Note: Descriptions are shown in the official language in which they were submitted.
CA 02533414 2006-01-23
SEMI-SYNTHETIC ROUTE FOR THE PREPARATION OF PACLITAXEL OCETAXEL
AND 10-DEACETYLBACCATIN III FROM 9-DIHYDRO-13-ACETYLBACCATIN HI
BACKGROUND OF INVENTION
FIELD OF THE INVENTION
[00011 The present invention relates to a semi-synthetic process for the
preparation docetaxel, an anticancer drug and 10-deacetylbaccatin III, a
useful precursor
for making paclitaxel, the most popular anticancer drug, and other taxane
compounds.
More particularly, this invention relates to a semi-synthetic route to
synthesize docetaxel
and 10-deacetylbaccatin III from 9-dihydro-l3-acetylbaccatin III, a taxane
compound
which is isolated from Mxus Canadensis, a evergreen bush found in Eastern
Canada and
Northeastern United States.
PRIOR ART
[0002] Taxanes are substances occurring naturally in yew trees such as Taxus
canadensis, which is common in Eastern Canada and the United States. One of
the
chemicals extracted from the needles of Taxus canadensis is 9-dihydro-l3-
acetylbaccatin
III, which is used to produce, inter alia, 10-deacetylbaccatin III, which is a
useful
intermediate for the preparation of paclitaxel and analogues thereof.
[0003] The taxane family of terpenes is considered to be an exceptionally
promising group of cancer chemotherapeutic agents. Many taxane derivatives,
including
paclitaxel, docetaxel, taxcultine canadensol are highly cytotoxic and possess
strong in
vivo activities in a number of leukemic and other tumor systems. Paclitaxel,
and a
number of its derivatives, have been shown to be effective against advanced
breast and
ovarian cancers in clinical trials. hey have also exhibited promising activity
against a
number of other tumor types in preliminary investigations. Paclitaxel has
recently been
approved in the U.S. and Canada for the treatment of ovarian cancers.
[0004] The only available natural source of paclitaxel to date are several
species
of a slow growing yew (genus Taxus), wherein paclitaxel is found in very low
concentrations (less than 400 parts per million) in the bark of these trees.
Thus, paclitaxel
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CA 02533414 2006-01-23
can be isolated from the bark of the pacific yew tree (Taxus brevifi~lia) and
ground
hemlock (7'axus Canadensis), but the yield is very low (0.01%-0.02%), and the
isolation
and purification process is too complicate. Furthermore the extraction is
difficult, and the
process is expensive. Since removal of the bark destroys the trees and
endangers the
species, isolation of taxanes from the stems and needles of various Taxus
species was
believed to offer hope that the supply of taxanes, in particular paclitaxel,
would become
more abundant. This led to the switching from paclitaxel derived from natural
to the
production of semi-synthetic, starting from 10-deacetylbaccatin III, which was
isolated
from the needles of English yew (Taxus baccata).
[0005] Due to the structural complexity of paclitaxel, and docetaxel, partial
synthesis is a far more viable approach to providing adequate supplies of
paclitaxel and
docetaxel. Docetaxel was originally invented by Aventis, It went to the market
in 1995
and it is a fast growing anticancer drug. This drug is semi-synthetic product,
also starting
from 10-deacetylbacatin III. So far the commercial supply of docetaxel comes
substantially completely from 10-deacetylbaccatin III. To date, however, the
supply of
10-deacetylbaccatin III is limited due to the limited biomass resource and low
isolation
yield (ranging from 50-165 mg per kilogram of needles of Taxus baccata.
[0006] Various processes of converting 9-dihydro-l3-acetylbaccatin III into 10-
deacetylbaccatin III have been proposed. However, it has been found that such
processes
result in poor yields of final product. Thus, a need still exists for an
efficient method for
converting 9-dihydro- 13 acetylbaccatin III to l0-deacetylbaccatin III (DAB
III).
[0007] The preparation of paclitaxel derivatives, some of which have been
reported to demonstrate enhanced chemotherapeutic activity, ultimately depends
upon the
supply of the parent compound, namely, baccatin III. The structure of baccatin
III has the
basic diterpenoid structure of paclitaxel without the side chain at the C-13
position.
