Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-05
2004-07-27
Desai, Rita (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000, C549S514000
Reexamination Certificate
active
06768012
ABSTRACT:
The present invention relates to a process for the preparation of Paclitaxel.
Paclitaxel is a molecule of natural origin having wide spectrum antitumor activity, with the following structural formula:
The compound, first recovered from Taxus brevifolia bark and from other natural sources, can be prepared semi-synthetically according to a number of procedures described in both scientific and patent literature.
U.S. Pat. No. 4,924,011 discloses the semi-synthesis of paclitaxel using 10-deacetylbaccatine III protected at the C-7 hydroxyl with a trialkylsilyl group and subsequently acetylated at C-10. The resulting intermediate is reacted with (2R,3S)-N-benzoyl-2-O-(1-ethoxyethyl)-3-phenyl-isoserine and the resulting product is deprotected to give paclitaxel.
WO-93/06094 discloses the preparation of paclitaxel by reacting a &bgr;-lactam precursor with 7-O-triethylsilyl-baccatine III, followed by mild acid hydrolysis.
According to U.S. Pat No. 5,476,954, paclitaxel is prepared starting from 10-deacetylbaccatine III esterified at C-7 with a 2,2,2-trichloroethoxycarbonyl group (TROC).
According to U.S. Pat. Nos. 5,917,062 and 6,020,507, the C-7 hydroxyl is protected with carbobenzoxy (CBZ) or with carbo-t-butoxy (Boc), followed by selective acetylation of C-10 hydroxyl,
It is apparent from literature that a crucial aspect of paclitaxel semi-synthesis is to selectively protect the hydroxyls on the diterpen moiety (10-deacetylbaccatine III skeleton). The C-7 position is the most reactive and is therefore functionalized with groups which are easy to remove subsequently. The most commonly used group is triethylsilyl (TES), which is stable under the conditions used for the esterification of the other hydroxyls involved in the synthesis, and provides about 85% conversion yield. Approximately 85% yields are obtained when an acetyl group is subsequently introduced at the C-10 position.
A novel process for the synthesis of paclitaxel has now been found, which provides higher final yields as well as other advantages compared with the known processes.
The process according to the invention comprises the following steps:
a) protection of the hydroxyls at the 7- and 10-positions of 10-deacetylbaccatine III (10-DAB III),
wherein R═R′=trichloroacetyl, or R′=acetyl and R is selected from t-butoxycarbonyl and trichloroacetyl,
b) esterification of the hydroxyl at 13 with 3-phenyl-2-epoxypropionic acid
c) removal of the protective groups at the 7- and 10-positions (1) if they are both tichloroacetyl groups, followed by selective acetylation at the 10-position (2) and opening of the epoxide with sodium azide (3);
or, alternatively,
c′) if R′=acetyl and R=trichloroacetyl, opening of the epoxide with sodium azide and simultaneous deprotection at the 7-position
d) reduction of the azido group to amino group
e) benzoylation to give the final product
The starting product is 10-deacetyl baccatine III (10-DAB III), which is extracted from the leaves of Taxus baccata. In the first step, 10-DAB III is quantitatively esterified at the C-7 and C-10 hydroxyls. When R═R′=trichloroacetyl, 10-DAB III is reacted with trichloroacetyl chloride in methylene chloride in the presence of triethylamine and of catalytic amounts of 4-dimethylaminopyridine (DMAP). When R≠R′, first 10-DAB III is selectively acetylated with acetic anhydride in the presence of cerium, scandium, ytterbium salts, preferably CeCl3.7H20. The resulting baccatine III is subsequently protected at C-7 with a t-butoxycarbonyl or trichloroacetyl group. The first can be introduced by reacting baccatine III with t-butoxy-pyrocarbonate in the presence of DMAP and ethyldiisopropylamine or, alternatively, following the procedure described in U.S. Pat. No. 5,917,062. The trichloracetyl group can be introduced at position 7 by reaction with trichloroacetyl chloride in pyridine.
In the subsequent step (b), the hydroxyl at position 13 is esterified with 3-phenyl-2-epoxypropionic acid, preferably with its ammonium salt in toluene in the presence of dicyclohexylcarbodiimide, DMAP and p-toluenesulfonic acid, thereby obtaining (2R,3R)-3-phenyl-2,3-epoxy-propionic acid baccatine III ester.
When both protective groups R and R′ are trichloroacetyl, they can be removed using the conditions and reagents described by Zheng et al., Tetrahedron Lett., 1995, 36, 2001, and by Datta et al., J. Org. Chem., 1995, 60, 761. Preferably, the two trichloroacetyl groups are removed with two equivalents of ammonium hydroxide. The deprotected compound is selectively acetylated at position 10 with acetic anhydride in the presence of cerium, scandium or ytterbium salts, preferably CeCl
3
.7H2O.
The resulting compound is reacted with NaN
3
in aqueous methanol in the presence of methyl formate, in the conditions reported in literature (Yamaguchi T., Tetrahedron Letters 39, 5575-78, 1998), to provide the corresponding azide.
Alternatively, when R=trichloroacetyl and R′=acetyl (d), the oxirane reacts with NaN
3
to give the corresponding azide with deprotection at the 7-position, corresponding to the compound obtained at step (c′).
The azide is reduced to amine in the subsequent step (d). The reduction can be carried out with hydrogen on catalyst or with PPh
3
. The product obtained at the last step (e) is benzoylated at the amino group to give paclitaxel. Benzoylation can be carried out with benzoic anhydride either simultaneously to reduction or subsequently on the isolated reduced product, using stoichiometric amounts of benzoyl chloride in the presence of potassium carbonate.
The following examples illustrate the invention in greater detail.
REFERENCES:
patent: 5917062 (1999-06-01), Bombardelli
patent: 6020507 (2000-02-01), Gibson
patent: 6706896 (2004-03-01), Holton et al.
Battaglia Arturo
Bombardelli Ezio
Dambruoso Paolo
Guerrini Andrea
Pontiroli Alessandro
Covington Raymond
Desai Rita
Indena S.p.A.
Young & Thompson
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