U.S. patent application number 12/939230 was filed with the patent office on 2011-03-03 for new methods for the preparation of taxanes using chiral auxiliaries.
This patent application is currently assigned to ACCORD HEALTHCARE LTD.. Invention is credited to Gaetan Caron, Mettilda LOURDUSAMY.
Application Number | 20110054191 12/939230 |
Document ID | / |
Family ID | 38005396 |
Filed Date | 2011-03-03 |
United States Patent
Application |
20110054191 |
Kind Code |
A1 |
LOURDUSAMY; Mettilda ; et
al. |
March 3, 2011 |
NEW METHODS FOR THE PREPARATION OF TAXANES USING CHIRAL
AUXILIARIES
Abstract
A stereoselective synthesis of novel .beta.-lactam dimers as
useful precursors for the preparation of paclitaxel, docetaxel, and
analogues thereof. More particularly, the new .beta.-lactams are
prepared from readily available and enantiomerically pure chiral
auxiliaries. The .beta.-lactams are then reacted with a suitably
protected taxane to produce diastereomerically enriched side
chain-bearing taxanes. Finally, the chiral auxiliary is cleaved and
protecting groups are removed to provide the desired taxane.
Inventors: |
LOURDUSAMY; Mettilda;
(Sainte-foy, CA) ; Caron; Gaetan; (Quebec,
CA) |
Assignee: |
ACCORD HEALTHCARE LTD.
Markham
CA
|
Family ID: |
38005396 |
Appl. No.: |
12/939230 |
Filed: |
November 4, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12092432 |
Jul 22, 2008 |
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PCT/CA2006/001806 |
Nov 3, 2006 |
|
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12939230 |
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60733172 |
Nov 4, 2005 |
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Current U.S.
Class: |
549/214 ;
549/448; 549/510 |
Current CPC
Class: |
Y02P 20/55 20151101;
C07F 7/1804 20130101; C07D 305/14 20130101; C07D 205/08
20130101 |
Class at
Publication: |
549/214 ;
549/510; 549/448 |
International
Class: |
C07F 7/18 20060101
C07F007/18; C07D 305/14 20060101 C07D305/14; C07D 407/14 20060101
C07D407/14 |
Claims
1. A compound of formula: ##STR00088## wherein Ar is an aryl, R is
an acyl, R.sub.1, and R.sub.2, identical or different, are
independently acyl, hydrogen or a hydroxy protecting group, L is a
cleavable linker, Y.sub.1 is hydrogen, a hydroxy or a protected
hydroxy group, Y.sub.2 is a hydrogen or a protected hydroxy group
or Y.sub.1 and Y.sub.2 taken together form a carbonyl group.
2. A compound as defined in claim 1, wherein Ar is phenyl
optionally substituted with one or more substituents.
3. A compound as defined in claim 1, wherein Ar is unsubstituted
phenyl.
4. A compound as defined in claim 1, wherein Y.sub.1 is a hydroxyl
and Y.sub.2 is a hydrogen.
5. A compound as defined in claim 4, wherein Y.sub.1 is a hydroxyl
having stereochemistry ##STR00089##
6. A compound as defined in claim 1, wherein Y.sub.1 and Y.sub.2
taken together form a carbonyl group.
7. A compound according to claim 1, wherein R is benzoyl, R.sub.1
is acetyl and R.sub.2 is a hydroxy protecting group.
8. A compound according to claim 7 wherein R.sub.2 is selected from
the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl.
9. A compound according to claim 1, wherein R is benzoyl, R.sub.1
is acetyl and R.sub.2 is a hydrogen.
10. A compound according to claim 1, wherein R is benzoyl and
wherein R.sub.1 and R.sub.2 are both hydrogen.
11. A compound according to claim 1, wherein R is benzoyl and
wherein R.sub.1 and R.sub.2 are both a hydroxy protecting
group.
12. A compound according to claim 11, wherein R.sub.1 and R.sub.2
are selected from the group consisting of ethoxyethyl,
triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl.
13. A compound according to claim 1, wherein R is
tert-butyloxycarbonyl, R.sub.1 is acetyl and R.sub.2 is a hydroxy
protecting group.
14. A compound according to claim 13, wherein R.sub.2 is selected
from the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl and R is phenyl or
tert-butoxy.
15. A compound according to claim 1, wherein R is
tert-butyloxycarbonyl, R.sub.1 is acetyl and R.sub.2 is a
hydrogen.
16. A compound according to claim 1, wherein R is
tert-butyloxycarbonyl and wherein R.sub.1 and R.sub.2 are both
hydrogen.
17. A compound according to claim 1, wherein R is
tert-butyloxycarbonyl and wherein R.sub.1 and R.sub.2 are both a
hydroxy protecting group.
18. A compound according to claim 17, wherein R.sub.1 and R.sub.2
are selected from the group consisting of ethoxyethyl,
triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl.
19. A compound according to claim 1, wherein L is a chiral tartaric
diester acetonide having enantiomerically enriched or substantially
pure (R, R) or (S, S) stereochemistry, or a mixture of (R, R) and
(S, S) enantiomers including racemic mixtures.
20. A compound according to claim 1, wherein L is a chiral
trans-1,2-cyclohexane di(carboxylate ester) having enantiomerically
enriched or substantially pure (R, R) or (S, S) stereochemistry or
a mixture of (R, R) and (S, S) enantiomers including racemic
mixtures.
21. A compound according to claim 1, wherein L is a chiral
1,1'-binaphthyl-2,2'-di(carboxylate ester) having enantiomerically
enriched or substantially pure (R) or (S) stereochemistry or a
mixture of (R) and (S) enantiomers including racemic mixtures.
22. A compound according to claim 1, wherein L is of formula:
##STR00090## wherein Rc and R'c, identical or different are alkyl,
aryl or hydrogen, Rd and R'd, identical or different are alkyl,
aryl or hydrogen, Rf and R'f, identical or different are alkyl,
aryl or hydrogen, Rg and R'g, identical or different are alkyl,
aryl or hydrogen; W is an alkyl.
23. A compound according to claim 1, wherein L is
--CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)--.
24. A process for producing a compound of formula: ##STR00091##
comprising treating a taxane precursor compound of formula:
##STR00092## with a compound of formula: ##STR00093## wherein Ar is
an aryl, R is an acyl, R.sub.1, and R.sub.2, identical or
different, are independently acyl, hydrogen or a hydroxy protecting
group, L is a cleavable linker, Y.sub.1 is hydrogen, a hydroxy or a
protected hydroxy group, Y.sub.2 is a hydrogen or a protected
hydroxy group or Y.sub.1 and Y.sub.2 taken together form a carbonyl
group.
25. A process according to claim 24, wherein R is an acyl that is
an aroyl or alkyloxycarbonyl.
26. A process according to claim 24, wherein Ar is phenyl
optionally substituted with one or more substituents.
27. A process according to claim 24, wherein Ar is unsubstituted
phenyl.
28. A process according to claim 24, wherein Y.sub.1 is a hydroxyl
and Y.sub.2 is a hydrogen.
29. A process according to claim 28, wherein Y.sub.1 is a hydroxyl
having stereochemistry ##STR00094##
30. A process according to claim 24, wherein, Y.sub.1 and Y.sub.2
taken together form a carbonyl group.
31. A process according to claim 24, wherein R is benzoyl, R.sub.1
is acetyl and R.sub.2 is a hydroxy protecting group.
32. A process according to claim 31, wherein R.sub.2 is selected
from the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl.
33. A process according to claim 24, wherein R is benzoyl, R.sub.1
is acetyl and R.sub.2 is a hydrogen.
34. A process according to claim 24, wherein R is benzoyl and
wherein R.sub.1 and R.sub.2 are both hydrogen.
