Process for the preparation of taxan derivatives

Details Process for the preparation of taxan derivatives Process for the preparation of taxan derivatives

2003-05-27

2004-05-18

Solola, Taofiq (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S297000

Reexamination Certificate

active

06737534

ABSTRACT:

The present invention relates to a process for the preparation of the compound 13-(N-Boc-&bgr;-isobutylisoserinyl)-14&bgr;-hydroxybaccatine III 1,14-carbonate, of formula (I):
Compound (I), disclosed in PCT WO 01/02407, is particularly active against breast, lung, ovary, colon, prostate, kidney and pancreas tumors, as well as against cells resistant to known antitumor agents, such as adriamycin, vinblastine and some Pt derivatives. 14&bgr;-Hydroxy-1,14-carbonate-deacetylbaccatine III derivatives are usually prepared starting from the precursor 14&bgr;-hydroxy-deacetylbaccatine III, a natural compound obtainable in small amounts by extraction of
Taxus wallichiana
leaves, as disclosed in EP 559,019. There is strong need for alternative processes for the easy and effective preparation of 14&bgr;-hydroxy-1,14-carbonate-deacetylbaccatine III derivatives, in particular of compounds (I).
The process according to the invention uses as starting material 10-deacetylbaccatine III which, contrary to 14&bgr;-hydroxy-baccatine III, may be easily recovered in large amounts from
Taxus baccata
leaves.
Therefore, the invention relates to a process for the preparation of the compounds of formula (I) which comprises the following steps:
a) protection of the hydroxyls at the 7- and 10-positions of 10 deacetylbaccatine III:
wherein R and R
1
, which can be the same or different, 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 or BOC and R
1
is acetyl;
b) two-step oxidation to give the derivative oxidized to carbonyl at the 13-position and hydroxylated at the 14-position:
c) carbonation of the vicinal hydroxyls at the 1- and 14positions to give the 1,14-carbonate derivative:
d) reduction of the carbonyl at the 13-position:
e) removal of the protective groups at the 7- and 10-positions:
f) selective acetylation of the hydroxyl at the 10-position:
g) transformation 14&bgr;-hydroxy-baccatine-1,14-carbonate III into the derivative triethylsilylated at the 7-position:
h) reaction of the compound from step (g) with (4S,5R)-N-Boc-2-(2,4dimethoxyphenyl)4isobutyl-1-oxazolidine-5-carboxylic acid:
i) removal of the triethylsilyl and dimethoxybenzylidene protective groups from the compound from step (h):
The procedures for the selective 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 7and 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. Similar selectivities are obtained starting:from 14&bgr;-bydroxybaccatine- 1,14-carbonate.
According to a preferred embodiment, deacetylbaccatine III is reacted with trichloroacetyl chloride in methylene chloride in the presence o triethylamine and using dimethylaminopyridine (DMAP) in catalytic amounts. The use of the protective trichloroacetic groups proved to be very advantageous in the subsequent oxidation, carbonation and reduction steps (respectively (b), (c) and (d)). In particular the 7,10-bis-trichloroacetate derivative, which is obtained in quantitative yields from the starting product, is oxidized and carbonated, then easily reduced at the 13-position with simultaneous deprotection of the trichloroacetic groups to give 14-hydroxy-1,14 carbonate-deacetylbaccatine III. The use of DMAP in catalytic amounts provides obvious advantages from the industrial and environmental point of views, considering that acylations of this substrate have up to now been carried out in pyridine, which involves problems of disposing of the residual solvent.
The oxidation step (b) of the hydroxyl at the 13-position is carried out with manganese dioxide or bismuth dioxide or ozone in a solvent selected from acetonitrile, acetone or ethyl acetate/methylene chloride 9:1 mixtures, under vigorous stirring, preferably with ozone or manganese dioxide in acetonitrile or acetone. The reaction with ozone rapidly forms the derivative oxidised at the 13-position, while with MnO
2
the reaction proceeds quickly to give the derivative oxidized 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 (c) of the hydroxyls at the 1- and 14-positions is usually effected with phosgene or 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 (step (d)). Said reduction takes place regioselectively at the carbonyl at 13-, while the carbonyl at 9- remains unchanged. This reaction is usually carried out with sodium borohydride in methanol or tetrabutylammonium borohydride and provides high yields. The subsequent step (e) consists in deprotecting the hydroxyls at the 7- and 10-positions to give 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 selective acetylation at the 10-position (step (f)) is carried out with acetic anhydride in the presence of cerium, scandium, or ytterbium salts, preferably CeCl
3
.7H
2
O. Afterwards, the hydroxyl at the 7-position is protected by silylation (step (g)). The subsequent step (h) involves the condensation between 14&bgr;-hydroxy-7-Tes- 1,14-carbonate-baccatine III and (4S,5R)N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic acid. The latter is prepared as described in PCT WO 01/02407. The reaction is carried out in dry apolar organic solvents, in the presence of a base and of a condensation agent such as dicyclohexylcarbodiimide (DCC).
Finally, in step (i), the triethylsilyl group can be removed with pyridinium fluoride in acetonitrile/pyridine solution under nitrogen, whereas the dimethoxybenzylidene group can be removed in methylene chloride by addition of methanol HCl and subsequently of NaHCO
3
.


REFERENCES:
patent: 5917056 (1999-06-01), Bombardelli
patent: WO 01/02407 (2001-01-01), None
Tetrahedron Letters, Robert Holton et al, “Selective Protection of the C(7) and C(10) Hydroxyl Groups in 10-Deacetyl Baccatin III”, 1998, pp. 2883-2886.

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