[0008] Since baccatin III is an important staring material in paclitaxel semi-
synthesis, the significance of baccatin III will likely increases as more
clinical studies are
performed using paclitaxel. One such reason is that it appears that water-
soluble
paclitaxel-like compounds with slightly modified C-13 side chains may be more
desirable
as cancer chemotherapeutic agents than the naturally-occurring, less water
soluble
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CA 02533414 2006-01-23
paclitaxel. This increases the urgent need for the production of baccatin III
as a starting
material to synthesize both paclitaxel and second or third generation
paclitaxel-like
compounds. There is, therefore, a need for an improved method of isolating
and/or
synthesizing Baccatin III.
[0009] In fact, most of the research to date regarding the semi-synthesis of
paclitaxel has involved 10-deacetylbaccatin III. The conversion of 10-
deacetylbaccatin III
into paclitaxel is typically achieved by protecting the hydroxy at C-7,
attachment of an
acetyl group at the C-10 position, attachment of a C-13 .beta.-amido ester
side chain at
the C-13 position through esterification of the C-13 alcohol with the .beta.-
lactam moiety,
and deprotecting C-7. Since the supply of 10-deacetylbaccatin III is limited,
other sources
should be pursued.
[00010] The following is a non-exhaustive list of patents which are believed
to be
relevant to the present invention.
[00011] Canadian Patent Application No. 2,188,190, published Apr. 18, 1998, in
the name of Zamir et al, described a semi-synthetic process to convert a
naturally-
occunng taxane into a suitable starting material for the synthesis of such
taxane
derivatives as paclitaxel, cephelomanine and other taxenes which are
structurally-related
to baccatn 111.
[00012] US Patent No 6,878,834, patented Apr 12, 2005 by R.H. Holton et al,
related to the preparation of a derivative, or analog of, baccatin III or 10-
desacatyl
baccatin having a C-9 substituent other that a keto substituent of a taxol. a
keto in which
the C-9 keto substituant of a toxo analalog, baccatinlll or 10-a taxol analog,
of 10-
desbaccatine bacatin III was selectively reduced to the conesponding hydroxyl
group.
[00013] US Patent No. 6,812,356, patented Nov 2, 2004, by Findly, provided a
process for the use of 9-hdroxyl3 9-baccatin III for the production of C-13
acyloxy
sidechain-bearing taxanes ,e.g., paclitaxol and analogs thereof . It related
particularly to
novel processes of coupling the oxazolines to form the taxanes.
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[00014] US Patent No. 6,734,304, patented Aug 31, 2004, by Bristol-Myers
Squibb Company provided novel oxazolidines, which found utility as
intermediates in the
preparation of C-13-acyloxy side chain-bearing toxanes, e.g., paclitaxol and
analogs
thereof. It related more specifically, to procedures for coupling the
oxazolidines to form
the taxanes.
[00015] US Patent 6,710,191, patented Mar 23, 2004 by R.A. Holton et al,
provided a process for the preparation of a derivative or analog of baccatin
III, or 10-
desacetyl baccatin III , having a C9 substituent other than a keto, in which
the C9 keto
substituent of taxol, a taxol analog, baccatin IlI, or 10-desacetyl baccatin
III was
selectively reduced to the corresponding hydroxyl group.
[00016] US Patent No. 6,593,482 patented Jul 15, 2003 by H. Bouchard et al,
provided a procedure for preparing methylthiomethyi taxoids from baccatin III
and beta-
lactam.
[00017] US Patent No. 6,576,777, patented Jun 10 2003 by L. Zamir et al,
provided a semi-synthetic process to convert a naturally-occuring taxane into
a suitable
starting compound for the synthesis of paclitaxol and related compounds. It
specifically
related to a process for the conversion of 9-dihydroxy-13-acetyl baccatin III
into a 7-
protected baccatin III., which can be used for the synthesis of taxol
derivatives, e.g.,
paclitaxol, docataxel cephalomannine and other taxanes which were structurally
related
to baccatin III..
[00018] US Patent No. 6 495,701, patented Dec 17, 2002 by R.A. Holton et al,
provided a process for the preparation of a derivative or analog of baccatin
III or 10-
desacetyl baccatin Ill having a C9 substituent other than keto in which the C9
keto, in
which the C9 keto substituent of taxol, a taxoi analog baccatinlII or 10-
dasacetyl baccatin
Ill was selectively reduced to the corresponding hydroxyl group.
[00019] Other patents which provided processes for the preparation of novel
taxoids included U.S. Patent No. 6,384,071 patented May 7, 2002 by Aventis
Pharma
S.A., US Patent No. 6,331, 635 patented Dec 18 2001, by Aventis Pharma S.A.
and US
Patent No. 6, 232,477 patented May 15, 2001 by Aventis Pharma S.A.