35. A process according to claim 24, wherein R is benzoyl and
wherein R.sub.1 and R.sub.2 are both a hydroxy protecting
group.
36. A process according to claim 24, wherein R.sub.1 and R.sub.2
are selected from the group consisting of ethoxyethyl,
triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl.
37. A process according to claim 24, wherein R is
tert-butyloxycarbonyl, R.sub.1 is acetyl and R.sub.2 is a hydroxy
protecting group.
38. A process according to claim 37, wherein R.sub.2 is selected
from the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl.
39. A process according to claim 24, wherein R is
tert-butyloxycarbonyl, R.sub.1 is acetyl and R.sub.2 is a
hydrogen.
40. A process according to claim 24, wherein R is
tert-butyloxycarbonyl and wherein R.sub.1 and R.sub.2 are both
hydrogen.
41. A process according to claim 24, wherein R is
tert-butyloxycarbonyl and wherein R.sub.1 and R.sub.2 are both a
hydroxy protecting group.
42. A process according to claim 41, wherein R.sub.1 and R.sub.2
are selected from the group consisting of ethoxyethyl,
triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, benzyl and tert-butyloxycarbonyl.
43. A process according to claim 24, wherein L is a cleavable
chiral linker.
44. A process according to claim 24, wherein L is a chiral tartaric
diester acetonide having enantiomerically enriched or substantially
pure (R, R) or (S, S) stereochemistry, or a mixture of (R, R) and
(S, S) enantiomers including racemic mixtures.
45. A process according to claim 24, wherein L is a chiral
trans-1,2-cyclohexane di(carboxylate ester) having enantiomerically
enriched or substantially pure (R, R) or (S, S) stereochemistry or
a mixture of (R, R) and (S, S) enantiomers including racemic
mixtures.
46. A process according to claim 24, wherein L is a chiral
1,1'-binaphthyl-2,2'-di(carboxylate ester) having enantiomerically
enriched or substantially pure (R) or (S) stereochemistry or a
mixture of (R) and (S) enantiomers including racemic mixtures.
47. A process according to claim 24, wherein L is of formula:
##STR00095## wherein Rc and R'c, identical or different are alkyl,
aryl or hydrogen, Rd and R'd, identical or different are alkyl,
aryl or hydrogen, Rf and R'f, identical or different are alkyl,
aryl or hydrogen, Rg and R'g, identical or different are alkyl,
aryl or hydrogen; W is an alkyl.
48. A process according to claim 24, wherein L is
.sup.--CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)--.
49. A process for producing a compound of formula: ##STR00096##
comprising treating a compound of formula: ##STR00097## with an
oxidizing agent; wherein Ar is an aryl, R is an acyl, R.sub.1, and
R.sub.2, identical or different, are independently acyl, hydrogen
or a hydroxy protecting group, L is a cleavable linker.
50. The process of claim 49 wherein the oxidizing agent is selected
from the group consisting of o-iodoxybenzoic acid (IBX),
Dess-Martin periodinane, iodosobenzene, iodozobenzene diacetate,
Jone's reagent, pyridinium dichromate, pyridinium chlorochromate,
potassium permanganate and Swern reagent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 12/092,432, filed on Jul. 22, 2008, which is a
national stage application of PCT/CA2006/001806, filed on Nov. 3,
2006, which claims the benefit of U.S. provisional application No.
60/733,172, filed Nov. 4, 2005. U.S. application Ser. No.
12/092,432, PCT/CA2006/001806, and U.S. provisional application No.
60/733,172 are each incorporated herein by reference in their
entirety.
TECHNICAL FIELD
[0002] The present invention is directed towards novel
.beta.-lactams used as starting material for the synthesis of
taxanes. The novel .beta.-lactams are chiral and are prepared by
enantioselective synthesis using chiral auxiliaries. The present
invention is also directed towards the use of the new
.beta.-lactams to convert 10-deacetylbaccatin III and
9-dihydro-13-acetylbaccatin III to paclitaxel, docetaxel and
analogs thereof.
BACKGROUND OF THE INVENTION
[0003] Paclitaxel, a naturally occurring diterpenoid extracted from
yew trees, has demonstrated great potential as an anti-cancer drug.
It is unique among antimitotic drugs in that it promotes the
assembly of stable microtubules from tubulin. It binds strongly to
microtubules, thus preventing depolymerisation of the tubulin and
inhibiting mitosis. The structure of paclitaxel and the numbering
system conventionally used is shown below. This numbering system is
also applicable to compounds used in the process of the present
invention.
##STR00001##
[0004] Docetaxel, a paclitaxel derivative, has also demonstrated
excellent antitumor activity over the past few years. Docetaxel has
the following structure:
##STR00002##
[0005] The chemical conversion of naturally occurring precursors
such as 10-deacetylbaccatin III (10-DAB III) and
9-dihydro-13-acetylbaccatin III (9-DHAB III) to paclitaxel and
docetaxel have been reported. Because of the congested position of
the 13-hydroxy group of 10-DAB-III and 9-DHAB-III, acylation with
.beta.-lactam has become the method of choice for acylation of that
position. An example of .beta.-lactam which has been extensively
used in the synthesis of paclitaxel and docetaxel is shown
below:
##STR00003##
where G is a benzoyl group when preparing paclitaxel or a
tert-butyloxycarbonyl (t-BOC) group when preparing docetaxel and P
is a "classical" hydroxy protecting group such as TES,
methyloxypropyl and 2,2,2-trichloroethoxycarbonyl.
[0006] An important limitation of the current method is that
although the syn lactam can be obtained by methods such as the
Staudinger reaction, the racemic form is always produced. The
racemic mixture must be submitted to a kinetic resolution either
prior to or during coupling with baccatin III. In either case half
of the lactam material must be discarded. A chiral synthesis of
.beta.-lactams would produce the desired isomer stereoselectively
but few such synthetic routes have been developed.
[0007] It would thus be highly desirable to be provided with new
routes for the enantioselective production of chiral .beta.-lactams
and new methods to use such .beta.-lactams in the synthesis of
paclitaxel, docetaxel and other biologically active taxanes.
SUMMARY OF THE INVENTION
[0008] In one aspect the present invention provides a process for
the preparation of paclitaxel, docetaxel, and analogs thereof where
novel .beta.-lactams of formula I:
##STR00004##
wherein R, Ar and L are as defined herein are reacted with a
suitable taxane precursor having a free C-13 hydroxy group.
[0009] In accordance with another aspect of the present invention,
there is provided novel .beta.-lactams of formula I and methods of
preparation thereof:
##STR00005##
wherein R, Ar and L are as defined herein.
[0010] In accordance with another aspect of the present invention,
there is provided a compound of formula V and methods of
preparation thereof:
##STR00006##
wherein R', R'' L, R.sub.1, R.sub.2, R'.sub.1, R'.sub.2, Y.sub.1
and Y.sub.2 are as defined herein.
[0011] In accordance with another aspect of the present invention,
there is provided a compound of formula VII
##STR00007##
wherein L is as defined herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0012] In accordance with one embodiment, there is provided
.beta.-lactam of formula I:
##STR00008##
wherein R is hydrogen, aryl or acyl, Ar is an aryl and L is a
cleavable linker, and more preferably a chiral auxiliary
(linker).
[0013] In one embodiment, there is provided a compound of formula
I
##STR00009##
in racemic or in either isomerically pure form, wherein R is
hydrogen, aryl or acyl, Ar is aryl, and L is a cleavable linker,
chiral or non chiral, preferably selected from the group consisting
of hydrolysable ketals, acetals, silyl, esters, diesters, and
hydrogenolyzable benzyl group.
