Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-25
2002-11-19
Aulakh, Charanjit S (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S412000
Reexamination Certificate
active
06482957
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a cyclopentenecarboxamide derivative and its intermediate. More specifically, the present invention relates to a cyclopentenecarboxamide derivative which is useful as an intermediate of a carbocyclic nucleoside usefully used as an anti-viral agent and a bicycloamide derivative which is an intermediate of the cyclopentenecarboxamide derivative, and methods for preparing these compounds.
2. Discussion of the Related Art
Carbocyclic nucleosides are structurally analogous to nucleosides in which the furanose oxygen is replaced by methylene group. Because of the structural resemblance to native nucleosides, carbocyclic nucleosides can behave as substrates or inhibitors of the enzymes which act on nucleosides in living cells. On the other hand, owing to the absence of a glycoside bond, they are not susceptible to the action of hydrolases such as phosphorylases and phosphotransferases that hydrolyze native nucleosides. Also, the metabolic route of carbocyclic nucleosides is different from that of native nucleosides. Because of these differences, carbocyclic nucleosides are endowed with a wide spectrum of biological activities. For example, carbovir, which is represented by the formula (D) set forth later in the present specification, is effective for the therapy and prevention of viral infection [J. Med. Chem., 33, 17 (1990)].
There have been disclosed several methods for preparing a carbocyclic nucleoside, which include the following methods:
(1) Using, as a starting compound, a cycloalkane substituted with an amino group or a cycloalkene substituted with an amino group, a base structure of a nucleic acid base is constructed on the nitrogen atom of the amino group [Protein, nucleic acid, and enzyme, 40, 1219 (1995)];
(2) A purine structure is directly introduced into a 1-alkoxy-2-cyclopentene derivative in the presence of a palladium catalyst [J. Chem. Soc. Parkin Trans. 1, 2605 (1991); Tetrahedron Letters, 33, 1085 (1992); and J. Am. Chem. Soc., 114, 8745 (1992)]; and
(3) A purine structure is directly introduced into a 2-cyclopentene-1-yl-N,N-ditosylimide derivative in the presence of a palladium catalyst [J. Org. Chem., 59, 4719(1994)].
All the above methods, however, arise a problem which causes to impair the cost-effectiveness of the production on an industrial scale. In the above method (1), the construct of a nucleic acid structure on the N-atom requires many reaction steps, which in turn increases the production cost. Although the above methods (2) and (3) are advantageous over the method (1) in that a nucleic acid base structure is directly introduced, they require many steps for the synthesis of a cyclopentene derivative used as a starting material. Therefore, none of the above methods (1) to (3) can be advantageously used for an industrial scale production of a carbocyclic nucleoside.
As a method for preparing an N-sulfonyl derivative of 2-azabicyclo[2.2.1]hept-5-en-3-one, there has been known a method comprising reacting in the presence of sodium hydride at room temperature p-toluenesulfonyl chloride with 2-azabicyclo[2.2.1]hept-5-en-3-one to give N-p-toluenesulfonyl-2-azabicyclo[2.2.1]hept-5-en-3-one [J. Org. Chem. 59, 4719 (1994); and Chem. Pharm. Bull., 39, 1112(1992)].
However, the above method using sodium hydride has a defect of low yield such as 40 to 46% as demonstrated in Comparative Examples described later in the present specification, therefore is not an advantageous method for the industrial production of an N-sulfonyl derivative of 2-azabicyclo[2.2.1]hept-5-en-3-one.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel compounds which are usefully employed as intermediates for preparing various carbocyclic nucleosides on an industrial scale and methods for preparing these compounds.
In one embodiment, the present invention relates to a cyclopentenecarboxamide derivative represented by the formula (I):
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to the nitrogen atom of the amido group, and Y is a residue of a substituted or unsubstituted nucleic acid base.
In another embodiment, the present invention relates to a method for preparing a cyclopentenecarboxamide derivative represented by the formula (I):
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to the nitrogen atom of the amido group, and Y is a residue of a substituted or unsubstituted nucleic acid base, comprising the step of:
reacting in the presence of a base and a palladium catalyst, a bicycloamide derivative represented by the formula (II):
wherein R
1
is defined as above, with a compound represented by the formula (III):
Y-H (III)
wherein Y is defined as above.
In still another embodiment, the present invention relates to a method for preparing a cyclopentenecarboxamide derivative represented by the formula (I):
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to the nitrogen atom of the amido group, and Y is a residue of a substituted or unsubstituted nucleic acid base, comprising the steps of:
(A) reacting in the presence of an organolithium compound and at a temperature of from −120° C. to 0° C., 2-azabicyclo[2.2.1]hept-5-en-3-one represented by the formula (IV):
with a compound represented by the formula (V):
R
1
-X (V)
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to X, and X is a halogen atom
to yield a bicycloamide derivative represented by the formula (II):
wherein R
1
is defined as above; and
(B) reacting the bicycloamide derivative obtained in the step (A) in the presence of a base and a palladium catalyst with a compound represented by the formula (III):
Y-H (III)
wherein Y is defined as above.
In still another embodiment, the present invention relates to a method for preparing a bicycloamide derivative represented by the formula (II):
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to the nitrogen atom of the amido group, comprising the step of:
reacting in the presence of an organolithium compound and at a temperature of from −120° C. to 0° C., azabicyclo[2.2.1]hept-5-en-3-one represented by the formula (IV):
with a compound represented by the formula (V):
R
1
-X (V)
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to X, and X is a halogen atom.
The present invention also relates to an N-sulfonylbicycloamide derivative represented by the formula (II-1):
wherein R
2
is an aromatic hydrocarbon group which may have a substituent having one or more atoms other than carbon and hydrogen atoms; an N-sulfonylbicycloamide derivative represented by the formula (II-2):
wherein R
3
is a substituted or unsubstituted saturated aliphatic hydrocarbon group; and an N-phophorylbicycloamide derivative represented by the formula (II-3):
wherein R
4
and R
5
are independently a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted saturated aliphatic hydrocarbon group.
These and other objects of the present invention will be apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described in detail below.
As mentioned above, the cyclopentenecarboxamide derivative of the present invention is a compound represented by the formula (I):
wherein R
1
is an electron withdrawing group having sulfur atom or phosphorus atom directly bonded to the nitrogen atom of the amido group, and Y is a residue of a substituted or unsubstituted nucleic acid base.
The cyclopentenecarboxamide derivative represented by the formula (I) can be obtained by reacting, in the presence of a base and a palladium catalyst, a b
Kanehira Koichi
Kaneko Chikara
Katagiri Nobuya
Sato Junko
Tamai Yoshin
Aulakh Charanjit S
Kuraray Co. Ltd.
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