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CA 02533414 2006-01-23
[00020] US Patent No. 6,222,053, patented Apr 24, 2001, by Institut National
de la
Research Scientific, provided a semi-synthetic process to convert a naturally
occurring
taxane into a suitable starting material for the synthesis of paclitaxel and
related
compounds. Specifically, it related to a process for the conversion of 9-
dihydro- 13-
acetylbaccatin III into a 7-protected baccatin III which can then be used as
starting
material for the synthesis of such taxane derivatives as paclitaxel,
docetaxel,
cephalomannine and other taxanes structurally related to baccatin III.
[00021] US Patent No 6,197,981, patented Mar 6, 2001, by J. Liu, provided a
process for preparing taxol, baccatin III and 10-deacetylbaccatin III by
oxidation of 9-
dihydroxy-13-acetylbaccatin.
[00022] US Patent No. 6, 175,023, patented Jan 16, 2001 by J. Liu, provided
for
the semisynthesis of 9-dihydrotaxanes using 9-dihydroxy-13-acetylbaccatinlIl
as the
initial compound.
[00023] US Patent No 6,066,747, patented May 23 2000 by R.H.Holton et al,
provided a process for the preparation of taxol, baccatin III and 10-
desacetylbaccatinlll
derivatives or other taxanes having new C9 functional groups.
[00024] US Patent No. 5,763,477, patented Jun 9 1998 by Dr Reddy's Resesarch
Foundation provided a process for the preparation of taxane derivatives from
14-beta-
hydroxy-l0-deacetlybaccatin.
[00025] US Patent No. 5,616,740, patented Apr 1, 1997 by Abbott Laboratories,
US Patent No 5,594,157, patented Jan 14, 1997 by Abbott Laboratories and US
Patent
No. 5,530,020 patented Jun 25, 1996 by Abbott Laboratories each provided
deoxygenated taxol compounds which were prepared from a natural product which
was
isolated from taxus canadansis, as well as analogs of taxol which were
prepared
therefrom.
[00026] US Patent No. 5,440,056, patented Aug 8, 1995 by Abbott Laboratories,
provided deoxygenated taxol products prepared from a natural product which is
isolated
from taxus canadansis.
CA 02533414 2006-01-23
[00027] U.S.Patent No. 5,352,806 patented Oct 4, 1994 by Abbott Laboratories
provided 9-dihydro-13-acetyl a natural product which is derived from taxus
canadansis.
[00028] U.S. Pat. US Patent No. 4,924,011, re-issued as U.S. Patent No. 34,277
by
Denis et al provided the first successful semi-synthesis of paclitaxel using
the starting
materi al l0-deacetylbaccatin III which can be extracted in relatively high
yield from the
needles of specific species.
[00029] The invention in its general form will first be described, and then
its
implementation in terms of specific embodiments will be detailed with
reference to the
drawings following hereafter. These embodiments are intended to demonstrate
the
principle of the invention, and the manner of its implementation. the
invention in its
broadest sense and more specific forms will then be further described, and
defined, in
each of the individual claims which conclude this Specification
SUMMARY OF THE INVENTION
[00030] It is therefore desirable to provide a process for the semi-synthesis
of
docataxel.
[000311 It is also desirable to provide a semi-synthesis of 10-
deacetylbaccatin III.
It is also desirable provide a semi-synthetic process for the preparation of
docatexel and
10-deacetylbaccatin III from 9-dihydrxy-13-acetylbaccatin III.
[00032] There is also a need for an improved proces of isolating and/or
synthesizing Baccatin III.
[00033] A need still exists for an efficient process for converting 9-dihydro-
13
acetylbaccatin III to 10-deacetylbaccatin III (DAB III).
STATEMENTS OF INVENTION
[00034] A first broad aspect of the present invention provides an improvement
in a
process for the conversion of 9-dihydro-13-acetylbaccatin III to docetaxel,
the
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improvement comprising the final step of removing the docetoxyl protective
side chain
from 7-O-triethylsilyl-9,10-diketodocetaxel.