[0014] In further embodiments, there is provided a compound of
formula I wherein:
[0015] R is hydrogen;
[0016] R is p-methoxyphenyl;
[0017] R is benzoyl; or
[0018] R is tert-butyloxycarbonyl (t-BOC).
[0019] In one embodiment, there is provided a compound of formula I
wherein Ar is aryl having 6 carbon atoms and which may be
optionally substituted with one or more substituents. In one
embodiment, Ar is phenyl optionally substituted with one or more
substituents. In a further embodiment, Ar is unsubstituted
phenyl.
[0020] Still in accordance with the present invention, there is
provided .beta.-lactams of the formula I in which chiral centers of
the .beta.-lactam moieties are optically pure or stereochemically
enriched by using a chiral auxiliary as the L group during their
preparation. Stereochemically enriched .beta.-lactams of formula I
can be used as intermediates in the synthesis of biologically
active taxanes such as paclitaxel, docetaxel and analogs thereof.
In such syntheses, .beta.-lactams of formula I are superior to
racemic ones in that less starting material is required and only
the desired taxane isomer is generated.
[0021] One advantage of the .beta.-lactams of formula I is that the
chiral linker L can be cleaved efficiently to provide side
chain-bearing taxanes.
[0022] Another advantage of the .beta.-lactams of formula I for
taxane synthesis is that their dimeric forms provide additional
steric hindrance during coupling reactions to baccatin III
compounds which in turns results in increased kinetic resolution
during coupling and better diastereomeric excess of the coupling
products. Simple non chiral linkers can also be used in instances
where the additional steric bulk provided by structures of formula
I generates sufficient kinetic resolution during the coupling
reaction to taxanes.
[0023] In one embodiment, there is provided a compound of formula
V
##STR00010##
wherein R' and R'', identical or different, are independently aryl,
alkyl or alkyloxy, R.sub.1 R'.sub.1, R.sub.2 and R'.sub.2,
identical or different, are independently acyl, hydrogen or a
hydroxy protecting group, L is a cleavable linker, and more
preferably a chiral linker, Y.sub.1 is a hydroxy or a protected
hydroxy group, Y.sub.2 is a hydrogen or a protected hydroxy group
or Y.sub.1 and Y.sub.2 taken together form a carbonyl group.
[0024] It is understood that the two molecules linked by the linker
need not to be identical. They may preferably be, but they
alternatively may be different. The present invention is to include
both possibilities, as one skilled in the art will appreciate that
both possibilities may be useful.
[0025] In one embodiment, there is provided a compound of formula
IIa or IIb
##STR00011##
wherein R' and R'', identical or different, are independently aryl,
alkyl or alkyloxy, R.sub.1 R'.sub.1, R.sub.2 and R'.sub.2,
identical or different, are independently acyl, hydrogen or a
hydroxy protecting group, L is a cleavable linker, and more
preferably a chiral linker, Y.sub.1 is hydrogen, a hydroxy or a
protected hydroxy group, Y.sub.2 is a hydrogen or a protected
hydroxy group or Y.sub.1 and Y.sub.2 taken together form a carbonyl
group.
[0026] In one embodiment there is provided a compound of formula
VI
##STR00012##
wherein Ar is an aryl, R is an acyl, preferably an aroyl or
alkyloxycarbonyl, R.sub.1, and R.sub.2, identical or different, are
independently acyl, hydrogen or a hydroxy protecting group, L is a
cleavable linker, and more preferably a chiral linker, Y.sub.1 is
hydrogen, a hydroxy or a protected hydroxy group, Y.sub.2 is a
hydrogen or a protected hydroxy group or Y.sub.1 and Y.sub.2 taken
together form a carbonyl group.
[0027] In one embodiment, there is provided a compound of formula
VIa or VIb
##STR00013##
wherein R is benzoyl or tert-butyloxycarbonyl, R.sub.1 and R.sub.2,
identical or different, are independently hydrogen, acyl or hydroxy
protecting group and L is a cleavable linker, chiral or non chiral,
preferably selected from the group consisting of hydrolysable
ketals, acetals, silyl, diesters, and hydrogenolyzable benzyl
group.
[0028] In one embodiment, there is provided a compound of formula
VI, VIa or VIb wherein R is benzoyl, R.sub.1 is acetyl and R.sub.2
is a hydroxy protecting group.
[0029] In one embodiment, R.sub.2 is selected from the group
consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and
tert-butyloxycarbonyl and R is benzoyl or tert-butyloxycarbonyl.
Preferably R.sub.2 is triethylsilyl.
[0030] In further embodiments, there is provided a compound of
formula VI, VIa or VIb wherein:
[0031] R is benzoyl, R.sub.1 is acetyl and R.sub.2 is a
hydrogen;
[0032] R is benzoyl and R.sub.1 and R.sub.2 are both hydrogen;
[0033] R is benzoyl and R.sub.1 and R.sub.2 are both a hydroxy
protecting group.
[0034] In further embodiments, there is provided a compound of
formula VI, VIa or VIb wherein R.sub.1 and R.sub.2 are selected
from the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl and R is benzoyl or
tert-butyloxycarbonyl. Preferably R.sub.1 and R.sub.2 are
triethylsilyl.
[0035] In one embodiment, there is provided compounds of formula
VI, VIa or VIb wherein R is tert-butyloxycarbonyl, R.sub.1 is
acetyl and R.sub.2 is a hydroxy protecting group. Preferably,
R.sub.1 and R.sub.2 are triethylsilyl.
[0036] In further embodiments, there is provided a compound of
formula VI, VIa or VIb wherein R.sub.2 is selected from the group
consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and
tert-butyloxycarbonyl and R is benzoyl or
tert-butyloxycarbonyl.
[0037] In further embodiments, there is provided a compound of
formula VI, VIa or VIb wherein:
[0038] R is tert-butyloxycarbonyl, R.sub.1 is acetyl and R.sub.2 is
a hydrogen;
[0039] R is tert-butyloxycarbonyl and R.sub.1 and R.sub.2 are both
hydrogen;
[0040] R is tert-butyloxycarbonyl and R.sub.1 and R.sub.2 are both
a hydroxy protecting group;
[0041] R.sub.1 and R.sub.2 are selected from the group consisting
of ethoxyethyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and
tert-butyloxycarbonyl and R is benzoyl or
tert-butyloxycarbonyl.
[0042] In one embodiment, there is provided a compound of formula
VII
##STR00014##
wherein L is a cleavable linker, chiral or non chiral, selected
from the group consisting of hydrolysable ketals, acetals, silyl,
diesters, and hydrogenolyzable benzyl group.
[0043] In further embodiments of the invention, there is provided a
compound of formula I, IIa, IIb, V, VI, VIa, VIb or VII
wherein:
[0044] L is a cleavable chiral auxiliary;
[0045] L is a chiral tartaric diester acetonide having
enantiomerically enriched or substantially pure (R, R) or (S, S)
stereochemistry, or a mixture of (R, R) and (S, S) enantiomers
including racemic mixtures;
[0046] L is a chiral trans-1,2-cyclohexane di(carboxylate ester)
having enantiomerically enriched or substantially pure (R, R) or
(S, S) stereochemistry or a mixture of (R, R) and (S, S)
enantiomers including racemic mixtures;
[0047] L is a chiral 1,1'-binaphthyl-2,2'-di(carboxylate ester)
having enantiomerically enriched or substantially pure (R) or (S)
stereochemistry or a mixture of (R) and (S) enantiomers including
racemic mixtures.
[0048] In a further embodiment, there is provided a compound of
formula I, IIa, IIb, V, VI, VIa, VIb or VII wherein L is a ketal or
acetal of formula
##STR00015##
wherein Rc and R'c, identical or different are alkyl, aryl or
hydrogen.
