Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-02
2002-11-12
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
06479678
ABSTRACT:
BACKGROUND OF THE INVENTION
Three esters of N-acyl phenyl isoserine, taxol, taxotere and cephaloniannine have been found to possess significant properties, as antitumor agents. This application describes a process for the preparation of N-acyl, N-sulfonyl and N-phosphoryl substituted isoserine esters, in general and to a semi-synthesis for the preparation of taxane derivatives such as taxol, taxotere and other biologically active derivatives involving the use of metal alkoxides and &bgr;-lactams, in particular.
The Laxane 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 Ph is phenyl and Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
The supply of taxol for these clinical trials 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, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxol. So far, the results have not been entirely satisfactory.
One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS 110, 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and costly process.
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 is converted to taxol by attachment of the C-10 acetyl group and by attachment of tile C-13 &bgr;-amido ester side chain through the esterification of the C-13 alcohol with a &bgr;-amido carboxylic acid unit. Although this approach requires relatively few steps, the synthesis of the &bgr;-amido carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield. However, this coupling reaction is a key step which is required in every contemplated synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS 93, 2325 (1971) that the presence of the &bgr;-amido ester side chain at C13 is required for anti-tumor activity.
More recently, it has been reported in Colin et al. U.S. Pat. No. 4,814,470 that taxol derivatives of the formula III below, have an activity significantly greater than that of taxol (I).
R′ represents hydrogen or acetyl and one of R″ and R′″ represents hydroxy and the other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof.
According to Colin et al., U.S. Pat. No. 4,418,470, the products of general formula (III) are obtained by the action of the sodium salt of tert-butyl N-chlorocarbamate on a product of general formula:
in which R′ denotes an acetyl or 2,2,2-trichloroethoxycarbonyl radical, followed by the replacement of the 2,2,2-trichloroethoxycarbonyl group or groups by hydrogen. It is reported by Denis et al. in U.S. Pat. No. 4,924,011, however, that this process leads to a mixture of isomers which has to be separated and, as a result, not all the baccatin III or 10-deactylbaccatin III employed for the preparation of the product of general formula (IV) can be converted to a product of general formula (III).
In an effort to improve upon the Colin et al. process, Denis et al. disclose a different process for preparing derivatives of baccatin III or of 10-deactylbaccatin III of general formula
in which R′ denotes hydrogen or acetyl wherein 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. However, this method employs relatively harsh conditions, proceeds with poor conversion, and provides less than optimal yields.
A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of a readily available method for easy attachment, to the C-13 oxygen, of the chemical unit which provides the &bgr;-amido ester side chain. Development of such a process for its attachment in high yield would facilitate the synthesis of taxol as well as related anti-tumor agents having a modified set of nuclear substituents or a modified C-13 side chain. This need has been fulfilled by the discovery of a new, efficient process for attachment, to the C-13 oxygen, of the chemical unit which provides the &bgr;-amido ester side chain.
Another major difficulty encountered in the synthesis of taxol is that known processes for the attachment of the &bgr;-amido ester side chain at C-13 are generally not sufficiently diastereoselective. Therefore the side chain precursor must be prepared in optically active form to obtain the desired diastereomer during attachment. The process of this invention, however, is highly diastereoselective, thus permitting the use of a racemic mixture of side chain precursor, eliminating the need for the expensive, time-consuming process of separating the precursor into its respective enantiomeric forms. The reaction additionally proceeds at a faster rate than previous processes, thus permitting the use of less side-chain precursor than has been required by such previous processes.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a process for the preparation of N-acyl, N-sulfonyl and N-phosphoryl esters of isoserine; the provision of a side chain precursor for the synthesis of taxane derivatives; the provision of a process for the attachment of the side chain precursor in relatively high yield to provide an intermediate which is readily converted to the desired taxane derivative; and the provision of such a process which is highly diastereoselective.
In accordance with the present invention, a process is provided for the preparation of isoserine esters having the formula
comprising reacting a &bgr;-lactam with a metal alkoxide, the &bgr;-lactam having the formula
and the metal alkoxide having the formula
MOCE
1
E
2
E
3
wherein
R
1
is —OR
6
, —SR
7
, or —NR
8
R
9
;
R
2
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R
3
and R
4
are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R
3
and R
4
are not both acyl;
R
5
is —COR
10
, —COOR
10
, —COSR
10
, —CONR
8
R
10
, —SO
2
R
11
, or —POR
12
R
13
,
R
6
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative,
R
7
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group,
R
8
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R
9
is an amino protecting group;
R
10
is alkyl, alkenyl, alkynyl, aryl, or heteroaryl,
R
11
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OR
10
, or —NR
8
R
14
,
R
12
and R
13
are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OR
10
, or —NR
8
R
14
,
R
14
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
E
1
, E
2
and E
3
are independently hydrogen, hydrocarbo
Florida State University
Senniger Powers Leavitt & Roedel
Trinh Ba K.
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