Process for the preparation of 10-deacetylbaccatin III

Details Process for the preparation of 10-deacetylbaccatin III Process for the preparation of 10-deacetylbaccatin III

2001-09-28

2002-08-20

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S511000

Reexamination Certificate

active

06437154

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 10-deacetylbaccatin III. More particularly, the present invention relates to a process for the preparation of 10-deacetylbaccatin III of the formula 1
from taxol analogues of the formula 2 where R is C
6
H
5
, CH
3
C═CHCH
3
or C
5
H
11
.
BACKGROUND OF THE INVENTION
The anticancer drug taxol and its precursor 10-deacetylbaccatin III have been isolated from Himalayan yew
Taxus wallichiana
[S. K. Chattopadhayay et al, Indian J. Chem., 33, B, 409-411 (1994)]. 10-deacetylbaccatin (10-DAB) is a very important precursor as it is used as a starting material for the semi-synthesis of taxol and another important anti-cancer drug taxotere.
It has recently been found that taxol analogues 7-xylosyl-10-deacetyl taxols of the formula 2 are important precursors of taxol and 10-deactyl taxols since they can be converted into the above taxols through chemical conversion procedures [Chattopadhyay et al, U.S. Pat. Nos. 5,856,532 and 6,028,206].
Prior art literature is silent on any process for the conversion of the taxol analogues 7-xylosyl-10-deacetyl taxols of formula 2 into 10-deacetylbaccatin III of formula 1.
OBJECTS OF THE INVENTION
The main object of the invention is to provide a process for the conversion of taxol analogues of the formula 2 into 10-deacetylbaccatin III of formula 1.
It is another object of the invention to provide an economical process for the conversion of taxol analogues of the formula 2 into 10-deacetylbaccatin III of the formula 1.
It is a further object of the process to provide a process for the conversion of taxol analogues of the formula 2 into 10-deacetylbaccatin III of the formula 1 in good yield.
It is another object of the invention to provide a process for the conversion of taxol analogues of the formula 2 into 10-deacetylbaccatin III of the formula 1 which is commercially viable.
SUMMARY OF THE INVENTION
A process has been developed for the conversion of a mixture of taxol analogues 7-xylosyl-10-deacetylbaccatin taxols of the formula 2 where R is C
6
H
5
, CH
3
C═CHCH
3
or C
5
H
11
into 10-deacetylbaccatin III of the formula 1 by dissolving the taxol analogue of formula 2 in a polar solvent, reaction the resultant solution with a base at a temperature of 20-50° C. for a time period in the range of 20-40 hours, and isolating 7-xylosyl-10-deacetylbaccatin III, dissolving the 7-xylosyl-10-deacetylbaccatin III in a polar solvent, reacting the resultant solution with a periodate at 20-40° C. for a time period in the range of 20-40 hours to cleave the diol system of the xyloside into dialdehyde, treating the generated dialdehyde in an organic acid medium with salts of amine at 0-40° C. for 12-18 hours and isolating 10-deacetylbaccatin III of formula 1.
Accordingly, the present invention provides a process for the preparation of 10-deacetylbaccatin III of the formula 1
(a) by dissolving a taxol analogue of the formula 2
 wherein R is selected from the group consisting of C
6
H
5
, CH
3
C═CHCH
3
or C
5
H
11
or a mixture thereof in a polar solvent;
(b) treating the resultant solution with a base at a temperature in the range of 20-40° C. for a time period in the range of 2-24 hours to obtain 7-xylosyl-10-deacetylbaccatin III;
(c) isolating 7-xylosyl-10-deacetylbaccatin III;
(d) dissolving the 7-xylosyl-10-deacetylbaccatin III so isolated in step (c) in a polar solvent;
(e) reacting the solution of 7-xylosyl-10-deacetylbaccatin III with a periodate at a temperature in the range of 20-40° C. for a time period in the range of 20-40 hours to obtain a dialdehyde;
(f) treating the dialdehyde so obtained with salts of amine in an organic acid medium at 0-40° C. for a time period in the range of 12-18 hours; and
(g) isolating the 10-deacetylbaccatin III of formula 1.