[0049] In further embodiments, Rc and R'c are independently an
alkyl of 1 to 6 carbon atoms, Rc and R'c are independently an alkyl
of 1 to 3 carbon atoms; Rc and R'c are independently an alkyl of 1
carbon atom; Rc and R'c are a methyl group; Rc and R'c form
together a cyclic alkyl ring of 3 to 6 carbon atoms.
[0050] In further embodiments, Rc and R'c are independently an aryl
having 6 to 10 carbon atoms and which may be optionally substituted
with one or more substituents; Rc and R'c are independently an aryl
having 6 carbon atoms; Rc and R'c are a phenyl optionally
substituted with one or more substituents. In a further embodiment,
Rc and R'c are unsubstituted phenyl.
[0051] In a further embodiment, there is provided a compound of
formula I, IIa, IIb, V, VI, VIa, VIb or VII wherein L is a silyl
linker of formula
##STR00016##
wherein Rd and R'd, identical or different are alkyl, aryl or
hydrogen.
[0052] In further embodiments, Rd and R'd are independently an
alkyl of 1 to 6 carbon atoms, Rd and R'd are independently an alkyl
of 1 to 3 carbon atoms; Rd and R'd are independently an alkyl of 1
carbon atom; Rd and R'd are a methyl group; Rd and R'd form
together a cyclic alkyl ring of 3 to 6 carbon atoms.
[0053] In further embodiments, Rd and R'd are independently an aryl
having 6 to 10 carbon atoms and which may be optionally substituted
with one or more substituents; Rd and R'd are independently an aryl
having 6 carbon atoms; Rd and R'd are a phenyl optionally
substituted with one or more substituents. In a further embodiment,
Rd and R'd are unsubstituted phenyl.
[0054] In a further embodiment, there is provided a compound of
formula I, IIa, IIb, V, VI, VIa, VIb or VII wherein L is a linker
of formula
##STR00017##
wherein Rf and R'f, identical or different are alkyl, aryl or
hydrogen.
[0055] In further embodiments, Rf and R'f are independently an
alkyl of 1 to 6 carbon atoms, Rf and R'f are independently an alkyl
of 1 to 3 carbon atoms; Rf and R'f are independently an alkyl of 1
carbon atom; Rf and R'f are a methyl group; Rf and R'f form
together a cyclic alkyl ring of 3 to 6 carbon atoms.
[0056] In further embodiments, Rf and R'f are independently an aryl
having 6 to 10 carbon atoms and which may be optionally substituted
with one or more substituents; Rf and R'f are independently an aryl
having 6 carbon atoms; Rf and R'f are a phenyl optionally
substituted with one or more substituents. In a further embodiment,
Rf and R'f are unsubstituted phenyl.
[0057] In a further embodiment, there is provided a compound of
formula I, IIa, IIb, V, VI, VIa, VIb or VII wherein L is a linker
of formula
##STR00018##
wherein Rg and R'g, identical or different are alkyl, aryl or
hydrogen; W is an alkyl.
[0058] In further embodiments, W is an alkyl of 1 to 30 carbon
atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6
carbon atoms. More preferably, W is --(CH.sub.2).sub.n-- wherein n
is 1 to 30, alternatively, n is 1 to 10 or 1 to 6.
[0059] In further embodiments, Rg and R'g are independently an
alkyl of 1 to 6 carbon atoms, Rg and R'g are independently an alkyl
of 1 to 3 carbon atoms; Rg and R'g are independently an alkyl of 1
carbon atom; Rg and R'g are a methyl group; Rg and R'g form
together a cyclic alkyl ring of 3 to 6 carbon atoms.
[0060] In further embodiments, Rg and R'g are independently an aryl
having 6 to 10 carbon atoms and which may be optionally substituted
with one or more substituents; Rg and R'g are independently an aryl
having 6 carbon atoms; Rg and R'g are a phenyl optionally
substituted with one or more substituents. In a further embodiment,
Rg and R'g are unsubstituted phenyl.
[0061] In a further embodiment, there is provided a compound of
formula I, IIa, IIb, V, VI, VIa, VIb or VII wherein L is
--CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)--.
[0062] In one embodiment, the present invention provides a compound
of formula III
##STR00019##
where the L group of compound of formula I is now an optically pure
chiral tartrate acetonide group. The compound of formula III can be
used in the synthesis of paclitaxel.
[0063] In another preferred embodiment, the present invention
provides a compound of formula IV
##STR00020##
Compound of formula IV can be used in the synthesis of
docetaxel.
[0064] Taxane precursors having a free C-13 hydroxy group suitable
for use in the present invention are not particularly limited. An
example of suitable taxane structure includes compounds defined by
the general formula
##STR00021##
wherein R.sub.1, R.sub.2, Y.sub.1 and Y.sub.2 are as defined herein
above. Preferably R.sub.1 and R.sub.2 are a hydroxy protecting
group and more preferably a triethylsilyl. Alternatively, R.sub.1
is an acyl, preferably an acetyl group, and R.sub.2 is a hydroxy
protecting group, preferably a triethylsilyl. Preferably, Y.sub.1
is a hydroxyl and Y.sub.2 is a hydrogen. More preferably Y.sub.1 is
a hydroxyl having stereochemistry
##STR00022##
[0065] Alternatively, Y.sub.1 and Y.sub.2 taken together form a
carbonyl group.
[0066] Examples of taxane precursors useful to practice the present
invention are described in WO 2006/102758, the content of which is
hereby incorporated by reference.
[0067] For the purpose of the present invention the following terms
are defined below.
[0068] The term "hydroxy protecting group" is intended to mean a
group that is attached to the oxygen of the hydroxyl group, for
protecting said group from reacting in a subsequent reaction. Such
groups are well known in the art and examples include without
limitation ethoxyethyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and
tert-butyloxycarbonyl. Preferably, the protecting group is
triethylsilyl.
[0069] The term "alkyl" represents a linear, branched or cyclic
hydrocarbon moiety having 1 to 30 carbon atoms, preferably 1 to 12
and more preferably 1 to 6, which is optionally substituted.
Examples include but are not limited to methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term alkyl
is also meant to include alkyls in which one or more hydrogen atom
is replaced by a halogen, i.e., an alkylhalide. Examples include
but are not limited to mono or polyfluorinated alkyl or mono or
polychlorinated alkyl such as trifluoromethyl, trichloromethyl,
trifluoroethyl, trichloroethyl. The expression "lower alkyl" refers
to alkoxy having 1 to 3 carbon atoms.
[0070] The term "alkyloxy" represents an alkyl which is covalently
bonded to the adjacent atom through an oxygen atom. Examples
include but are not limited to methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,
isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy
and neohexyloxy. The expression "lower alkoxy" refers to alkoxy
having 1 to 3 carbon atoms.
[0071] The term "acyl" is defined as a radical derived from a
carboxylic acid, obtained by replacement of the --OH group. Like
the acid to which it is related, an acyl radical may be linear,
branched or cyclic alkyl, alkyloxy or aryl, which are optionally
substituted. Examples include but are not limited to formyl,
acetyl, propionyl, butyryl, alkyloxycarbonyl (such as
terbutyloxycarbonyl), isobutyryl, valeryl, isovaleryl, pivaloyl,
caproyl, isocaproyl, acryloyl, propioloyl, methacryloyl, crotonoyl,
isocrotonoyl, aroyls (such as benzoyl, naphthoyl, toluoyl,
cinnamoyl), furoyl, glyceroyl, salicyloyl.
[0072] The term "aryl" represents a carbocyclic moiety containing
one benzenoid-type ring having 6 to 14 carbon atoms, preferably 6
to 10 carbon atoms, more preferably 6 carbon atoms and which may be
optionally substituted with one or more substituents. Examples
include but are not limited to phenyl, tolyl, dimethyphenyl,
aminophenyl, anilinyl.
