Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-11
2002-09-10
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
06448417
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to the synthesis of paclitaxel and paclitaxel analogs from precursor compounds. More particularly, though, this invention concerns the synthesis of paclitaxel and analogs thereof through the step of esterifying C-7, C-10 di-CBZ 10-deacetylbaccatin III with a suitably protected 3-phenylisoserine side chain, followed by subsequent deprotections and acylations. The present invention also relates to methods of acylating C-2′-O-protected-10-hydroxy-paclitaxel and its analogs selectively at the C-10 hydroxy position over the C-7 hydroxy position. The present invention further relates to C-10 metal alkoxide intermediate compounds useful in producing paclitaxel and paclitaxel analogs.
BACKGROUND OF THE INVENTION
The chemical compound referred to in the literature as taxdl, and more recently “paclitaxel”, has received increasing attention in the scientific and medical community due to its demonstration of anti-tumor activity. Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity. As is known, paclitaxel is a naturally occurring taxane diterpenoid having the formula and numbering system as follows:
While the paclitaxel molecule is found in several species of yew (genus Taxus, family Taxaceae), the concentration of this compound is very low. Moreover, these evergreens are slow-growing. Thus, a danger exists that the increasing use of paclitaxel as an effective anti-cancer agent will deplete natural resources in the form of the yew trees. Indeed, while the bark of the yew trees typically exhibit the highest concentration of paclitaxel, the production of 1 kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long term prospects for the availability of paclitaxel through isolation is discouraging.
The paclitaxel compound, of course, is built upon the baccatin III backbone, and there are a variety of other taxane compounds, such as baccatin III, cephalomannine, 10-deacetylbaccatin III, etc., some which are more readily extracted in higher yields from the yew trees. Indeed, a relatively high concentration of 10-deacetylbaccatin III can be extracted from the leaves of the yew as a renewable resource. Typically, however, these other taxane compounds present in the yew tree do not exhibit the degree of anti-tumor activity shown by the paclitaxel compound.
Since the paclitaxel compound appears so promising as a chemotherapeutic agent, organic chemists have spent substantial time and resources in attempting to synthesize the paclitaxel molecule. A more promising route to the creation of significant quantities of the paclitaxel compound has been proposed for the semi-synthesis of paclitaxel by the attachment of the A-ring side chain to the C-13 position of the naturally occurring baccatin III backbone derived from the various taxanes present in the yew. See, Denis et al, a “Highly Efficient, Practical Approach to Natural Taxol”,
Journal of the American Chemical Society
, page 5917 (1988). In this article, the partial synthesis of paclitaxel from 10-deacetylbaccatin III is described.
The most straightforward implementation of partial synthesis of paclitaxel requires convenient access to a chiral, non-racemic side chain and derivatives, an abundant natural source of baccatin III or closely related diterpenoid substances, and an effective means of joining the two. Of particular interest then is the condensation of baccatin III or 10-deacetylbaccatin III with the paclitaxel A-ring side chain. However, the esterification of these two units is difficult because of the hindered C-13 hydroxyl of baccatin III located within the concave region of the hemispherical taxane skeleton. For example, Greene and Gueritte-Voegelein reported only a 50% conversion after 100 hours in one partial synthesis of paclitaxel.
J. Am. Chem. Soc
., 1988, 110,5917.
In U.S. Pat. No. 4,929,011 issued May 8, 1990 to Denis et al entitled “Process for Preparing Taxol”, the semi-synthesis of paclitaxel from the condensation of a (2R,3S) side chain acid of the general formula:
wherein P
1
is a hydroxy protecting group with a taxane derivative of the general formula of:
wherein P
2
is a hydroxy protecting group is described wherein the condensation product is subsequently processed to remove the P
1
and P
2
protecting groups. In Denis et al, the (2R,3S) 3-phenylisoserine derivative, with the exception of the P
1
protecting group, is the A-ring side chain for the paclitaxel molecule. The P
2
protecting group on the baccatin III backbone is protected by, for example, a trimethylsilyl or a trialkylsilyl radical.
An alternative semi-synthesis of paclitaxel is described in U.S. Pat. No. 5,770,745 to Swindell et al. That patent discloses semi-synthesis of paclitaxel from a baccatin III backbone by the condensation with a side chain having the general formula:
wherein R
1
is alkyl, olefinic or aromatic or PhCH
2
and P
1
is a hydroxyl protecting group.
The side chain in Swindell et al is distinct from the side chain attachment used in Denis et al, above in that the nitrogen is protected as a carbamate. Preferably, the A-ring side chain is benzyloxycarbonyl (CBZ) protected. After esterification, the CBZ protecting group is removed and replaced by PhCO to lead to paclitaxel. This process generated higher yields than that described in Denis et al. In Swindell et al, the preferred masking groups were selected to be trichloroethoxymethyl or trichloroethoxycarbonyl. Benzyloxymethyl (BOM) was, however, disclosed as a possible side chain protecting group, but, according to the processes described therein, the BOM protecting group could not be removed from the more encumbered C-2′ hydroxyl in the attached 3-phenylisoserine side chain. The use of the BOM protected side chain was not extensively investigated, for that reason.
U.S. Pat. No. 5,675,025 issued Oct. 7, 1997 to Sisti et al describes methodology for successfully using the C-2′OBOM side chain in paclitaxel synthesis. More particularly, the '025 Patent teaches a method to remove the C-2′OBOM group in C-2′OBOM paclitaxel to produce paclitaxel.
U.S. Pat. No. 5,684,175 to Sisti et al and WO 96/40666 each describe the production of paclitaxel which includes esterfying a suitably protected side chain with a C-7 TES protected baccatin III. Notably, the C-10 acetate is present prior to the attachment of the C-13 side chain.
U.S. Pat. No. 4,924,012, issued May 8, 1990 to Colin et al discloses a process for preparing derivatives of baccatin III and of 10-deacetylbaccatin III, by condensation of an acid with a derivative of a baccatn III or of 10-deacetylbaccauin III, with the subsequent removal of protecting groups by hydrogen. Several syntheses of TAXOTERE® (Registered to Rhone-Poulenc Sante) and related compounds have been reported in the Journal of Organic Chemistry: 1986, 51, 46; 1990, 55, 1957; 1991, 56, 1681; 1991, 56, 6939; 1992, 57, 4320; 1992, 57, 6387; and 993, 58, 255; also, U.S. Pat. No. 5,015,744 issued May 14, 1991 to Holton describes such a synthesis.
European Patent No. 0522958A1 appears to relate to the preparation of various derivatives of baccatin III and 10-deacetybaccatin III, and particularly ones having C-7 and/or C-10 protecting groups. In particular, that reference appears to teach the esterification of an appropriate paclitaxel or docetaxel side chain with a suitably protected baccatin III or 10-deacetylbaccatin III backbone.
WO 98/13360 teaches a method for paclitaxel synthesis that includes esterfying C7-CBZ baccatin III with C-3′ N-CBZ -C2′-O-protected (2R, 3S)-3-phenyl isoserine, and thereafter performing varous deprotections and acylations to obtain paclitaxel.
WO 98/02427 teaches a method of converting 10-deacetylbaccatin III to baccatin III by acylating 10-deacetylbaccatin III selectively at the C-10 position over the C-7 hydroxy position thereof. The select
Brinkman Herbert R.
Chander Medhavi C.
Liang Xian
McChesney James D.
Sisti Nicholas J.
Henson Michael R.
Martin Timothy J.
NaPro BioTherapeutics, Inc.
Trinh Ba K.
Weygandt Mark H.
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