In one embodiment of the invention, the polar solvent used in steps (a) through (d) above is an alkanol selected from the group consisting of methanol, ethanol, propanol and butanol.
In a further embodiment of the invention, the alkanol solvent used is preferably ethanol.
In another embodiment of the invention, the base used in step (b) is selected from hydrazine hydrate and hydroxyl amine.
In a further embodiment of the invention, the base used in step (b) is preferably hydrazine hydrate.
In another embodiment of the invention, the isolation of the products in steps (c) and (f) is done by chromatography using adsorbents selected from silica gel, flurosil, celite and alumina.
In another embodiment of the invention, the periodate used in step (e) is selected from sodium periodate and potassium periodate.
In a further embodiment the invention the periodate used in step (e) is preferably sodium periodate.
In another embodiment the organic acid used in step (f) is selected from the group consisting of acetic acid, propionic acid and methane sulphonic acid.
In a further embodiment of the invention, the organic acid used in step (f) is preferably acetic acid.
In another embodiment of the invention, the amine salt used in step (f) is selected from the group consisting of phenylhydrazine hydrochloride, hydrazine hydrochloride and hydroxyl amine hydrochloride.
In a further embodiment of the invention, the amine salt used in step (f) comprises hydroxyl amine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of 10-deacetylbaccatin III of the formula 1
from taxol analogues of the formula 2 where R is C
6
H
5
, CH
3
C═CHCH
3
or C
5
H
11
. The starting material 7-xylosyl-10-deacetyl taxols used in the above conversion reaction can be isolated from the stem bark of
Taxus wallichiana
by process described in U.S. Pat. No. 5,856,532 (Chattopadhyay et al).
The process of the present invention comprises dissolving the taxol analogue of formula 2 wherein R is selected from the group consisting of C
6
H
5
, CH
3
C═CHCH
3
or C
5
H
11
or a mixture thereof
in a polar solvent, reaction the resultant solution with a base at a temperature of 20-50° C. for a time period in the range of 20-40 hours, and isolating 7-xylosyl-10-deacetylbaccatin III, dissolving the 7-xylosyl-10-deacetylbaccatin III in a polar solvent, reacting the resultant solution with a periodate at 20-40° C. for a time period in the range of 20-40 hours to cleave the diol system of the xyloside into dialdehyde, treating the generated dialdehyde in an organic acid medium with salts of amine at 0-40° C. for 12-18 hours and isolating 10-deacetylbaccatin III of formula 1.
The polar solvent used in steps (a) through (d) is an alkanol such as methanol, ethanol, propanol and butanol, ethanol being the most preferred solvent. The base used in step (b) is generally hydrazine hydrate or hydroxyl amine, preferably hydrazine hydrate.
The product in step (c) 7-xyloxyl-10-deacetylbaccatin is preferably isolated by chromatography using adsorbents selected from silica gel, flurosil, celite and alumina, preferably silica gel.
The periodate used in step (e) is selected from sodium periodate and potassium periodate, preferably sodium periodate. The organic acid used in step (f) is selected from the group consisting of acetic acid, propionic acid and methane sulphonic acid, preferably acetic acid.
In another embodiment of the invention, the amine salt used in step (f) is selected from the group consisting of phenylhydrazine hydrochloride, hydrazine hydrochloride and hydroxyl amine hydrochloride, preferably hydroxyl amine hydrochloride.
Similar to step (a), the polar solvent used in step (d) is also an alkanol such as methanol, ethanol, propanol and butanol, ethanol being the most preferred solvent. The product in step (g) is isolated using chromatography using adsorbents selected from silica gel, flurosil, celite and alumini, preferably silica gel.
A significant feature of this invention is that acid is not used for the periodate oxidation thereby enhancing the yield of the 10-deacetylbaccatin III of formula 1. The starting materials are also cheaply available rendering

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