Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-23
2002-01-29
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06342606
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for producing pyridine derivatives, and to intermediates in the synthesis thereof. The pyridine derivatives produced by the present invention are useful as intermediates in the synthesis of compounds having a pyridine skeleton in the molecule, such as furopyridine derivatives having antiviral activity (see WO 96/35678).
2. Description of the Related Art
Several methods have been disclosed in the past as methods for the synthesis of condensed pyridines such as furopyridines (see Heterocycles, 45(5) (1997), p. 975), but the only known methods for producing 5-substituted furo[2,3-c]pyridines which can be converted to the aforementioned furopyridine derivatives having antiviral activity are methods in which synthesis is achieved through multiple stages using 2-chloro-3-hydroxypyridine as the starting material (see WO 96/35678), and methods in which furfural oxime as the starting material is made into 5-substituted furo[2,3-c]pyridine-N-oxide as a result of ring formation by the Aza Diels-Alder reaction and subsequent dehydrogenation (see Tetrahedron Lett., 32, 3199(1991)).
Problems in the former of the aforementioned methods, however, are the large number of steps as well as the expensive starting materials and reaction agents, while the latter method needs expensive dehydrogenating agents such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and needs the reduction of the pyridine oxide to pyridine, and hence both methods cannot be considered to be industrially useful.
SUMMARY OF THE INVENTION
An object of the present invention is to provide methods in which pyridine derivatives, that allow condensed pyridines such as furopyridine derivatives to be readily produced, can be manufactured with good yields in an industrially useful manner under moderate conditions.
Another object of the present invention is to provide a synthetic intermediate and its method of production giving an industrially useful method for producing the aforementioned pyridine derivatives.
The aforementioned objects have been achieved in the following present invention.
The present invention provides a method for producing a pyridine alcohol derivative represented by General Formula III
(where A represents a divalent organic group which may contain one to three oxygen atoms, nitrogen atoms and/or sulfur atoms, wherein A may form a 5-, 6-, 7-, or 8-membered ring together with two bonded carbon atoms, and said ring may form a condensed ring with one or more additional rings; R
5
represents a hydrogen atom, —CHR
1
R
2
, or an alkenyl group, an aryl group or an aralkyl group which may be substituted; R
1
and R
2
each independently represent a hydrogen atom or a hydrocarbon group which may be substituted; and R
6
represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may be substituted), wherein the method comprises:
reacting a pyridine ester derivative represented by General Formula I-1
where Z
1
represents —COX; X represents an alkoxyl group, an alkenyloxy group, an aryloxy group or an aralkyloxy group which may be substituted; and A is the same as above)
with a reducing agent, an alkylating agent, an alkenylating agent, an arylatihg agent or an aralkylating agent to obtain a pyridine carbonyl derivative represented by General Formula II
(where A and R
5
are the same as above); and
reacting the resulting pyridine carbonyl derivative represented by General Formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to obtain the pyridine alcohol derivative of the General Formula III.
The present invention also provides a method for producing a pyridine alcohol derivative represented by General Formula III, wherein the method comprises:
reacting a pyridine carbonyl derivative represented by General Formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to obtain the pyridine alcohol derivative of the General Formula III.
The present invention further provides a pyridine carbonyl derivative represented by General Formula II-1
(where R
5
represents a hydrogen atom, —CHR
1
R
2
, or an alkenyl group, an aryl group or an aralkyl group which may be substituted; R
1
and R
2
each independently represent a hydrogen atom or a hydrocarbon group which may be substituted; Q represents a divalent group selected from —ND—, —O—, and —S—; and D represents a hydrogen atom or a hydrocarbon group which may be substituted).
The present invention still further provides a method for producing a pyridine carbonyl derivative represented by General Formula II, wherein the method comprises:
reacting a pyridine ester derivative represented by General Formula I-1 with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent.
The present invention also provides a method for producing a pyridine alcohol derivative represented by General Formula III, wherein the method comprises:
reacting a pyridine ester derivative represented by General Formula I-1 in the presence of a base with an ester compound represented by General Formula IV
R
1
R
2
CHCO
2
R
3
(IV)
(where R
1
and R
2
are the same as above; and R
3
represents a hydrocarbon group which may be substituted)
to obtain a pyridine &bgr;-ketoester derivative represented by General Formula V
(where R
1
, R
2
, and A are the same as above; and R
4
is a hydrocarbon group which may be substituted); and
hydrolyzing and decarboxylating the resulting pyridine &bgr;-ketoester derivative represented by General Formula V to obtain the pyridine carbonyl derivative represented by General Formula II; and
reacting the pyridine carbonyl derivative represented by General Formula II with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent to obtain the pyridine alcohol derivative represented by General Formula III.
The present invention further provides a method for producing a pyridine &bgr;-ketoester derivative represented by General Formula V, wherein the method comprises:
reacting a pyridine ester derivative represented by General Formula I-1 with in the presence of a base with an ester compound represented by General Formula IV to obtain the pyridine &bgr;-ketoester derivative represented by General Formula V.
The present invention still further provides a pyridine &bgr;-ketoester derivative represented by General Formula V-1
(where R
1
and R
2
each independently represent a hydrogen atom or a hydrocarbon group which may be substituted; R
4
represents a hydrocarbon group which may be substituted; Q represents a divalent group selected from —ND—, —O—, and —S—; and D represents a hydrogen atom or a hydrocarbon group which may be substituted).
The present invention also provides a method for producing a pyridine carbonyl derivative represented by General Formula II, wherein the method comprises:
hydrolyzing and decarboxylating a pyridine &bgr;-ketoester derivative represented by General Formula V to obtain the pyridine carbonyl derivative represented by General Formula II.
The present invention also provides a pyridine ester derivative represented by General Formula I-1′
(where Z
1
represents —COX; and X represents an alkoxyl group, alkenyloxy group, aryloxy group or aralkyloxy group which may be substituted).
The present invention also provides a sulfonylpyridine derivative represented by General Formula I-2
(where Z
2
represents an organic sulfonyl group represented by —SO
2
R
9
; R
9
represents an organic group; and A represents a divalent organic group which may contain one to three oxygen atoms, nitrogen atoms and/or sulfur atoms, wherein A may form a 5-, 6-, 7-, or 8-membered ring together with two bonded carbon atoms, and said ring may form a condensed ring with one or more additional rings).
The present invention also provides a method for producing
Asanuma Goro
Kikuyama Shigeki
Matsuda Hideki
Shin Takanobu
Shiono Manzo
Dentz Bernard
Kuraray Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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