[0073] The term "independently" means that a substituent can be the
same or a different definition for each item.
[0074] The terms "substituted" or "substituent" represent one or
more halogen, amino, cyano, hydroxyl, nitro, acyl or --O-acyl,
lower alkyl or lower alkoxy; preferably, halogen, lower alkyl or
lower alkoxy.
[0075] The terms "leaving group" is an atom or molecule that
detaches from the parent compound. Examples include halogen such as
chloride, bromide and iodide, anhydrides such as an acetoxy or a
group derived from the parent compound such as a succinimide, a
pyridinium or an amino pyridinium such as
dimethylaminopyridinium.
[0076] There is also provided "enantiomers" of the present
invention. It will be appreciated that the compounds in accordance
with the present invention can contain a chiral center. The
compounds in accordance with the present invention may thus exist
in the form of two different optical isomers, that is (+) or (-)
enantiomers. All such enantiomers and mixtures thereof, including
racemic or other ratio mixtures of individual enantiomers, are
included within the scope of the invention. The single enantiomer
can be obtained by methods well known to those of ordinary skill in
the art, such as chiral HPLC, enzymatic resolution and chiral
auxiliary derivatization.
[0077] It will also be appreciated that the compounds in accordance
with the present invention can contain more than one chiral centre.
The compounds of the present invention may thus exist in the form
of different diastereomers. All such diastereomers and mixtures
thereof are included within the scope of the invention. The single
diastereomer can be obtained by method well known in the art, such
as HPLC, crystallization and chromatography.
[0078] The terms "isomerically pure form" with reference to
enantiomers of the compounds of the invention means
enantiomerically enriched or substantially pure enantiomers or with
reference to diastereomers of the compounds of the invention means
diastereomerically enriched or substantially pure
diastereomers.
[0079] In another embodiment, the present invention also provides a
process for the preparation of compounds of formula I from chiral
auxiliaries. The present invention also provides a process for the
use of a compound of formula I in the synthesis of taxanes.
[0080] In one embodiment, there is provided a process for producing
a compound of formula 5''
##STR00023##
wherein Ar is an aryl group and L is a cleavable linker, chiral or
non chiral, preferably selected from the group consisting of
hydrolysable ketals, acetals, silyl, diesters, and hydrogenolyzable
benzyl group, comprising reacting a compound of formula 3'
##STR00024##
wherein Rb is an alkyloxy and L is as defined above, with a
compound of formula
##STR00025##
wherein Ar is as defined above and Ra is a group cleaveable in situ
from the reaction condition or from an isolation process.
[0081] In further embodiments:
[0082] Rb is an alkyloxy of 1 to 12 carbon atoms,
[0083] Rb is an alkyloxy of 1 to 6 carbon atoms,
[0084] Rb is an alkyloxy of 1 to 3 carbon atoms,
[0085] Rb is a methoxy or an ethoxy.
[0086] In further embodiments:
[0087] Ra is a trialkyl silyl, wherein each of the alkyl is
independently selected and is a linear or branched alkyl of 1 to 4
carbon atoms;
[0088] Ra is a trimethyl silyl;
[0089] Ra is a triethyl silyl
[0090] Ra is a triisopropylsilyl;
[0091] Ra is a t-butyldimethylsilyl;
[0092] Ra is a t-butyldiphenylsilyl.
[0093] In one embodiment, there is provided a process comprising
reacting a compound of formula
##STR00026##
wherein R is alkyl, with a compound of formula
##STR00027##
so as to provide a compound of formula
##STR00028##
chiral or racemic, wherein Ar is an aryl group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenolyzable benzyl group.
[0094] In one embodiment, there is provided a process for producing
a compound of formula 5'
##STR00029##
wherein Ar is an aryl group and L is a cleavable linker, chiral or
non chiral, preferably selected from the group consisting of
hydrolysable ketals, acetals, silyl, diesters, and hydrogenolyzable
benzyl group; Ra is a group cleaveable under oxydative condition;
comprising reacting a compound of formula 3'
##STR00030##
wherein Rb is leaving group and L is as defined above, with a
compound of formula
##STR00031##
wherein Ar and Ra are as defined above.
[0095] In further embodiments,
[0096] Ra is 4-methoxyphenyl;
[0097] Rb is a chloride, a bromide or an iodide;
[0098] Ra is 4-methoxyphenyl and Rb is a chloride.
[0099] In one embodiment, there is provided a process comprising
reacting a compound of formula
##STR00032##
with a compound of formula
##STR00033##
so as to provide a compound of formula
##STR00034##
chiral or racemic, wherein Ar is an aryl group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenatable benzyl group.
[0100] In one embodiment, there is provided a process for producing
a compound of formula 5''
##STR00035##
wherein Ar is an aryl group and L is a cleavable linker, chiral or
non chiral, preferably selected from the group consisting of
hydrolysable ketals, acetals, silyl, diesters, and hydrogenolyzable
benzyl group, comprising reacting a compound of formula 5'
##STR00036##
with an oxidant reagent, wherein Ar and L are as defined above and
Ra is a group cleavable under oxydative condition.
[0101] In one embodiment, the oxidant reagent is ceric (IV)
ammonium nitrate.
[0102] In a further embodiment, Ra is 4-methoxyphenyl.
[0103] In still a further embodiment there is provided a process
comprising oxidation of a compound of formula
##STR00037##
using an oxidizing agent to provide a compound of formula
##STR00038##
chiral or racemic, wherein Ar is an aryl group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenolyzable benzyl group.
[0104] In one embodiment, there is provided a process for producing
a compound of formula 5'''
##STR00039##
wherein Ar is an aryl group and L is a cleavable linker, chiral or
non chiral, preferably selected from the group consisting of
hydrolysable ketals, acetals, silyl, diesters, and hydrogenolyzable
benzyl group, R is an acyl group; preferably an aroyl or
alkyloxycarbonyl, comprising treating a compound of formula 5''
##STR00040##
wherein Ar and L are as described above, with an acylating agent to
produce compound of formula 5'''.
[0105] In one embodiment, R is a tert-butyloxycarbonyl or a
benzoyl. In a further embodiment, the acylating agent is benzoyl
halide and preferably benzoyl chloride. In a further embodiment the
acylating agent is diterbutyl dicarbonate.
[0106] In one embodiment, there is provided a process comprising
acylation of a compound of formula
##STR00041##
with benzoyl chloride or di-tert-butyldicarbonate, (BOC).sub.2O to
provide a compound of formula
##STR00042##
chiral or racemic, wherein Ar is an aryl group, R is acyl and L is
a cleavable linker, chiral or non chiral, preferably selected from
the group consisting of hydrolysable ketals, acetals, silyl,
diesters, and hydrogenatable benzyl group.
[0107] With reference to scheme 1, compound of formula I, in
accordance with the present invention, can be prepared as described
from the compounds 5', 5'' and 5''' together. More particularly, a
linker "L" having two leaving groups such as an halogen or a group
derived from a carboxylic acid group (e.g. acyl chloride, a
carbodiimide derived group, a pyridinium group) is treated with a
glycolate ester 2', in which Rb is a group such as an alkyloxy, to
produce a compound 3' that is further treated with an aldimine 4'
to produce a compound 5' or 5''. Ra is a group susceptible to be
cleaved in situ from the reaction condition or the isolation
process (such as trimethyl silyl).
[0108] Alternatively, when Rb is a leaving group such as a halide
(e.g. chloride) Ra is a group that is susceptible to be cleaved at
a later stage for example by oxydative cleavage (e.g.
