

400g protected Docetaxel are dissolved in 4L acetic acid and 4L methanol. Activated 250g Zn powder with 5% HCI, are added to the above solution. 2L water are added and reacted at 40-80°C, the reaction being monitored by TLC. After the reactant is consumed, the solution is filtered to remove solid. The solution is concentrated and re-dissolved with ethylacetate, washing by NaHCO3, water and NaCI, finally dried and concentrated to get crude Docetaxel, 184g with a purity of 96.4%. The crude Docetaxel is purified on a silica column in a mixture of ethyl acetate and petroleum ether to obtain purified Docetaxel 126g having an HPLC purity of 99.6%

Claims

We Claim,

1. A novel process for the preparation of docetaxel, comprising the following steps,

a) condensation of protected 10-DAB III with 3-[N-(BOC) amino]- 3-phenyl-2-hydroxy propanoic acid followed by esterification of the hydroxyl group at the C-13 position of the protected 10-DAB III with the COOH group of the N-protected amino acid,

b) deprotection of the protected Docetaxel into Docetaxel using a novel zinc-nickel alloy to afford high yielding and purer Docetaxel, taking a required quantity of pretected docetxel dissolved in acetic acid and methanol, added activated alloy powder along with HCI to the above solution, then water is added and allowed to heat between 30 - 9OC and reaction being monitored by TLC, after completion of reaction the resultant solution is filtered to remove solid, said solution is further concentrated and re-dissolved with ethyl acetate, allowed to wash using NaHCo3, water and Nacl, finally dried and concentrated to get crude docetaxel, the crude docetaxel is purified using a silica column in a mixture of ethyl and petroleum ether to obtain pure docetaxel having HPLC obtained pure docetaxel 99.6%,