[00035] A second broad aspect of the present invention provides an improvement
in a process for the conversion of 9-dihydro-13-acetylbaccatin III to
docetaxel, the
improvement comprising the two steps of firstly, reacting a beta-lactam
protected
docetaxel side chain precursor with 7- 7-O-triethylsilyl-9,10-diketobaccatin
III, thereby
to produce 7-O-triethylsilyl-9,10-diketodocetaxel containing a beta-lactam
protected
docetaxel side chain, and the second or final step of removing the beta-lactam
protected
side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
[00036] A third broad aspect of the present invention provides an improvement
in
a process for the conversion of 9-dihydro-l3-acetylbaccatin III to docetaxel,
the
improvement comprising the sequential steps of converting 7-0-triethylsilyl-l0-
deacetylbaccatin II to 10-deacetylbaccatin III, converting said 10-
deacetylbaccatin III to
7-O-trisilyl-9,10-diketobaccatin III, reacting said 7-O-trisilyl-9,10-
diketobaccatin III,
with a beta-lactam docetaxel protective side chain precursor to produce 7-0-
triethylsilyl-
9,10-diketobaccatin III, and the final step of removing the beta-lactam
docetoxyl
protective side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
[00037] A fourth broad aspect of the present invention provides an improvement
in
a process for the conversion of 9-dihydro-13-acetylbaccatinIIi to docetaxel
the
improvement of which comprises the sequential steps of: effecting a
triethylsilylation
reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while
substantially-
simultaneously converting the 10-acetyl group to a 10-hyroxy group, thereby to
produce
7-O-triethylsilyl-10-deacetyl-9-dihydro-l3-acetylbaccatin III; converting the
13-acetyl
group on 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III to a 13-
hydroxy
group, thereby to produce 7-O-triethylsilyl-9,10-diketo-13-hydroxy-
acetylbaccatin III;
reducing the 9-ketogroup on 7-O-triethylsilyl-9,10-diketo-l3-hydroxy-
acetylbaccatin III,
thereby to produce 7-0-triethylsilyl-l0-deacetylbaccatin III; reducing the 9-
1 0-dihydrxy
groups from 7-0-triethylsilyl-l0-deacetyl-9,10-dihydroxy-l3-acetylbaccatin
III, thereby
to produce 7-0-triethylsilyl-9,10-diketo-baccatin III; effecting a
triethylsilylation reaction
on the 9-hyroxy group of 9-dihydro-l3-acetylbaccatin III , thereby to produce
7,9-0- di(-
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triethylsilyl)-10-deacetyl-9-ketobaccatin III ; reacting 7,9-0- di(-
triethylsilyl)- 10-
deacetyl-9-ketobaccatin III with a protected beta-lactam docatexi side chain
precursor
thereby to produce 7-0-triethylsilyl-9,10-diketodocetaxel;and removing the
beta-lactam
docatexl side chain precursor, thereby to produce docetaxel.
2. OTHER FEATURES OF THE INVENTION
[00038] By one feature of the above aspects of the present invention, the
deprotection step is carried out using lithium aluminum hydride.
[00039] The foregoing summarizes the principal features of the invention and
some of its optional aspects. The invention may be further understood by the
description
of the preferred embodiments which now follow.
DESCRIPTION OF PREFERRED EMBODIMENTS
[00040] The following are non-limiting examples of the process of aspects of
the
present invention.
EXAMPLE 1: PREPARATION OF 7-TES-10-DEACETYL-9-DIHYDRO-13-
ACETYLBACCATIN III
[000411 To 10 ml of acetonitrile, 102 mg of 9-dihydro-13-acetylbaccatin III
and
173 mg of n-tetrabutylammonium iodide were added, the mixture was stirred for
5
minutes until 9-dihydro-13-acetylbaccatin III was completely dissolved. The
mixture was
kept in -10 C, then chlorotriethylsilane was added dropwise. The mixture was
stirred for
another 5-10 minutes at -10 C before 26 mg of sodium methoxide was poured
into the
round bottom flask. This mixture was kept stirred for another one hour at the
same
temperature then the temperature was raised to 0 C, and maintained at 0 C for
about I
hour. Then the temperature was raised to room temperature the mixture was kept
stirred
for 2 more hours. The reaction was quenched by dilution with brine, and
extracted with
ethyl acetate for three times. The organic phase was combined and evaporated
to dryness
in vacuum. The residue was purified by preparative TLC to yield 7-0-
triethylsilyl-l0-
deacetyl-9-dihydro-I3-acetylbaccatin III as a white solid (85 mg, 85%).