4-methoxyphenyl group). Compound 5'' can be acylated to produce a
compound 5''' in which R is an acyl group such as
tert-butyloxycarbonyl or a benzoyl.
##STR00043##
[0109] With reference to scheme 2, compounds of formulas III and IV
are prepared from a chiral auxiliary such as the acetonide of
optically pure tartaric acid, compound 1. Compound 1 is reacted
with ethyl glycolate, 2 under coupling conditions to provide
compound 3. Reacting compound 3 with aldimine 4 provides compound 5
in which diastereomeric excess is induced at the .beta.-lactam
chiral centers by the presence of the chiral tartrate group.
Compound 5 is converted to a compound of formula III in the
presence of benzoyl chloride or to a compound of formula IV in the
presence of di-tert-butyldicarbonate.
##STR00044##
[0110] With reference to scheme 3, compound of formula 5 (as
described in scheme 2) can be prepared when compound 6 is reacted
with aldimine compound 7, to provide compound 8 in which
diastereomeric excess is again induced at the .beta.-lactam chiral
centers by the presence of the chiral tartrate group. Compound 8 is
oxidized to compound 5 in the presence of an oxidizing agent such
as the CAN reagent.
##STR00045##
[0111] In one aspect, there is provided a process for producing a
compound of formula VI
##STR00046##
comprising treating a taxane precursor compound of formula
##STR00047##
with a compound of formula
##STR00048##
wherein R, R.sub.1, R.sub.2, Y.sub.1, Y.sub.2, Ar and L are as
defined herein.
[0112] In one aspect the present invention provides a process for
the preparation of paclitaxel, docetaxel, and analogs thereof where
.beta.-lactams of formula I:
##STR00049##
[0113] Further in accordance with the present invention, there is
provided a method to use .beta.-lactams of formula I for the
preparation of paclitaxel, docetaxel and analogs thereof.
[0114] In one embodiment, the 13-hydroxy group of a suitably
protected baccatin III compound is reacted with the .beta.-lactam
of formula I to provide a compound of formula II
##STR00050##
wherein R identical or different, are independently aryl, acyl or
acyloxy, R.sub.1, R.sub.2, identical or different, are
independently acyl, hydrogen or a hydroxy protecting group and L is
a cleavable linker, and more preferably a chiral auxiliary
(linker). The linker is then removed by hydrolysis or hydrogenation
and protecting groups are removed to provide the require
paclitaxel, docetaxel and analogs thereof.
[0115] In one embodiment of the invention, there is provided a
process comprising reacting of a compound of formula
##STR00051##
with a compound of formula
##STR00052##
to provide a compound of formula
##STR00053##
wherein R.sub.2 is a hydroxy protecting group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenolizable benzyl group.
[0116] In one embodiment of the invention, there is provided a
process comprising reacting of a compound of formula
##STR00054##
with a compound of formula
##STR00055##
to provide a compound of formula
##STR00056##
wherein R.sub.2 is a hydroxy protecting group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenolizable benzyl group.
[0117] In a further embodiment, there is provided a process
comprising reacting of a compound of formula
##STR00057##
with a compound of formula
##STR00058##
to provide a compound of formula
##STR00059##
wherein R.sub.1 and R.sub.2 are a hydroxy protecting group and L is
a cleavable linker, chiral or non chiral, preferably selected from
the group consisting of hydrolysable ketals, acetals, silyl,
diesters, and hydrogenolizable benzyl group.
[0118] In a further embodiment, there is provided a process
comprising reacting a compound of formula
##STR00060##
with a compound of formula
##STR00061##
to provide a compound of formula
##STR00062##
wherein R.sub.1 and R.sub.2 are a hydroxy protecting group and L is
a cleavable linker, chiral or non chiral, preferably selected from
the group consisting of hydrolysable ketals, acetals, silyl,
diesters, and hydrogenolisable benzyl group.
[0119] Preferably, the hydroxy protecting group is selected from
the group consisting of ethoxyethyl, triethylsilyl,
triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyl and tert-butyloxycarbonyl. More preferably, the hydroxy
protecting group is triethylsilyl.
[0120] In a further aspect, there is provided a process for
producing a compound of formula
##STR00063##
comprising treating a compound of formula
##STR00064##
with an oxidizing agent; wherein R, R.sub.1, R.sub.2, Ar and L are
as defined herein.
[0121] In one embodiment, there is provided a process comprising
oxidation of a compound of formula
##STR00065##
with an oxidizing agent to provide a compound of formula
##STR00066##
wherein R.sub.2 is a hydroxy protecting group and L is a cleavable
linker, chiral or non chiral, preferably selected from the group
consisting of hydrolysable ketals, acetals, silyl, diesters, and
hydrogenolyzable benzyl group.
[0122] In one embodiment, there is provided a process comprising
oxidation of a compound of formula
##STR00067##
with an oxidizing agent to provide a compound of formula
##STR00068##
wherein R.sub.1 and R.sub.2 are a hydroxy protecting group and L is
a cleavable linker, chiral or non chiral, preferably selected from
the group consisting of hydrolysable ketals, acetals, silyl,
diesters, and hydrogenolizable benzyl group.
[0123] In one embodiment, the oxidizing agent is selected from the
group consisting of o-iodoxybenzoic acid (IBX), Dess-Martin
periodinane, iodosobenzene, iodozobenzene diacetate, Jone's
reagent, pyridinium dichromate, pyridinium chlorochromate,
potassium permanganate and Swern reagent. Preferably, the oxidizing
agent is Dess-Martin periodinane.
[0124] Preferably, hydroxy protecting group is selected from the
group consisting of ethoxyethyl, triethylsilyl, triisopropylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl and
tert-butyloxycarbonyl. More preferably, hydroxy protecting group is
triethylsilyl.
[0125] In a further embodiment, L, R.sub.1 and R.sub.2 are as
defined herein.
[0126] In accordance with one aspect of the invention, there is
provided a process of preparing docetaxel comprising the reaction
sequence
##STR00069##
wherein L, R.sub.1 and R.sub.2 are as defined herein and said
process comprising the steps of: a) cleaving the linker L releasing
docetaxel protected at the 7 and 10-hydroxy positions and
deprotecting the hydroxy groups at the 7 and 10-hydroxy positions
to obtain docetaxel or b) deprotecting the hydroxy groups at the 7
and 10-hydroxy positions followed by the cleaving of the linker L
releasing docetaxel.
[0127] In a further embodiment, docetaxel is obtained in the
anhydrous form from crystallization in non protic solvents. In a
further embodiment, docetaxel is obtained as the trihydrate form
from crystallization in protic solvents.
[0128] In accordance with one aspect of the invention, there is
provided a process of preparing paclitaxel comprising the reaction
sequence
##STR00070##
wherein L, and R.sub.2 are as defined herein and said process
comprising the steps of: a) cleaving the linker releasing
paclitaxel protected at the 7-hydroxyl position and deprotecting
the hydroxy groups at the 7-hydroxyl position to obtain paclitaxel
or b) deprotecting the hydroxy groups at the 7-hydroxy positions
and cleaving the linker L releasing paclitaxel.
[0129] In a further embodiment, paclitaxel is obtained in the
anhydrous form from crystallization in non protic solvents. In a
further embodiment, paclitaxel is obtained in the trihydrate form
from crystallization in protic solvents.
[0130] With reference to scheme 4, paclitaxel is synthesized using
a compound of formula III. Compound 9, obtained from naturally
occurring 10-DAB as described in WO 2006/102758, is reacted with a
compound of formula III in the presence of a base to provide
compound 10. The compound 10 is then cleaved by hydrolysis in the
presence of a mild base and the 7-hydroxy protecting group is
removed with acid to provide paclitaxel.
