Process for the preparation of baccatin III derivatives

Details Process for the preparation of baccatin III derivatives Process for the preparation of baccatin III derivatives

2003-02-06

2004-12-07

Stockton, Laura L. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06828445

ABSTRACT:

The present invention relates to novel intermediates useful in the synthesis of 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III derivatives, and to a process for the preparation thereof. The intermediates obtained with the process of the invention can be used in the preparation of novel taxan derivatives with antitumor activity.
Taxanes are one of the most important classes of antitumor agents developed in recent years. Paclitaxel is a complex diterpene isolated from the bark of
Taxus brevifolia
and is considered a “lead compound” for cancer therapy. Extensive research is at present being carried out for taxan derivatives having higher pharmacological activity and improved pharmacokinetic profile. A particular approach relates to the baccatin III derivatives variously modified with respect to the basic structure. Examples of said compounds are the 14&bgr;-hydroxy baccatin III derivatives disclosed in U.S. Pat. No. 5,705,508, WO 97/43291, WO 96/36622. At present, 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III derivatives are prepared starting from the 14&bgr;-hydroxy-deacetylbaccatin III precursor, which is a natural compound obtainable in small amounts by extraction of leaves of
Taxus wallichiana
, as disclosed in EP 559,019. There is strong need for novel intermediates or alternative processes to those commonly used, which allow to prepare 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III derivatives simply and effectively.
It has now been found that 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III can be prepared by means of a process using 10-deacetylbaccatin III as starting compound which, contrary to 14&bgr;-hydroxy-baccatin III, can be easily isolated in large amounts form
Taxus baccata
leaves.
Therefore, the present invention provides a process for the preparation of 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III comprising the following steps:
1. protection of the hydroxy groups at the positions 7 and 10 of 10 deacetylbaccatin III:
wherein R and R
1
are selected from hydrogen, C
1
-C
10
alkyl or aryl, C
1
-C
10
alkyl- or aryl-carbonyl, trichloroacetyl, C
1
-C
4
trialkylsilyl; preferably, when R and R
1
are the same, they are trichloroacetyl, whereas when they are different, preferably R is trichloroacetyl and R
1
is acetyl, or R is triethyl or trimethylsilyl and R
1
is acetyl;
2. two-step oxidation to give the derivative oxidised at the 13-position and hydroxylated at the 14-position:
3. carbonation of the vicinal hydroxyls at the 1- and 14-positions to give the 1,14-carbonate derivative:
4. reduction of the carbonyl at the 13-position:
5. removal of the protective groups at the 7- and 10-positions:
The procedures for the protection of the 7- and 10-hydroxyls are described by Holton et al., Tetrahedron Letters 39, (1998) 2883-2886. The selective protection of the hydroxyls of the starting compound deacetylbaccatin III is possible due to their different reactivity. In particular, the reactivity towards acylating, alkylating or silylating agents has been found to vary in the order C(7)—OH>C(10)—OH>C(13)—OH>C(1)—OH, therefore the groups at 7- and 10-can be selectively protected while keeping the hydroxyls at 1- and 13-free. Furthermore, by changing the reaction conditions, it is possible to reverse the reactivity order of the hydroxyls at 7- and 10-thus allowing the differential substitution thereof. Examples of reactants and reaction conditions usable in the protection of the hydroxyls at 10- and 7- are reported in the above cited publication.
The oxidation step of the hydroxyl at the 13-position is achieved with manganese dioxide or bismuth dioxide in a solvent selected from acetonitrile, acetone or ethyl acetate/methylene chloride 9:1 mixtures, under vigorous stirring, preferably with manganese dioxide in acetonitrile or acetone. The reaction proceeds quickly to give the oxidised derivative at the 13-position, which can be recovered from the reaction medium, whereas a longer reaction yields the 13-oxidised and 14-hydroxylated derivative.
The subsequent carbonation step of the hydroxyls at the 1- and 14-positions is usually effected with phosgene or triphosgene in a methylene chloride/toluene mixture in the presence of pyridine. Subsequently, the resulting 1,14-carbonate derivative can be easily reduced at the 13-position to give the corresponding 13-hydroxy derivative. Said reduction takes place regioselectively on the carbonyl at 13-while the carbonyl at 9-remains unchanged, and stereoselectively, affording almost exclusively the 13-&agr; isomer. This reaction is usually carried out with sodium borohydride in methanol and provides high yields. The last step consists in deprotecting the hydroxyls at the 7- and 10-positions to give the final product 14&bgr;-hydroxy-1,14-carbonate deacetylbaccatin III. The conditions and the reactants which can be used in the selective deprotection of the hydroxyls at 7- and 10- are described in Zheng et al., Tetrahedron Lett., 1995, 36, 2001, and in Datta et al., J. Org. Chem., 1995, 60, 761. The resulting final product is an extremely useful intermediate for the synthesis of a variety of taxan derivatives. As mentioned above, said intermediate was prepared until now starting from 14&bgr;-hydroxy baccatin III extracted from the leaves of
Taxus wallichiana
in low yields. The process of the present invention allows to prepare the same intermediate in high yields starting from a compound available in large amounts. Examples of compounds with antitumor activity which can be prepared starting from 14&bgr;-hydroxy-1,14-carbonate deacetylbaccatin III are reported in U.S. Pat. No. 5,705,508, WO 97/43291, WO 96/36622.
According to a preferred embodiment of the process of the invention, deacetylbaccatin III is reacted with trichloroacetyl chloride in methylene chloride in the presence of triethylamine and using N,N-dimethylaminopyridine (DMAP) in catalytic amounts. The use of trichloroacetate as protecting group proved to be very advantageous in the oxidation, carbonation and reduction steps according to the process of the invention. In particular, the 7,10-bis-trichloroacetate derivative, which is obtained in quantitative yields from the starting compound, after oxidation and carbonation is easily reduced at the 13-position with simultaneous deprotection of the trichloroacetic groups to give 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatin III. The use of DMAP in catalytic amounts provides definite advantages from the industrial and environmental point of views, when considering that until now the acylations of this substrate were carried out in pyridine with consequent discharge problems of the residual solvent.
The following intermediates obtained according to the preferred embodiment described above are part of the present invention:
The following examples illustrate the invention in greater detail.


REFERENCES:
patent: 5698712 (1997-12-01), Bombardelli et al.
patent: 5750562 (1998-05-01), Bombardelli et al.
patent: WO 96 36622 (1996-11-01), None
patent: WO 00 52003 (2000-09-01), None

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