Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-07
2003-05-20
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S426000
Reexamination Certificate
active
06566535
ABSTRACT:
TECHNICAL FIELD
The present invention relates to processes for the preparation of 2,3-dihydrothiepine derivatives.
BACKGROUND ART
Heretofore, a process for synthesizing a 2,3-dihydrobenzothiepine derivative by subjecting phenylthiobutyric acid to an intramolecular cyclodehydration, introducing a C1 unit into the &agr;-position of the obtained ketone body, and conducting reduction and dehydration is disclosed in patent applications such as PCT/JP98/05708 (WO99/32100) and Japanese Patent Application No. 10-363404 (PCT/JP99/07148). Moreover, as a cyclization reaction of the Dieckmann type, a process proposed by Nagamatsu et al., (J. Heterocyclic Chem., 28, 513 (1991)), a process disclosed in WO098/55475, etc. are known. However, these processes use raw material difficult to get, reagents having a disposal problem or reagents not suitable for large-scale synthesis. In addition, the processes have long steps and require complicated operations.
Because of the above-mentioned present conditions, there is a demand for a process for producing a 2,3-dihydrothiepine derivative, the process being inexpensive, simple and more suitable for large-scale synthesis.
DISCLOSURE OF INVENTION
The inventors of the present invention made a variety of studies, and as a result, they have found a process for preparing a 2,3-dihydrothiepine derivative by causing a sulfide having a propyl group as a substituent, the propyl group having an &agr;,&bgr; unsaturated carbonyl group and an electron-attracting group at its end, to react with a base in a solvent. Furthermore, they found a process for preparing a 2,3-dihydrothiepine derivative by causing an orthohalogenobenzaldehyde to react with a propanethiol having an electron-attracting group at its 4-position. As a result of further studies based on these findings, they have accomplished the present invention.
Namely, the present invention relates to:
(1) a process for preparing a compound represented by the following formula:
wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula:
wherein R
1
is an electron-attracting group; R
2
, R
3
, R
4
, R
5
R
6
and R
7
are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, provided that R
6
and R
7
may be united to form a ring; and R
8
is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to a ring-closing reaction;
(2) the preparation process according to the above-mentioned (1) wherein R
1
is an esterified carboxyl group;
(3) the preparation process according to the above-mentioned (1) wherein R
8
is a hydrogen atom;
(4) the preparation process according to the above-mentioned (1) wherein R
2
, R
3
, R
4
and R
5
are each a hydrogen atom;
(5) the preparation process according to the above-mentioned (1) wherein the reaction is conducted in the presence of a base;
(6) the preparation process according to the above-mentioned (5) wherein the base is an alcoholate;
(7) the preparation process according to the above-mentioned (1) wherein the reaction is conducted in a solvent containing a carbonic acid diester;
(8) a process for preparing a compound represented by the following formula:
wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula:
wherein R
1
is an electron-attracting group; R
2
, R
3
, R
4
and R
5
are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; ring A is an optionally substituted benzene ring; and R
8
is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to a ring-closing reaction;
(9) the preparation process according to the above-mentioned (8) wherein R
1
is an esterified carboxyl group;
(10) the preparation process according to the above-mentioned (8) wherein R
8
is a hydrogen atom;
(11) the preparation process according to the above-mentioned (8) wherein R
2
, R
3
, R
4
and R
5
are each a hydrogen atom;
(12) the preparation process according to the above-mentioned (8) wherein the reaction is conducted in the presence of a base;
(13) the preparation process according to the above-mentioned (12) wherein the base is an alcoholate;
(14) the preparation process according to the above-mentioned (8) wherein the reaction is conducted in a solvent containing a carbonic acid diester;
(15) a process for preparing a compound represented by the following formula:
wherein each symbol is as defined below, or a salt thereof, characterized by causing a compound represented by the following formula:
wherein X is a leaving group; and R
6
and R
7
are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, provided that R
6
and R
7
may be united to form a ring; and R
8
is a hydrogen atom or an optionally substituted hydrocarbon group, or a salt thereof, to react with a compound represented by the following formula:
wherein R
1
is an electron-attracting group; R
2
, R
3
, R
4
and R
5
are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or a salt;
(16) the preparation process according to the above-mentioned (15) wherein X is a halogen atom;
(17) the preparation process according to the above-mentioned (15) wherein X is a fluorine atom;
(18) the preparation process according to the above-mentioned (15) wherein R
1
is an esterified carboxyl group;
(19) the preparation process according to the above-mentioned (15) wherein R
8
is a hydrogen atom;
(20) the preparation process according to the above-mentioned (15) wherein R
2
, R
3
, R
4
and R
5
are each a hydrogen atom;
(21) A process for preparing a compound represented by the following formula:
wherein each symbol is as defined below, or a salt thereof, characterized by causing a compound represented by the following formula:
wherein X is a leaving group; R
8
is a hydrogen atom or an optionally substituted hydrocarbon group; and ring A is an optionally substituted benzene ring, or a salt thereof, to react with a compound represented by the following formula:
wherein R
1
is an electron-attracting group; R
2
, R
3
, R
4
and R
5
are each a hydrogen atom, a halogen atom, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or a salt thereof;
(22) the preparation process according to the above-mentioned (21) wherein X is a halogen atom;
(23) the preparation process according to the above-mentioned (21) wherein X is a fluorine atom;
(24) the preparation process according to the above-mentioned (21) wherein R
1
is an esterified carboxyl group;
(25) the preparation process according to the above-mentioned (21) wherein R
8
is a hydrogen atom;
(26) the preparation process according to the above-mentioned (21) wherein R
2
, R
3
, R
4
and R
5
are each a hydrogen atom;
(27) a process for preparing a compound represented by the following formula:
wherein each symbol is as defined below, or a salt thereof, characterized by subjecting a compound represented by the following formula:
wherein R
1
is an electron-attracting group; R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are each a hydrogen atom, a halogen ato
Ikemoto Tomomi
Ito Tatsuya
Tomimatsu Kiminori
Chao Mark
Lambkin Deborah C.
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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