Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-17
2002-08-13
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S214000, C549S432000, C549S484000, C560S116000
Reexamination Certificate
active
06433189
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to the synthesis of taxol and other tricyclic and tetracyclic taxanes and novel intermediates thereof.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has the following structure:
wherein Ac is acetyl.
The supply of taxol is presently being provided by the bark from
Taxus brevifollia
(Western Yew). However, taxol is found only in minute quantities in the bark of these slow growing evergreens. Consequently, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxol. To date, the results have not been entirely satisfactory.
A semi-synthetic approach to the preparation of taxol has been described by Greene, et al. in JACS 110, 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure of formula II shown below:
10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the needles of
Taxus baccata.
According to the method of Greene et al., 10-deacetyl baccatin III (“10-DAB”) is converted to taxol by attachment of the C-10 acetyl group and by attachment of the C-13 &bgr;-amido ester side chain through the esterification of the C-13 alcohol with a &bgr;-amido carboxylic acid unit.
Denis et al. in U.S Pat. No. 4,924,011 disclose another process for preparing derivatives of baccatin III or of 10-deacetylbaccatin III of general formula
in which R′ denotes hydrogen or acetyl. As reported, an acid of general formula:
in which R
1
is a hydroxy-protecting group, is condensed with a taxane derivative of general formula:
in which R
2
is an acetyl hydroxy-protecting group and R
3
is a hydroxy-protecting group, and the protecting groups R
1
, R
3
and, where appropriate, R
2
are then replaced by hydrogen.
Other semisynthetic approaches for the preparation of taxol and for the preparation of other taxanes which possess tumor-inhibiting properties have been reported in recent years, but each of these approaches requires 10-DAB or baccatin III as a starting material. As such, the supply of taxol and other taxane derivatives remains dependent at least to some extent upon the collection of various parts of plants from the remote corners of the world and the extraction of 10-DAB and/or baccatin III therefrom.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a process for the synthesis of taxol and other tetracyclic taxanes; the provision of such a process which is highly diastereoselective; the provision of such a process which proceeds in relatively high yield; and the provision of key intermediates and processes for their preparation.
Briefly, therefore, the present invention is directed to a process for the preparation of taxol and other tricyclic and tetracyclic taxanes.
In accordance with one aspect of the present invention, the process comprises reacting a compound having the formula
with BrMgN(iPr)
2
, an aldehyde (or ketone), followed by phosgene and an alcohol to form a compound having the formula:
wherein
R
1
is hydrogen or protected hydroxy; R
2
is hydrogen or protected hydroxy;
R
3
is oxo;
R
7b
is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or —OCOR
36
;
R
7c
and R
7d
are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R
9
is hydrogen, protected hydroxy, or oxo;
R
10
is —OP
10
;
R
13
is —OP
13
;
R
36
is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX
8
X
10
, —SX
10
, monocyclic aryl or monocyclic heteroaryl;
X
8
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X
10
is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
P
10
and P
13
are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula
with lithium tetramethylpiperidide to form a compound having the formula:
wherein
R
1
is hydrogen or protected hydroxy;
R
7c
, is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R
9
is hydrogen, protected hydroxy, or oxo; and
P
10
and P
13
are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula:
with lithium tetramethylpiperidide and camphosulfonyl oxaziridine to form a compound having the formula:
wherein R
9
is hydrogen, protected hydroxy, or oxo; R
7c
is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P
10
and P
13
are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula:
with a hydride reducing agent, preferably Red-Al, to form a compound having the formula:
wherein R
9
is hydrogen, protected hydroxy, or oxo; R
7c
is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P
10
and P
13
are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula:
with lithium diisopropylamide to form a compound having the formula:
wherein R is lower alkyl, R
1
is hydrogen, protected hydroxy or R
1
and R
2
together form a carbonate, R
2
is hydrogen, protected hydroxy or R
1
and R
2
together form a carbonate, R
9
is hydrogen, protected hydroxy, or oxo; and P
10
and P
13
are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula:
with DBU to form a compound having the formula:
wherein
R
1
is hydrogen, hydroxy, protected hydroxy or —OCOR
30
, or together with R
2
is a carbonate;
R
2
is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR
31
, or together with R
1
is a carbonate;
R
4a
is hydrogen, alkyl, hydroxy, or protected hydroxy, or together with R
2
is a carbonate;
R
4b
is hydroxymethylene;
R
5
is —OMs, —OTs or a bromide;
R
7a
is hydrogen, protected hydroxy, or —OCOR
34
, or together with R
9
is a carbonate;
R
9
is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR
33
, or together with R
7a
or R
10
is a carbonate;
R
10
is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR
29
, or together with R
9
is a carbonate;
P
13
is a hydroxy protecting group;
R
29
, R
30
, R
31
, R
33
and R
34
are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX
8
X
10
, —SX
10
, monocyclic aryl or monocyclic heteroaryl;
X
8
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
X
10
is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula:
with KOtBu and (PhSeO)
2
O to form a compound having the formula:
which rearranges in the presence of additional KOtBu, silica gel, or other acids or bases, or with heat to a compound having the formula:
wherein
R
1
is hydrogen, hydroxy, protected hydroxy, or —OCOR
30
, or together with R
2
is a carbonate;
R
2
is hydrogen, protected hydroxy, or —OCOR
31
, or together with R
1
or R
4a
is a carbonate;
R
4a
is hydrogen, alkyl, hydroxy, protected hydroxy, or —OCOR
27
, together with R
4b
is an oxo, or together with R
2
, R
4b
, or R
5
is a carbonate;
R
4b
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cyano, together with R
4a
is an oxo, together with R
4a
or R
5
is a carbonate, or together with R
5
and the carbons to which they are attached form an oxetane ring;
R
5
is hydrogen, protected hydroxy, —OCOR
37
, together with R
4a
or R
4b
is a carbonate, or together with R
4b
and the carbons to which they are attached form an oxetane ring;
R
7a
is hydrogen, halogen, protected hydroxy, or —OCOR
34
;
P
13
is a hydroxy protecting group;
R
27
, R
30
, R
31
, R
34
and R
37
are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX
8
X
10
, —SX
10
Biediger Ronald J.
Boatman P. Douglas
Holton Robert A.
Kim Hyeong Baik
Liang Feng
Florida State University
Senniger Powers Leavitt & Roedel
Trinh Ba K.
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