Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-05-04
2002-05-07
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S004100, C536S018100, C536S018200, C536S124000, C536S127000
Reexamination Certificate
active
06384201
ABSTRACT:
TECHNICAL FIELD
This invention is directed to an improved synthetic method for the preparation of etoposide, particularly in the context of improved yield, reduced reaction times and simplified isolation procedures.
BACKGROUND OF THE INVENTION
Etoposide is an antineoplastic agent having the following structure (1):
Etoposide has been used effectively as an anti-tumor drug for a variety of conditions. For example, it has been employed in the treatment of acute monocytic leukemia (Schilling's leukemia), as well as medullary monocytic leukemia, and has proved effective for the treatment of recticulum cell sarcoma, tissue-cellular lymphoma, lymphasarcoma and Hodgkin's disease. Due to the well recognized activity of etoposide, a number of techniques have been developed directed to its synthesis.
One synthetic technique is that reported by Kuhn et al. in Swiss Patent No. 514,578, and related techniques disclosed in U.S. Pat. Nos. 3,408,411 and 3,524,844. Kuhn et al. discloses the preparation of etoposide by the reaction of 4′-demethyl-epipodophyllotoxin (2) with chloroformic acid benzyl ester (as a protecting group for the 4′-phenolic alcohol) to give 4′-carbobenzoxy-4′-demethyl-epipodophyllotoxin (3), followed by reaction of (3) with 2,3,4,6-tetra-O-acetyl-&bgr;-D-glucose (4) in the presence of boron trifluoride diethyl etherate to give tetra-O-acetyl4′-carbobenzoxy-4′-demethyl-epipodophyllotoxin-&bgr;-D-glucoside (5):
The carbobenzoxy protecting group of compound (5) is removed to give tetra-O-acetyl-4′-demethyl-epipodophyllotoxin-&bgr;-D-glucoside (6), which is then deacylated in the presence of zinc acetate to form 4′-demethyl-epipodophyllotoxin-&bgr;-D-glucoside (7):
Conversion of 4′-demethyl-epipodophyllotoxin-&bgr;-D-glucoside (7) to etoposide is achieved by reacting with acetaldehyde-dimethylacetal and p-toluene sulphonic acid. This synthetic method, however, in addition to requiring numerous reaction steps, is of low yield. That is, only about 18% etoposide based on 4′-demethyl-epipodophyllotoxin (2).
Another synthetic method is disclosed by Kurabayashi and Kalsuhiko et al. in Japanese Patent No. 84/98098. Unlike the method of Kuhn et al., 2,3-di-O-chloroacetyl-(4,6-O-ethylidene)-&bgr;-D-glucopyranose (8)—as opposed to glucose (4) of Kuhn et al.—is reacted directly with a 4′-(protected)-4′demethyl-epipodophyllotoxin (9) in the presence of boron trifluoride etherate to give intermediate (10):
The resulting intermediate (10) is then converted to etoposide by reaction with zinc acetate. While this method represents an improvement of the technique of Kuhn et al., strict reaction conditions are required for controlling monoacylation of the 4′-phenolic hydroxyl group to generate compound (9) from 4′-demethyl-epipodophyllotoxin.
A further improvement to the synthesis of etoposide is disclosed in U.S. Pat. No. 5,206,350 by Wang et al. In that method, direct addition of 2,3-di-O-chloroacetyl-(4,6-O-ethylidene)-&bgr;-D-glucopyranose (8) to 4′-demethyl-epipodophyllotoxin (2) is achieved in the presence of boron trifluoride etherate as catalyst without having to employ a protecting group on the 4′-phenolic hydroxyl group, giving 4′-demethylepipodophyllotoxin4-(2,3-di-O-chloroacetyl-4,6-O-ethylidene)-&bgr;-D-glucopyranoside (11):
After removal of the chloroacetyl protecting groups from compound (11) with zinc acetate in methanol, etoposide is obtained at a reported yield of 54% (based on 4′-demethyl-epipodophyllotoxin).
