Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-02-09
2001-07-17
Trinh, Ba K. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06262281
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the synthesis production of taxol, taxol analogs and their intermediates.
BACKGROUND OF THE INVENTION
Taxol is a naturally occurring taxane diterpenoid that has exhibited significant clinical activity as an antineoplastic agent with considerable potential for further development. The widespread treatment of candidates for taxol therapy is limited by the current scarcity of the drug. The low abundance of taxol in its natural source, the bark of the slow-growing Pacific yew, makes the long term prospects for the availability of taxol through isolation discouraging. Taxol has the general formula and a corresponding numbering system, as shown below:
Among the solutions to the taxol supply problem addressable by organic chemists is the partial synthesis of the drug, or of clinically effective analogs, by the attachment to naturally derived substances like baccatin III of the A-ring side chain that protrudes from the C-13 position. The preparation of taxol and its analogs is known. For example, U.S. Pat. No. 4,924,011, issued May 8, 1990 to Denis et al discloses the process for preparing taxol by the condensation of a (2R,3S) side chain acid with a taxane derivative, followed by the removal of various groups protecting the hydroxyl groups. 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-deacetyl-baccatin III, by condensation of an acid with a derivative of baccatin III or of 10-deacetylbaccatin 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.
The most straightforward implementation of partial synthesis of taxol requires convenient access to 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 and 10-deacetyl Baccatin III of the formulae:
with the 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 taxol.
J. Am. Chem. Soc.,
1988, 110, 5917. The Holten patent addresses one method of more efficient synthesis.
Still, a need exists for further efficient protocols for the attachment of the taxol A-ring side chain to the taxane skeleton (e.g., baccatin III) and for the synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures.
SUMMARY OF THE INVENTION
It is the object of this invention to provide compounds that is an intermediate in the semi-synthesis of paclitaxel.
It is another object to provide new compounds each in the form of a suitable baccatin III or 10-deacetylbaccatin III backbone which has attached thereto at the C-13 position a suitable A-ring side chain C-3′ amine or amine salt.
In its broad form, the present invention is directed to a compound having a generalized formula:
wherein R
1
=NH
2
or
+
NH
3
X
−
where X is a deprotonated organic acid,
R
2
=Acetyl or hydrogen, and
p
1
=hydrogen or a benzyl-type protecting group.
More particularly, the preferred compound has a benzyloxymethyl protecting group at C-2′, an acetyl group at C-10 and/or an amino group at C-3′.
Where the compound is an amine salt, it is preferred that the deprotonated organic acid is triflouroacetic acid.
REFERENCES:
patent: 4857653 (1989-08-01), Colin et al.
patent: 5319112 (1994-06-01), Kingston et al.
patent: 5470866 (1995-11-01), Kingston et al.
patent: 5621121 (1997-04-01), Commercon et al.
patent: 5679807 (1997-10-01), Murray et al.
patent: WO 93/16060 (1993-08-01), None
patent: WO 94/18186 (1994-08-01), None
“New and Efficient Approaches to the Semisynthesis of Taxol and its C-13 Side Chain Analogs by Means of B-Lactam Synthon Method”, Ojima et al,Tetrahedron, vol. 48, No. 34, pp. 6985-7012, 1992.
Improved Protection and Esterification of a Predursor of the Taxotere and Taxol Side chains, Commercon et al,Tetrahedron Letters, vol. 33, No. 36, pp. 5185-5188, 1992.
“Application of the vicinal Oxyamination Reaction with Asymmetric Induction to the Hemisynthesis of Taxol and Analogues”, Mangatal et al,Tetrahedron Letters, vol. 45, No. 13, pp. 4177-4190, 1989.
“The Chemistry of Taxol”, Kingston,Pharma: Ther., vol. 52, pp. 1-34, 1991.
“Efficient and Practical Asymmetric Synthesis of Taxol C-13 Side Chain, N-Benzoyl-(2R, 3S)-3-phenylisoserine, and its Analogues via Chiral 3-Hydroxy-4-aryl-B-lactams through Chiral Ester Enolate Imine Cyclocondensation”, Ojima et al,American Chemical Society, vol. 56, No. 5, 1991.
“Synthesis of a Photoaffinity Taxol Analogue and its Use in Labeling Tubulin”, Dasgupta et al,J. Med. Chem., 1994, 37, 2976-2979.
“Aminohydroxylation, Catalytic Asymmetric Reaction Achieved”,C&EN, Feb. 19, 1996, pp. 6-7.
Krauss Nancy
Swindell Charles S.
Bryn Mawr College
Henson Michael R.
Martin Timothy J.
Trinh Ba K.
Weygandt Mark H.
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