U.S. patent application number 09/785320 was filed with the patent office on 2001-09-20 for process for preparing 2-alkyl-3-aminothiophene derivative and 3-aminothiophene derivative.
Invention is credited to Ishii, Seiichi, Katsuta, Hiroyuki, Kodaka, Kenji, Tomiya, Kanji.
Application Number | 20010023295 09/785320 |
Document ID | / |
Family ID | 13401143 |
Filed Date | 2001-09-20 |
United States Patent
Application |
20010023295 |
Kind Code |
A1 |
Katsuta, Hiroyuki ; et
al. |
September 20, 2001 |
Process for preparing 2-alkyl-3-aminothiophene derivative and
3-aminothiophene derivative
Abstract
A compound represented by the formula (1) which is useful as an
agricultural fungicide or an intermediate thereof can be obtained
by reacting a compound of the general formula (2) with a compound
of the general formula (3) in the presence of an acid-and reducing
the resulted reaction mixture. 1 wherein, each of R.sup.1 to
R.sup.4 and R.sup.1a to R.sup.4a independently represents a
hydrogen atom or an alkyl group, and R represents an alkyl group,
alkoxy group, phenyl group or 5-membered or 6-membered heterocyclic
group.
Inventors: |
Katsuta, Hiroyuki;
(Chiba-ken, JP) ; Ishii, Seiichi; (Chiba-ken,
JP) ; Tomiya, Kanji; (Chiba-ken, JP) ; Kodaka,
Kenji; (Chiba-ken, JP) |
Correspondence
Address: |
Robert G. Mukai
BURNS, DOANE,SWECKER & MATHIS, L.L.P.
P.O.Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
13401143 |
Appl. No.: |
09/785320 |
Filed: |
February 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09785320 |
Feb 20, 2001 |
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09524007 |
Mar 13, 2000 |
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6239282 |
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Current U.S.
Class: |
549/76 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 333/38 20130101; C07D 333/36 20130101; C07D 411/12 20130101;
C07D 417/12 20130101; C07D 333/40 20130101 |
Class at
Publication: |
549/76 |
International
Class: |
C07D 333/22 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 16, 1999 |
JP |
HEI 11-69387 |
Claims
What is claimed is:
1. A process for preparing a 2-alkyl-3-aminothiophene derivative
represented by the formula (1): 37wherein, R represents a hydrogen
atom, alkyl group or alkoxy group which may be substituted,
aromatic or non-aromatic hydrocarbon ring which may be substituted,
aromatic or non-aromatic heterocyclic ring which may be
substituted, each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4
independently represents a hydrogen atom or straight or branched
alkyl group having 1 to 12 carbon atoms, and R.sup.1 and R.sup.2,
R.sup.3 and R.sup.4, R.sup.1 and R.sup.3, R.sup.1 and R.sup.4,
R.sup.2 and R.sup.3 or R.sup.2 and R.sup.4 may together form a
cycloalkyl group, comprising reacting a compound represented by the
formula (2): 38wherein, R is as defined above, with a compound
represented by the formula (3): 39wherein, each of R.sup.1a,
R.sup.2a, R.sup.3a and R.sup.4a independently represents a hydrogen
atom, straight or branched alkyl group having 1 to 12 carbon atoms
or straight or branched alkenyl group having 1 to 12 carbon atoms,
and R.sup.1a and R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and
R.sup.3a, R.sup.1a and R.sup.4a, R.sup.2 and R.sup.3a or R.sup.2a
and R.sup.4a may together form a cycloalkyl group or cycloalkenyl
group, in the presence of an acid, and reducing the resulted
reaction mixture.
2. The process according to claim 1 wherein R represents a hydrogen
atom, alkyl group or alkoxy group which may be substituted or
phenyl group which may be substituted.
3. The process according to claim 2 wherein each of R.sup.1,
R.sup.2and R.sup.3 represents a hydrogen atom, R.sup.4represent an
isopropyl group, each of R.sup.1a, R.sup.2a and R.sup.3a represents
a hydrogen atom and R.sup.4a represent an isopropyl group.
4. The process according to claim 1 wherein R represents a group
represented by any of the following (A1) to (A12): 40wherein,
R.sup.5 represents a trifluoromethyl group, difluoromethyl group,
methyl group, ethyl group or halogen atom, R.sup.6 represent a
hydrogen atom, methyl group, trifluoromethyl group, halogen atom,
methoxy group or amino group, R.sup.1 represents a hydrogen atom,
halogen atom, methyl group or methoxy group, R.sup.8 represents a
hydrogen atom, methyl group, ethyl group or halogen atom, and n
represents an integer from 0 to 2, and herein, in the case of (A9),
(A10) or (A11), R.sup.5 is not a halogen atom.
5. The process according to claim 4 wherein R represents (A1),
(A2), (A3), (A4) or (A9).
6. The process according to claim 5 wherein R represents (A1),
(A2), (A3) or (A4).
7. The process according to claim 6 wherein R represents (A1).
8. The process according to claim 7 wherein R.sup.5 represents a
trifluoromethyl group and R.sup.7 represents a hydrogen atom.
9. The process according to claim 8 wherein each of R.sup.1,
R.sup.2 and R.sup.3 represents a hydrogen atom, R.sup.4 represent
an isopropyl group, each of R.sup.1a, R.sup.2a and R.sup.3a
represents a hydrogen atom and R.sup.4a represent an isopropyl
group.
