Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-01
2003-01-14
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S225000, C548S226000, C548S229000, C549S510000
Reexamination Certificate
active
06506905
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel oxazolidine carboxylic acid and a process for its preparation. The invention further relates to a process for the preparaton of paclitaxel (taxol) using such oxazolidine carboxylic acid. Paclitaxel (Taxol) (1) is a terpene of taxane family and has the formula shown below and has an application for treatment of various types of cancer. Non-natural analog of paclitaxel (taxol), docetaxel (taxotere) (2) is also an approved anticancer drug. Thus, there is great interest in molecules having similar structures for development of new anticancer drugs and SAR studies.
1. Taxol R
1
=H, R
2
=Ac, R
3
=
2. Taxotere R
1
=R
2
=H, R
3
=
3. Baccatin R
1
=R
3
=H, R
2
=Ac
4. 10-Deacetylbacctin (DAB) R
1
=R
2
=R
3
H
BACKGROUND OF THE INVENTION
The structure of paclitaxel (taxol) has two distinct units. One is baccatin (3) and other is N-benzoylphenylisoserine, the side chain, connected to baccatin at C-13 through ester linkage. It has been shown that the -amido-hydroxy ester side chain at C-13 is very essential for anticancer activity of taxol and any other taxol analogs. The supply of taxol from natural sources is very limited and so there is great interest in its synthesis. 10-deacetyl baccatin (4) is more readily available than taxol from the leaves of yew tree and comprises a starting material for semisynthesis of taxol and taxol analogs. It is known in the literature, that it is very difficult to esterify 13 hydroxy of bacctin with -amido-hydroxy carboxylic acid. The difficulty has been ascribed to spatial disposition of 13 hydroxy in the baccatin nucleus. Therefore, considerable efforts have been made to find precursors of -amido-hydroxy carboxylic acid which can be coupled with bacctin in high yield and the resultant couple product can be processed to afford 13-O-(-amido-hydroxycarbonyl) baccatin in high yield and purity.
The following types of cyclic derivative of phenylisoserine are known to couple with 13-hydroxy of baccatin.
R, R
1
, R
2
and R
3
=Protecting groups
In the literature, various protecting groups, R
1
, are described in oxazolidinecarboxylic acid (5). However, alk-2-ynyloxycarbonyl group have not been described so far; The utility of this group over other commonly used protecting groups lies in the fact that this group can be cleaved under neutral condition. All other known protecting groups (R
1
) are cleaved under either acidic conditions or by hydrogenolysis. The subsequent cleavage of protecting groups R
2
and R
3
are normally very fast, once R
1
is cleaved. Since the baccatin part of taxol is very prone to degradation even under mild acidic or basic conditions, removal of alk-2-ynyloxycarbonyl group under neutral condition facilitates the conversion of taxol intermediate such as 10 to taxol in high yield and high purity.
OBJECTS OF THE INVENTION
An object of this invention is to propose a novel oxazolidine carboxylic acid and a process for the preparation thereof.
Another object of this invention is to propose oxazolidine carboxylic acid which can advantageously be used in the preparation of anticancer drugs.
Still another object of this invention is to propose a process for the preparation of taxol and its synthetic analogs using the proposed oxazolidine carboxylic acid.
DESCRIPTION OF THE INVENTION
The present invention is directed to 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid and its analogs having a formula
and wherein R
1
is hydrogen, aryl, heteroaryl, alkyl alkenyl, alkynyl, R
2
and R
3
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl; R
4
is hydrogen, alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl. R
5
and R
6
independently selected from hydrogen, alkyl, alkenyl, alkynyl, arly, heteroaryl, alkoxy, alkeyloxy, alkynyloxy, aryloxy, heteroaryloxy.
The oxazoldine alkyl groups either alone or with the variable substituents defined above are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. The alkyl part of alkoxy groups defined above are same as a alkyl groups.
The oxazoldine alkenyl groups either alone or with the various substituents defined above are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight chain and include ethenyl, propenyl, isopropenyl butenyl, isobutenyl, pentenyl, hexenyl, and the like. The alkenyl part of alkenyloxy groups defined above are same as a alkenyl groups.
The oxazoldine alknyl groups, either along or with the various substituents defined above are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight chain and include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like. The alkynyl part of alkynyloxy groups defined above are same alkynyl groups.
The oxazoldine aryl moieties eiher alone or with various substituents contain from 6 to 10 carbon atoms and include pheny, -naphthyl etc. substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino; amido etc.
As defined herein, the term aryloxy includes aromatic heterocyclic moieties the term aryl includes any compound having an aromatic ring of which no hetero atom is a member, and the term heteroaryl includes any compound having an aromatic ring which comprises a hetero atom.
Most preferably, the oxazolidine carboxylic acid has a formula wherein R
1
, R
2
and R
3
are hydrogen, R
4
is phenyl and R
5
and R
6
are methyl.
The present invention also describes process of preparation of 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid and its analogs.
The present invention also describes the preparation of taxol intermediates of following structural formula:
wherein
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy aryloyloxy or; A and B together form an oxo;
L and D are independently hydrogen on hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy alkoxycarbonyloxy, aryloxycarbonyloxy or alkylsilyloxy;
E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy aryloyloxy; or E and F together form an oxo;
G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or;
G and M together form an oxo or methylene or oxirane ring or
M and F together form an oxetane ring;
J is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or
I is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or
I and J together form an oxo; and
K is hydrogen or hydroxy, lower alkoxy, alkenoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy
P and Q are independently hydrogen or hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy or alkylsilyloxy or P and Q together form an oxo; and
S and T are independently hydrogen, lower alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, substituted aryl or substituted aryloxy; and
U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl or substituted aryl or heteroaryl and
W and W′ are independently hydrogen or lower alkyl, aryl or substituted aryl; and
Y is hydrogen or lower alkyl, aryl or substituted aryl.
The present invention also describes the preparation of taxol intermediates, natural taxol and non-natural occurring taxols of following structural formula:
wherein
A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, or;
A and B together form an oxo;
L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy or alkylsilyloxy;
E and F are independently hydrogen or lower alkanoyloxy,
Prakash Sharma Arun
Subrata Sarkar
Dabur India Limited
McKane Joseph K.
Saeed Kamal
Spencer George H.
Venable
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