[0131] Still with reference to scheme 4, in the synthesis of
docetaxel compound 11, obtained from naturally occurring 10-DAB as
described in WO 2006/102758, is reacted with a compound of formula
IV in the presence of a base to provide compound 12. Removal of the
linker L by hydrolysis in the presence of a mild base and removal
of the hydroxy protecting groups at the 7 and 10 positions with
mild acid provides docetaxel.
##STR00071##
[0132] With reference to scheme 5, compound 13, is prepared from
9-DHAB III, a naturally occurring taxane found in the needles of
the Canada yew as described in WO 2006/102758. Compound 13, is
reacted with a compound of formula III in the presence of a base to
provide compound 14. Oxidation of the 9-hydroxy groups of each of
the two taxane moieties of compound 14 using an oxidizing agent
provides compound 10 Compound 10, is then transformed to paclitaxel
using successive treatment with mild base and mild acid.
[0133] With reference to scheme 5, compound 15 is prepared from
naturally occurring 9-DHAB III as described in WO 2006/102758.
Compound 15, is reacted with a compound of formula IV in the
presence of a base such as to provide compound 16. Oxidation of the
9-hydroxy groups of each of the two taxane moieties of compound 16
using an oxidizing agent provides compound 12. The oxidized
product, compound 12, is then transformed to docetaxel using
successive treatment with mild base and mild acid.
##STR00072##
[0134] Compounds of formula I
##STR00073##
are prepared as described before using a compound of general
formula 3'
##STR00074##
wherein Ar, R, Rb are as defined above. The linker L is as
described herein and examples include ketal or acetal linker, silyl
linker of formulas
##STR00075##
wherein Rc and R'c, Rd and R'd, Rf and R'f, Rg and R'g and W are as
defined herein.
[0135] The compounds of formula 3' are typically prepared as
described in scheme 1 using the appropriate linker L. The reagent
"Leaving group-L-Leaving group" referred to in scheme 1 can be
prepared in accordance with conditions known in the art.
[0136] For instance, when the linker is
##STR00076##
a compound of general formula 2', wherein Rb is a group such as an
alkyloxy, is treated with a ketone or aldehyde of formula Rc-C(O)13
R'c (e.g. as acetone, acetaldehyde, cyclohexanone) under water
removal conditions (e.g. azeotropic solvent or water trapping agent
such as methylorthoformate) and a trace of an acid catalyst (e.g.
PTSA).
[0137] When the linker is
##STR00077##
or
##STR00078##
a compound of general formula 2', wherein Rb is a group such as an
alkyloxy, is treated with a reagent having the general formula
Rd-Si(leaving group).sub.2-R'd (e.g. (CH.sub.3).sub.2SiCl.sub.2) or
RfR'f-Si(leaving group)-O--Si(leaving group)-RfR'f (e.g.
(CH.sub.3).sub.2ClSi--O--SiCl(CH.sub.3).sub.2) under appropriate
basic conditions.
[0138] When the linker is
##STR00079##
a compound of general formula 2', wherein Rb is a group such as an
alkyloxy, is treated with a reagent having the general formula
RgR'g-Si(leaving group)-W--Si(leaving group)-RgR'g. An example
wherein Rg and R'g are i-propyl, the leaving group is chloride and
W is a methyl is
##STR00080##
[0139] The linkers described above may be cleaved at a suitable
stage of the process using standard conditions such as mild
hydrolytic conditions, for example using a dilute inorganic acid
solution such as HCl or a source of fluoride ions in case where a
silicon based linker is used.
[0140] When the linker is
--CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)-- a compound of general
formula 2', wherein Rb is a group such as an alkyloxy, is treated
with a reagent having the general formula (leaving
group)-CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)-(leaving group) such
as Cl--CH.sub.2--(C.sub.6H.sub.5)--(CH.sub.2)--Cl.
[0141] The above-described linker having benzylic position may be
cleaved at a suitable stage of the process using standard
hydrogenolysis conditions such as hydrogen or a source of hydrogen
(e.g. cyclohexanediene) and a suitable catalyst.
[0142] The present invention will be more readily understood by
referring to the following examples which are given to illustrate
the invention rather than to limit its scope.
EXAMPLE 1
[0143] Preparation of Compound of Formula III
[0144] Compound 1 is reacted with two equivalents of ethyl
glycolate, in the presence of 3.0 equivalents of
dicyclohexylcarbodiimide (DCC) and a catalytic amount of
dimethylaminopyridine (DMAP) in dichloromethane for 18 hours and
purified on silica gel to provide compound 3. Reacting compound 3
with 2.2 equivalents each of aldimine 4 and LDA in THF at
-10.degree. C. for 18 hours provides compound 5. Compound 5 is
converted to a compound of formula III in the presence of 3.0
equivalents of benzoyl chloride and 10 equivalents of triethylamine
in dichloromethane.
EXAMPLE 2
[0145] Preparation of Compound of Formula IV
[0146] Compound of formula IV is prepared as described in example
1, with the exception that compound 5 is treated in the presence of
3.0 equivalents of di-tert-butyldicarbonate in dichloromethane.
EXAMPLE 3
[0147] Alternative Preparation of Compound of formula 5
[0148] Compound 6 is reacted with 2.2 equivalents of
p-methoxyaniline, aldimine compound 7, in dichloromethane to
provide compound 8. Compound 8 is oxidized to compound 5 in the
presence of 5.6 equivalents of ceric ammonium nitrate (CAN) reagent
in acetonitrile and water (in a ratio of 1:1).
EXAMPLE 4
[0149] Synthesis of Compound of Formula 10
[0150] Compound 9, obtained from naturally occurring 10-DAB, is
reacted with a compound of formula III in the presence of lithium
hexamethyldisilizide (LHMDS) in THF to provide compound 10.
EXAMPLE 5
[0151] Synthesis of Paclitaxel
[0152] The linker in compound 10, as prepared in example 4, is
cleaved by hydrolysis in the presence of 2 equivalents of sodium
carbonate in 3.5 volume of methanol and the 7-hydroxy protecting
group is removed with dilute (0.2M) methanolic hydrochloric acid to
provide paclitaxel.
EXAMPLE 6
[0153] Synthesis of Compound of Formula 12
[0154] Compound 11, obtained from naturally occurring 10-DAB, is
reacted with 1.5 equivalents of a compound of formula IV in the
presence of 3 equivalents of LHMDS in THF to provide compound
12.
EXAMPLE 7
[0155] Synthesis of Compound of Formula 14
[0156] Compound 13 is reacted with 1.5 equivalents of a compound of
formula III in the presence of 3 equivalents of lithium
hexamethyldisilizide (LHMDS) in THF to provide compound 14.
EXAMPLE 8
[0157] Alternative Synthesis of Compound of Formula 10
[0158] Oxidation of the 9-hydroxy groups of each of the two taxane
moieties of compound 14, as provided in example 7, is carried out
using the 3 equivalents of Dess-Martin periodinane for each
equivalent of compound 14 in dichloromethane to provide compound
10.
EXAMPLE 9
[0159] Alternative Synthesis of Compound of Formula 12
[0160] Compound 15 is reacted with 1.5 equivalents of a compound of
formula IV in the presence of 3 equivalents of lithium
hexamethyldisilizide (LHMDS) in THF to provide compound 16.
Oxidation of the 9-hydroxy groups of each of the two taxane
moieties of compound 16 using 3 equivalents of the Dess-Martin
periodinane for each equivalents of compound 16 in dichloromethane
provides compound 12.
EXAMPLE 10
[0161] Synthesis of Docetaxel
[0162] Docetaxel is prepared from compound of formula 12 using
conditions similar to what is described in example 5.
