Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-06
2003-06-24
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S239000, C549S510000
Reexamination Certificate
active
06583292
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods for esterifying alcohols. In particular, the invention provides novel compounds and methods useful in the production of Taxol and Taxol analogs.
BACKGROUND OF THE INVENTION
The esterification of alcohols is a common reaction in organic synthesis. Once the ester is produced, the ester can undergo further reactions to produce complex molecules. This approach is especially significant in the synthesis of natural products and non-natural synthetic compounds that exhibit biological activity. By converting a hydroxyl group to an ester, the chemical properties of the compound can change dramatically. An example of this improved property is the anti-cancer drug, Taxol.
Taxol and other antitumor taxoids constitute some of the most important discoveries in cancer chemotherapy in recent years. Taxol and Taxotere, which is a semi-synthetic analog of Taxol, have been approved by the FDA for the treatment of advanced ovarian and breast cancer. Additionally Taxol and Taxotere may be useful for the treatment of non-small-cell lung cancer, head and neck cancer and several other cancers. The structures of Taxol and Taxotere are shown below.
Taxol and Taxotere differ in their structure at the C-10 and C-3=positions. While Taxol was first isolated from the bark of the pacific yew tree,
Taxus brevifola
, Taxotere, a synthetic analog of Taxol, possesses better bioavailability than Taxol. Due to the limited availability of Taxol from the yew tree (1 Kg from 10000 Kg of bark), different strategies including total synthesis, semisynthesis, cell and tissue culture of taxus spp., have been investigated so that large amounts of Taxol can be produced. Although the total synthesis of Taxol was accomplished in 1994, lengthy multi-step sequences led to poor overall yield of Taxol. Therefore, total synthesis has not to date been a viable alternative to solve the supply problem.
One approach to a large scale production of Taxol and Taxotere is their semisynthesis from 10-deacetyl baccatin III (referred to as baccatin III or baccatin), shown below. Baccatin III can be readily obtained from the needles of the yew tree
Taxus baccata
. Importantly, yew needles can be quickly regenerated; therefore, a continuous supply of Taxol may be available without affecting the yew population.
Structure-activity relationships of Taxol derivatives indicate that the C-13 N-benzoyl-3-phenyl isoserine side chain, with the 2′R, 3′S stereochemistry, is of crucial importance for Taxol's cytotoxicity. Although there are methods in the art for the asymmetric synthesis of the C-13 side chain, coupling the side chain to the C-13 hydroxyl group is not a simple endeavor. The coupling reaction is complicated by the fact that the C-13 hydroxyl group is situated in the skeletal concavity of baccatin III, which makes this hydroxyl group sterically hindered. Furthermore, the C-13 hydroxyl group has been proposed to form a stabilizing hydrogen bond with the C-4 acetate moiety. These two factors contribute to the difficulty encountered in attaching the side chain to the C-13 hydroxyl group.
One approach to attaching the isoserine side chain to the C-13-hydroxyl group involves a condensation reaction between baccatin and an isoserine acid. Greene et al. (
J. Ami. Chem. Soc.
1988, 110, 5917) discloses the direct esterification reaction of a protected form of baccatin III and an isoserine acid under vigorous conditions (73° C. for 4 days). International Patent Application No. WO 94/18186 to Swindell et al.; U.S. Pat. No. 5,675,025 to Sisti et al.; and U.S. Pat. No. 5,597,931 to Danishefsky et al. also disclose the condensation reaction between protected baccatins and isoserine acids and esters.
Another approach involves the condensation reaction between a heterocycle containing a carboxylic acid group and baccatin, followed by treatment with an acid to open the ring and produce the side chain at C-13. Kingston et al. (
Tetrahedron Letters
1994, vol 35, no. 26, pp 4483) and International Patent Application No. WO 97/00870 to Gennari et al. disclose the coupling of oxazolidines and baccatin via a condensation reaction. U.S. Pat. No. 5,599,942 to Bouchard et al.; International Patent Application No. WO 94/10169 to Denis et al.; International Patent Application No. WO 94/10169; and Kanazawa et al. (
J. Chem. Chem. Com.
1994, 2591) disclose the coupling of a 1,3-oxazole with baccatin followed by acid hydrolysis produced Taxol and derivatives thereof. In the respective condensation reactions disclosed in the above-identified patents and articles, the stereochemistry at C-2 of the heterocycle, wherein C-2 is the carbon bonded to the carboxylic acid group, has to be established (either S or R stereochemistry).
Gennari et al. (
Angew. Chem. Int. Ed. Engl.
1996, 35, 1723) discloses the reaction between a protected baccatin and a thioester of an oxazolidine in the presence of a base. In the case of the oxazolidine, seven steps were required to produce the oxazolidine with the thioester group, wherein the first step involves the use of chiral boron agent. The resulting oxazolidine thioester produced and subsequently coupled with baccatin is the anti isomer and not the syn isomer. The coupling reaction involves adding a base to a mixture of the protected baccatin and the oxazolidine thioester. An excess of oxazolidine thioester (3.5 equivalents) and base (4.5 equivalents) are used in the coupling reaction. Similar to the condensation reactions described above, the stereochemistry at C-2 of the oxazolidine thioester is also established.
Therefore, there remains a need for a more efficient, high yield synthesis of Taxol and other similar compounds. In addition, there exists a need for synthetic methods where the stereochemistry at C2 of the precursor to the side chain does not have to be established.
SUMMARY OF THE INVENTION
To overcome the shortcomings described above, the present invention, in one aspect, relates to a method for preparing an ester, comprising:
(a) admixing a compound having the structure I:
wherein,
R
1
and R
2
are, independently, from C
1
to C
12
branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR
3
, wherein R
3
is from C
1
to C
12
branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)
2
R
41
, wherein R
41
is C
1
to C
12
branched or straight chain alkyl; or substituted or unsubstituted aryl,
with a base to form an intermediate; and
(b) admixing the intermediate of step (a) with an alcohol, an alkoxide, or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing a compound having the structure III:
wherein,
R
1
and R
2
are, independently, from C
1
to C
12
branched or straight chain alkyl or substituted or unsubstituted aryl,
with an alcohol, an alkoxide or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof; and
(c) a compound having the structure I:
wherein,
R
1
and R
2
are, independently, from C
1
to C
12
branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR
3
, wherein R
3
is from C
1
to C
12
branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, S(O)
2
R
41
, wherein R
41
is C
1
to C
12
branched or straight chain alkyl; or substituted or unsubstituted aryl.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof; and
(c) a compound having the structure IV:
wherein,
R
9
and R
10
are, independently, an aralkyl or C(O)R
31
, wherein R
31
is C
1
to C
12
straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl;
R
11
is from C
1
to C
12
branched or straight chain alkyl or substituted or unsubstituted aryl;
R
12
is silyl, alkyl, acyl, aryl, or aralkyl; and
Y i
Captain Laura
Liotta Dennis C.
Schestopol Marcus A.
Snyder James P.
Venkatesan Hariharan
Emory University
Needle & Rosenberg P.C.
Raymond Richard L.
Tucker Zachary C.
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