Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-26
2004-11-02
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
06812356
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of converting 9-dihydro-13-acetylbaccatin III to 10-deacetylbaccatin III.
2. Discussion of the Prior Art
Many taxanes, e.g. paclitaxel and docetaxol are being aggressively studied and tested for use as cancer treating agents. As described in many publications such as Canadian Patent Application No. 2,188,190, published Apr. 18, 1998 in the name of Zamir et al, which is incorporated herein by reference, the taxanes are active in various tumor systems. Taxanes are substances occurring naturally in yew trees such as
Taxus canadensis
, which is common in Eastern Canada and the United States. One of the chemicals extracted from the needles of
Taxus canadensis
is 9-dihydro-13-acetylbaccatin III, which is used to produce, inter alia, 10-deacetylbaccatin III—a useful intermediate for the preparation of paclitaxel and analogues thereof.
Various methods of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III have been proposed (see, for example the above mentioned CA 2,188,190). However, it has been found that such methods result in poor yields of finished product. Thus, a need still exists for an efficient method for converting 9-dihydro-13 acetylbaccatin III to 10-deacetylbaccatin III (DAB III).
GENERAL DESCRIPTION OF THE INVENTION
The object of the present invention is to meet the above defined need by providing a relatively efficient method of converting 9-dihydro-13-acetylbaccatin III to DAB III.
Accordingly, the invention relates to a method of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III comprising the steps of
(a) protecting the C-7 group of 9-dihydro-13-acetylbaccatin III by replacing the C-7 hydroxyl group with a protecting group;
(b) oxidizing the C-9 hydroxyl group in the resulting product to produce a C-9 ketone; and
(c) deprotecting the C-9 ketone to form 10-deacetylbaccatin III.
DESCRIPTION OF THE PREFERRED EMBODIMENT
General Procedure
The first step in the method of the present invention involves the dissolving of 9-dihydro-13-acetylbaccatin III in dry solvent such as CH
2
Cl
2
, CHCl
3
, THF, Et
2
O or Bz. A dry base, e.g. pyridine, TEA or NaHCO
3
and/or a catalytic amount of p-N,N-dimethylaminopyridine (DMAP) is added to the solution, followed by 1-6 equivalents of a protecting reagent (TMSCl, TESCl or Ac
2
O) at a temperature of between room temperature and −78° C. The mixture is stirred continuously for 0.5-6 hours before being quenched by the addition of water. The mixture is poured into ethyl acetate and washed sequentially with dilute acid, water and brine, and dried over magnesium sulfate. The solution is evaporated under vacuum to give a crude solid (7-OH protected-9-baccatin III up to 91% yield)
A 3,5-disubstituted pyrazole such as 3,5-dimethyl-pyrazole is added to a suspension of metal oxide, e g. chromium trioxide (2-20 equivalents) in a solvent. Suitable solvents include CH
2
Cl
2
, CHCl
3
, THF, Et
2
O and Bz. The mixture is stirred at room temperature for at least 15 minutes. A 7-OH protected 9-dihydro-13-acetylbaccatin III in the same solvent is added to the solution in one portion, and the mixture is stirred for 0.5 hour to one week to produce a C-9 ketone in up to 90% yield.
The C-9 ketone is dissolved in a suitable organic solvent such as an alcohol, an ether, CH
2
Cl
2
or CHCl
3
with or without water, and reacted with an acid, a base, or a strong nucleophile, such as a bicarbonate, a carbonate, ammonia, an amine, a hydrazine, a hydroxide, a hydroperoxide or an alyllithium. The reaction mixture thus produced is stirred at a controlled temperature (0° C. to solvent reflux). The reaction is monitored by thin-layer chromatography until it has progressed satisfactorily. Routine liquid extraction is performed followed by solvent evaporation to produce crude 10-deacetylbaccatin III in up to 85% yield.
The reaction scheme for the above described general procedure is as follows
In accordance with a preferred embodiment of the invention, R in the above formula is an acetyl group. The reaction scheme for the preferred embodiment is as follows
REFERENCES:
patent: 6576777 (2003-06-01), Zamir et al.
patent: 2002/0128498 (2002-09-01), Zamir et al.
patent: 2 188 190 (1998-04-01), None
patent: WO 98 50378 (1998-11-01), None
patent: WO 99 54322 (1999-10-01), None
patent: WO 01 70717 (2001-09-01), None
Corey, EJ: “Chromium trioxide-3, 5-dimethylpyrazole complex as a reagent for oxidation of alcohols to carbonyl compounds”, Tetrahedron Letters, vol. 45, 1973, pp. 4499-4501.
Deslongchamps Ghislain
Findlay John
Li Guoqiang
Stikeman & Elliott LLP
Trinh Ba K.
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