EXAMPLE 11
[0163] Synthesis of Bis(diisopropylchlorosilyl)methane
[0164] Step 1: Synthesis of Bis(diisopropylsilyl)methane
##STR00081##
[0165] A solution of bis(dichlorosilyl)methane and CuCl.sub.2 in
THF was treated with isopropylmagnesium chloride, over 2 h. The
product was extracted in Hexane, dried over MgSO.sub.4 and
distilled to obtain the Bis(diisopropylsilyl)methane in 78%
yield.
[0166] Step 2: Synthesis of Bis(diisopropylchlorosilyl)methane
##STR00082##
[0167] To a mixture of Bis(diisopropylsilyl)methane, from step 1,
and PdCl.sub.2 was added dry CCl.sub.4 and kept the mixture at
60.degree. C. over 2 h. Then it was filtered and distilled to
obtain Bis(diisopropylchlorosilyl)methane in 87% yield. (see Ke
Wen, Suetying Chow, Yogesh S. Sanghvi, and Emmanuel A. Theodorakis,
J. Org. Chem. Vol. 67, No. 22, 2002).
EXAMPLE 12
[0168] Synthesis of
Bis(diisopropyl-9-Dihydro-7,10-bis-triethylsilyl-10-deacetyl-baccatin-III-
-silyl)methane
##STR00083##
[0169] The bis protected taxane
##STR00084##
(200 mg, 0.26 mmol) was solubilized in 2 ml of THF. The solution
was cooled to -45.degree. C. and 1.0 M LiHMDS was added (258 ul,
0.26 mmol) under an atmosphere of argon and left stirring over 15
min. Then was added the reagent
##STR00085##
(99 mg, 0.13 mmol) in 2 ml of THF and left stirring over 2 h at
-45.degree. C., and at -25.degree. C. overnight. The solution was
quenched with sat. NH4Cl (15 ml) and extracted with
(EtOAc.times.3.times.25 ml). The organic phase was washed with
brine (2.times.20 ml), dried over sodium sulfate, taken to dryness,
passed over silica gel, (EtOAc/Hexane 10% -25%,) to obtain 245 mg
of the dimer in 82% yield. 1H NMR (Acetone-d6, 600 MHz) .delta.
8.01-7.45, (20H, o-Bz and Ph); 6.07 (t; 2H, J=8.6 Hz; H13); 5.93
(br, d; 2H, J=8.9 Hz; NH41); 5.81 (br.d; 2H, J=5.3 Hz; H2); 5.25
(br, d; 2H, J=9.4 Hz; H31); 5.03 (d; 2H, J=9.4 Hz; OH9); 4.91 (d;
2H, J=9.4 Hz; H5); 4.87 (br.d; 2H, J=9.4 Hz; H21); 4.84 (d; 2H,
J=9.4 Hz; H10); 4.58 (dd; 2H, J=9.9, 7.1 Hz; H7); 4.18 (o; 2H, H9);
4.18 (o; 2H, H20a); 4.15 (d; 2H, J=8.1 Hz; H20b); 3.62 (s; 2H,
OH1); 3.14 (d; 2H, J=5.5 Hz; H3); 2.57 (o, 2H, 6Ha); 2.55 (o.s; 6H,
OAc); 2.42 (br; 2H, H14a); 2.27 (br, 2H, H14b); 1.92 (m; 2H, H6b);
1.86 (br.s; 6H, Me18); 1.82 (s; 6H, Me19); 1.74 (s, 6H, Me17); 1.37
(s; 18H, tBu-CO-Me18); 1.32 (s, 6H, Me16); 1.07 (o.t; 6H,
Si7-CH2-Me); 1.01 (o.t; 6H, Si10-CH2-Me); 1.05-0.85 (m; 2H,
Si--CH(Me)2); 0.79 (q; 4H, Si7-CH2-Me); 0.69 (m; 4H, Si10-CH2-Me);
-0.14 (s; 2H, Si--CH2-Si).
[0170] Characterization of the bis-Lactam reagent: Rf value of 0.3
on the TLC (Hexane/Acetone 30%). 1H NMR (Acetone-d6, 600 MHz)
.delta. 7.36 (o; 4H, Ph-3m); 7.30 (o; 4H, Ph-3o); 7.30 (t; 2H,
Ph-3p); 5.29 (d; 2H, J=5.9 Hz; H2); 5.15 (d; 2H, J=6 Hz; H3); 1.35
(s; 18H, C--O-Me3); 0.86-0.80 (o.d; 24H, Me2); 0.64 (septet; 2H,
J=7.4 Hz; Si--CH); -0.18 (s, 2H, Si--CH2-Si).
EXAMPLE 13
[0171] Synthesis of
Bis(diisopropyl-7,10-bis-triethylsilyl-10-deacetyl-baccatin-III-silyl)met-
hane
##STR00086##
[0172] To the Dess-Martin periodinane (110 mg, 0.26 mmol) in 6 ml
of dichloromethane was added 250 ul of pyridine. A solution of 200
mg (0.086 mmol) of the compound from example 12 in 4 ml of
CH.sub.2Cl.sub.2 was added to the periodinane solution and left it
standing over 18 h at room temperature. Saturated sodium bisulfite
solution (5 ml) was added and the solution was extracted with ethyl
acetate (3.times.30 ml). The organic phase was washed with brine
(2.times.20 ml), then with water (2.times.20 ml), dried over sodium
sulfate and evaporated to afford 178 mg of oxidized product in 89%
yield. 1H NMR (Acetone-d6, 300 MHz) .delta. 8.62 (br.d; 2H, J=8.9
Hz; NH41); 8.12, (m; 4H, o-Bz); 7.75-7.28 (m; 16H, O-Bz and Ph);
6.19 (t; 2H, J=8 Hz; H13); 5.68 (d, 2H, J=7 Hz; H2); 5.40 (br, d;
2H, J=8 Hz; H31); 5.32 (b.s; 2H, 1OH); 5.16 (s; 2H, H10); 4.92 (d;
2H, J=8 Hz; H5); 4.73 (s; 2H, H21); 4.41 (dd; 2H, J=10 Hz, 7 Hz;
H7); 4.30 (d; 2H, J=8; H20b); 4.18 (dd; 2H, J=8 Hz, H20a); 4.18 (o;
2H, H20a); 3.86 (d; 2H, J=7 Hz; H3); 2.52 (s; 6H, OAc); 2.52 (o;
2H, H6a); 2.40-2.15 (m; 4H, H14a and H14b); 1.93 (o; 2H, H6b); 1.89
(s; 6H, Me18); 1.69 (s; 6H, Me19); 1.32 (s; 18H, tBu-C-Me3); 1.24
(s, 12H, Me16 and Me17); 1.04-0.56 (m; 88H, --SiEt3, Si--CH(CH3)2,
Si--CH(CH3)2); -0.42 (s; 2H, Si--CH2-Si).
EXAMPLE 14
[0173] Synthesis of Docetaxel
##STR00087##
[0174] The starting material from example 13 (150 mg, 0.065 mmol)
was dissolved in 20 ml of acetonitrile. A 0.2 M HCl solution (6 ml)
was added and the solution was stirred at room temperature for 3 h.
The pH of the solution was raised to 5.5 with aqueous sodium
bicarbonate. Most of the acetonitrile was evaporated and ethyl
acetate (50 ml) and water (50 ml) were added. The solution was
extracted with ethyl acetate (3.times.50 ml). The organic phase was
washed with water (2.times.50 ml), dried over sodium sulfate and
evaporated. The product was purified on silica gel eluting with
Acetone/Hexane (0-40%) to afford 94 mg of Docetaxel in 90%
yield.
[0175] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth, and as follows in the scope of the appended
claims.
* * * * *