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EXAMPLE 2: PREPARATION OF 7-TES-9,10-DIKETO-13-ACETYLBACCATIN
III
[00042] To 5ml of acetonitrile and acetone mixture (3:1), 73 mg of 7-TES-9,10-
diketo-l3-acetylbaccatin III was added. 4-methylmorpholine-N-oxide (NMO) in a
round
bottom flask, and the mixture was dissolved in 3 ml dichloromethane. 4 A
molecular
sieve was added to the mixture which stirred for 5 minutes. 5 mg of tetra-n-
propylammonium perruthenate (TPAP) was added, and the mixture was stirred for
about
6 hours at room temperature, following which the temperature was raised to 40
C. The
mixture was maintained at that temperature overnight until the reaction was
completed.
Once the reaction was completed, the mixture was poured into a short silica
gel column.
The column was eluted with 50 ml of dichloromethane (CH2C12) to give a CH2CI2
fraction which was concentrated to dryness. The residue was purified by
preparative TLC
to yield 60 mg white solid which identified as 7-TES-9,10-diketo-l3-
acetylbaccatin III
(yield: ? ).
EXAMPLE 3: PREPARATION OF 10-DEACETYLBACCATIN III
[00043] Step A: To a solution of 95% of ethanol, 45 mg of the compound 2 was
added and stirred until the solid was completely dissolved, and then hydrazine
monohydrate (0.6m1) and 10 mg of LiAII-I4 was added, then the solution was
stirred for 8
hours at room temperature, after that the reaction was quenched by brine and
extracted
with dichloromethane and organic phase was collected and concentrated to
dryness in
vacuum. The residue was purified through silica gel column. Product 7-TES-10-
deacetylbaccatin III was obtained as slightly yellow crystals.
[00044] Step B: 7-TES-10-deacetylbaccatin III was dissolved in a mixture of
acetonitrile and acetone (3:1), the solution then was stirred at room
temperature for a few
minutes before 5 ml of sodium hypochloride was added dropwise. The mixture was
reacted at room temperature for 2 hours and then quenched with brine and
extracted with
ethyl acetate. The ethyl acetate phase was concentrated to dryness and the
residue was re-
crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white
powder.
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EXAMPLE 4: PREPARATION OF 7-TES-9,10-DIKETODOCETAXEL
[00045] Step A: To a solution of 95% ethanol, 40 mg of compound 2 was added
and stirred for a few minutes until the solid was dissolved, then 1 mi of
hydrazine
monohydrate was added. The mixture was stirred at room temperature for 2
hours, then
diluted with ethyl acetate (50 ml) and poured into saturated MT,CI solution
(40ml). The
organic layer was separated and concentrated. The residue was purified by
precipitation
using TLC to obtaining 7-TES-9,10-diketobaccatin III. Yield, 30 mg (?).
[00046] Step B: 35 mg of 7-TES-9,10-diketobaccatin III was placed in a 25 ml
round bottom flask, and 3 mole equivalents of protected 13-lactam docetaxel
side chain
precursor were dissolved in 20 ml of tetrahydrofuran (THF) at -45 C, then 6
mole
equivalents of LiHMDS was added slowly. The mixture was stirred at -45 C for
30minutes then warmed to room temperature. The reaction progress was detected
by TLC
until completion. Once completed, the mixture was diluted with dichloromethane
(50 ml)
and poured into saturated NH4Cl solution (40m1). The organic layer was
separated and
concentrated. The residue was purified by precipitation using TLC to yield 7-
TES-9,10-
diketodocetaxel.
EXAMPLE 5: PREPARATION OF DOCETAXEL
[00047] Step A: 7-TES-9,10-diketodocetaxel was dissolved in tetrahydrofuran
(THF), and then LiA1I-I4 was added, the mixture was stirred at -15 C for
about I hour or
until the reaction was completed. The reaction was quenched with 50 ml of
ethyl acetate
and saturated NH4Cl mixture (3:1). The organic layer was separated and
concentrated to
dryness, the residue was took to next step without purification.
[00048] Step B: The residue was redissolved in THF, and sodium hypochloride
(NaOCI) was added dropwise. The mixture was stirred for 2hours at room
temperature
then work-up as above. The residue was purified through flash column
chromatography.
Docetaxel was obtained as white needles.
CA 02533414 2006-01-23
CONCLUSION
[00049] The foregoing has constituted a description of specific embodiments
showing how the invention may be applied and put into use. these embodiments
are only
exemplary. The invention in its broadest form, and more specific aspects is
further
described and defined in the claims which follow.
[00050] These claims, and the language used therein are to be understood in
terms
of the variants of the invention which have been described. They are not to be
restricted
to such variants, but are to be read as covering the full scope of the
invention as is
implicit within the invention and the disclosure that has been provided
herein.
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