While eliminating the need to protect the 4′-phenolic hydroxyl group of compound (2), Wang et al. still suffers drawbacks with regard to yield, extended reaction times and isolation methodology. Accordingly, there exists a need in the art for improved synthetic methods for making etoposide which overcome these deficiencies. The present invention fulfills these needs and provides further related advantages.
SUMMARY OF THE INVENTION
This invention is directed to an improved synthetic procedure for the synthesis of etoposide. Due to the well know utility of etoposide, particularly in the context of cancer treatment, synthetic methods which result in higher yields of etoposide are of particular interest, especially with regard to commercial manufacture of the same. The present invention provides a relatively simple method of making etoposide at higher yields than existing techniques, and under more favorable reaction times and much simplified isolation procedures.
In one embodiment, a method for making etoposide is disclosed comprising the steps of:
condensing 4′demethyl-epipodophyllotoxin of formula (2) with a glucopyranose of formula (13) in an organic solvent at a temperature below −30° C. and in the presence of trimethylsilyl triflate catalyst to give a compound of formula (14):
where R
1
is —COCH
3
, —COCH
2
X, —COCHX
2
or —COCX
3
, and each occurrence of X is independently selected from a halogen; and
converting compound (14) to etoposide (1) having the following formula:
In more specific aspects of this embodiment, the compound of formula (13) is present in about 1.5 to about 2.0 equivalents based on the compound of formula (2), and trimethylsilyl triflate is present in about 1.5 to about 2.5 equivalents based on the compound of formula (2). Condensation of the compound of formula (13) and the compound of formula (2) is typically in the range from −40° C. to −60° C., and may be performed in the presence of a drying agent such as dry molecular sieve or zeolite. The organic solvent is typically a halogenated or non-halogenated organic solvent, including (but not limited to) acetonitrile, acetone, diethylether, chloroform, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Preferred R, groups of the glucopyranose of formula (3) include —COCHCl
2
and —COCH
2
Cl.
In the condensing step, the trimethylsilyl triflate may be added to the mixture of the compound of formula (13) and the compound of formula (2) over a period of about 30 minutes, with the temperature of the mixture being maintained at about −50° C. to about −40° C. The condensing step may be completed in about 1 to 2 hours.
In the converting step, such conversion may be accomplished by alcoholysis with, for example, a transesterification catalyst such as zinc acetate dihydrate. The zinc acetate dihydrate may be present in about 1.0 to about 2.0 equivalents based on the compound of formula (14). The converting step may be performed in the presence of an organic solvent, including (but not limited to) a C
1-4
alkanol such as methanol. The compound of formula (14) and zinc acetate dihydrate may be heated to a temperature ranging from about 60° C. to about 75° C. for up to about 2 hours.
In a further embodiment, compound (14) may be eluted through a celite/basic alumina column, or a silica gel, prior to being converted to etoposide. In still a further embodiment, the resulting etoposide may be purified. Such purification may be accomplished by, for example, crystallization, extraction or column chromatography. Crystallization may be from a C
1-4
alkanol, a C
1-4
aliphatic ester, or a non-polar solvent, where the C
1-4
alkanol includes methanol and ethanol, the C
1-4
aliphatic ester includes ethyl acetate, and the non-polar solvent includes n-pentane or hexanes or petroleum ether. The temperature of such crystallization may be from −4° C. to 0° C. for 8 to 12 hours.
Preferably, the etoposide of this invention is at least 99% pure, is substantially free of a dimer of 4′demethyl-4-epipodophyllotoxin, and is substantially free of etoposide in the &agr;-glucoside form. In this context, the term “substantially” means less than 0.5% by weight.
In another embodiment of this invention, a method for making etoposide is disclosed comprising the steps of:
condensing 4′-demethyl-epipodophyllotoxin of formula (2) with 2,3-di-O-dihaloacetyl-(4,6-O-ethylidene)-&bgr;-D-glucopyranose of formula (13) in an organic solvent at a temperature below
Phytogen Life Sciences Inc.
SEED Intellectual Property Law Group PLLC
White Everett
LandOfFree
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