Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-18
2002-08-20
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S301000
Reexamination Certificate
active
06437132
ABSTRACT:
TECHNICAL FIELD
The present invention relates to synthetic intermediates for production of compounds having thienopyridine skeleton and being useful for medicines, agricultural chemicals, and so forth, especially thienopyridine derivatives exhibiting gonadotropin releasing hormone (GnRH) antagonizing activity, and their production.
As a basic structure of a thienopyridine, 4,7-dihydro-4-oxo-thieno[2,3-b]pyridine of the formula:
or thieno[2,3-b]pyridine of the formula:.
is exemplified.
BACKGROUND ART
Thienopyridines are known to have antibacterial activities as well as other activities found recently such as angiotensine II antagonistic activities and GnRH antagonistic activities, due to which they are expected to be used widely in the fields of medicines and agricultural industries. Concerning the synthetic method for 5-acyl-4-hydroxythieno[2,3-b]pyridine derivative, one of such thienopyridines, there are examples reported on a direct synthesis of 5-acetyl-4-hydroxythieno[2,3-b]pyridine from 2-aminothiophene by a method called Gould-Jacobs method characterized by employing an ethoxymethylene compound of an active methylene compound as shown below [M. A. -Khan et al., J. Heterocyclic Chem., Vol. 14, p. 807 (1977)]:
a synthesis from a corresponding acyl group-containing polysubstituted pyridine as shown below (F. A. Abu-Shanab et al., J. Chem. Soc. Perkin Trans. 1, 1994, page 1449):
and a synthesis through functional group conversion in the 5-position of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof obtained by a conventional procedure as shown below [WO 95/28405 (JP-A-8-295693)]:
wherein R
51
represents hydrogen or a group through a carbon, nitrogen, oxygen or sulfur atom, R
52
represents hydrogen or alkyl, R
53
a hydrocarbon group, and R
54
represents phenyl-alkylene which may be substituted.
In order to produce a thienopyridine derivative having a GnRH antagonistic effect, a compound having a nitrophenyl in the 2-position and a halogenomethyl in the 3-position is produced as an intermediate in WO 95/28405 (JP-A-8-295693). In the production of this compound, a nitro group is first introduced into the phenyl of the compound having a phenyl in the 2-position and a methyl in the 3-position and then the methyl in the 3-position is converted into a halogenomethyl.
Also in WO 95/28405 (JP-A-8-295693), a compound having an acid amide in the 5-position is produced from a compound having a carboxylic acid ester in the 5-position.
In the method by M. A. Khan et al. described above, the product is provided via an undesirable step such as the involvement of an organotin compound in an attempt to avoid the formation of an unstable 2-aminothiophene as an intermediate, while the method by F. A. Abu-Shanab et al. provides a O-ethylated product and involves a limitation in terms of the substituents on the thiophene ring, because of which the range of the application is limited.
On the other hand, the method for obtaining a 5-acyl form by the functionality conversion of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof which are obtained by a conventional method involves a less efficient multiple-stage synthesis. In the production of a GnRH antagonistic thienopyridine derivative employing this conventional method disclosed in WO 95/28405 (JP-A-8-295693) involves a large number of the production steps, which also make this method less efficient.
Accordingly, there has still been a desire to develop a method for producing a 5-acyl-4-hydroxythieno[2,3-b]pyridine skeleton conveniently and efficiently.
In the method disclosed in WO 95/28405 (JP-A-8-295693) which involves a conversion of the methyl in the 3-position of a compound having a nitrophenyl in the 2-position and the methyl in the 3-position into a halogenomethyl, carbon tetrachloride is employed as a solvent (see Example 6 in this publication). Since carbon tetrachloride has a high toxicity, an industrial or safety and sanitary consideration encourages to use a method employing no carbon tetrachloride. Nevertheless, no use of carbon tetrachloride results in a disadvantageous intermission of a brominating reaction.
In the method disclosed in WO 95/28405 (JP-A-8-295693), for producing a compound having an acid amide structure in the 5-position from a compound having a carboxylic acid ester in the 5-position, trimethylaluminum is used (see Example 50 in this publication). Since this trimethylaluminum is readily flashing and flammable, highly toxic and should be free from water, it should be handled with a great care. Industrially, a safe production method requiring no use of trimethylaluminum is desired.
DISCLOSURE OF THE INVENTION
We made an effort under the circumstance mentioned above and finally found that by halogenating the methyl in the 3-position of 4,7-dihydro-4-oxothieno[2,3-b]pyridine represented by the formula:
having a phenyl in the 2-position and a methyl in the 3-position followed by introducing a nitro group into the phenyl in the 2-position of a resultant compound, a rapid halogenation in a solvent other than carbon tetrachloride, such as an easily-handled solvent such as ethyl acetate, under a gentle and convenient condition is possible in a halogenation process, and an easily-operable nitration by dissolving said halogenated compound in a solvent such as methanesulfonic acid followed by reacting with various nitrates in a nitration process is also possible.
It is also found that by producing a compound having an acid amide structure in the 5-position from a compound having a free carboxylate in the 5-position a target compound can be produced safely and conveniently in a high yield and a high purity without requiring the use of dangerous trimethylaluminum.
Also, the present inventors found out that a compound of the formula:
or a salt thereof, is obtained in high yield by subjecting a compound of the formula:
or a salt thereof to cyclization.
The inventors conducted further investigation based on this finding, and developed the present invention.
The present invention, therefore, relates to:
(1) a compound of the formula:
wherein R
11a
represents hydrogen or halogen, and R
41a
represents C
1-6
alkyl, C
1-6
alkoxy or C
6-10
aryl, with proviso that R
41a
is not ethoxy when R
11a
is hydrogen, or a salt thereof;
(2) a compound of the above (1) or a salt thereof, wherein R
11a
is hydrogen or bromo;
(3) a compound of the above (1) or a salt thereof, which is 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylthieno[2,3-b]pyridine;
(4) a compound of the above (1) or a salt thereof, which is 4 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-2-phenylthieno[2,3-b]pyridine;
(5) a compound of the above (1) or a salt thereof, which is 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phenylthieno[2,3-b]pyridine-5-carboxylic acid ethyl ester;
(6) a process for producing a compound of the formula:
wherein X represents halogen, R
12a
represents a divalent hydrocarbon group which may be substituted, R
3a
represents a hydrocarbon group which may be substituted, R
4a
represents a hydrocarbon group or a hydrocarbon-oxy group, and R
22a
represents a hydrocarbon group substituted by nitro, or a salt thereof, which comprises subjecting a compound of the formula:
wherein R
21a
represents a hydrocarbon group and other symbols are as defined above, or a salt thereof to nitration;
(7) a process of the above (6), wherein R
12a
is methylene, R
21a
is phenyl, R
22a
is nitrophenyl, R
3a
is difluorophenyl-methyl, and R
4a
is isopropyl or ethoxy;
(8) a process for producing a compound of the formula:
wherein X represents halogen, R
12a
represents a divalent hydrocarbon group, and R
4a
represents a hydrocarbon group or a hydrocarbon-oxy group, or a salt thereof, which comprises subjecting a compound of the formula:
wherein R
1a
repres
Fukuoka Koichiro
Miki Shokyo
Chao Mark
Desai Rita
Ramesh Elaine M.
Rotman Alan L.
Takeda Chemical Industries Ltd.
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