10. A process for preparing a mixture of 2-alkenyl-3-aminothiophene
derivatives containing compounds represented by the formulae (4a),
(4b), (4c) and (4d) respectively: 41wherein, R represents a
hydrogen atom, alkyl group or alkoxy group which may be
substituted, aromatic or non-aromatic hydrocarbon ring which may be
substituted, aromatic or non-aromatic heterocyclic ring which may
be substituted, each of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a
independently represents a hydrogen atom, straight or branched
alkyl group having 1 to 12 carbon atoms or straight or branched
alkenyl group having 1 to 12 carbon atoms, and R.sup.1a and
R.sup.2a R.sup.3a and R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a and
R.sup.4a, R.sup.2a and R.sup.3a or R.sup.2a and R.sup.4a may
together form a cycloalkyl group or cycloalkenyl group, comprising
reacting a compound represented by the formula (2): 42wherein, R is
as defined above, with a compound represented by the formula (3):
43wherein, R.sup.1a to R.sup.4a are as define above, in
the-presence of an acid.
11. The process according to claim 10 wherein R represents a
hydrogen atom, alkyl group or alkoxy group which may be substituted
or phenyl group which may be substituted.
12. The process according to claim 11 wherein each of R.sup.1a,
R.sup.2a and R.sup.3a represents a hydrogen atom and R.sup.4a
represent an isopropyl group.
13. The process according to claim 10 where-in R represents a group
represented by any of the following (A1) to (A12): 44wherein,
R.sup.5represents a trifluoromethyl group, difluoromethyl group,
methyl group, ethyl group or halogen atom, R.sup.6 represent a
hydrogen atom, methyl group, trifluoromethyl group, halogen atom,
methoxy group or amino group, R.sup.7 represents a hydrogen atom,
halogen atom, methyl group or methoxy group, R.sup.8 represents a
hydrogen atom, methyl group, ethyl group or halogen atom, and n
represents an integer from 0 to 2, and herein, in the case of (A9),
(A10) or (A11), R.sup.5 is not a halogen atom.
14. The process according to claim 13 wherein R represents (A1),
(A2), (A3), (A4) or (A9).
15. The process according to claim 14 wherein R represents (A1),
(A2), (A3) or (A4).
16. The process according to claim 15 wherein R represents
(A1).
17. The process according to claim 16 wherein R.sup.5 represents a
trifluoromethyl group and R.sup.7 represents a hydrogen atom.
18. The processs according to claim 17 wherein each of R.sup.1a,
R.sup.2a and R.sup.3a represents a hydrogen atom and R~a represent
an isopropyl group.
19. A process for preparing 2-alkyl-3-aminothiophene represented by
the formula (la): 45wherein, R.sup.a represents a group represented
by any of the following (A1) to (A12): 46wherein, R.sup.5
represents a trifluoromethyl group, difluoromethyl group, methyl
group, ethyl group or halogen atom, R.sup.6 represent a hydrogen
atom, methyl group, trifluoromethyl group, halogen atom, methoxy
group or amino group, R.sup.7 represents a hydrogen atom, halogen
atom, methyl group or methoxy group, R.sup.8 represents a hydrogen
atom, methyl group, ethyl group or halogen atom, and n represents
an integer from 0 to 2, and herein, in the case of (A9), (A10) or
(A11), R.sup.5 is not a halogen atom, each of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 independently represents a hydrogen atom or
straight or branched alkyl group having 1 to 12 carbon atoms, and
R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.1 and R.sup.3,
R.sup.1 and R.sup.4, R.sup.1 and R.sup.3 or R.sup.2 and R.sup.4 may
together form a cycloalkyl group, comprising reacting a compound
represented by the formula (2): 47wherein, R represents a hydrogen
atom, alkyl group or alkoxy group which may be substituted,
aromatic or non-aromatic hydrocarbon ring which may be substituted
or aromatic or non-aromatic heterocyclic ring which may be
substituted, with a compound represented by the formula (3):
48wherein, each of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a
independently represents a hydrogen atom, straight or branched
alkyl group having 1 to 12 carbon atoms or straight or branched
alkenyl group having 1 to 12 carbon atoms, and R.sup.1a and
R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a
and R.sup.4a, R.sup.2a and R.sup.3a or R.sup.2a and R.sup.4a may
together form a cycloalkyl group or cycloalkenyl group, in the
presence of an acid, reducing the resulted reaction mixture to
obtain a compound represented by the formula (1): 49wherein, R,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, further
hydrolyzing the resultant compound under acidic or alkaline
condition to obtain a compound represented by the formula (5):
50wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined
above, and reacting this compound with a compound represented by
the formula (8a): 51wherein, R.sup.a is as defined above.
20. The process according to claim 19 wherein R represents a
hydrogen atom, alkyl group or alkoxy group which may be substituted
or phenyl group which may be substituted, R.sup.a represents (A1),
(A2), (A3), (A4) or (A9).
21. The process according to claim 20 wherein R.sup.a represents
(A1), R.sup.5 represents a trifluoromethyl group, R.sup.7
represents a hydrogen atom, each of R.sup.1, R.sup.2 and R.sup.3
represents a hydrogen atom, R.sup.4 represent an isopropyl group,
each of R.sup.1a, R.sup.2a and R.sup.3a represents a hydrogen atom
and R.sup.4a represent an isopropyl group.
22. A 3-aminothiophene derivative represented by the formula (6a):
52wherein, R.sup.9 represents a hydrogen atom, carboxyl group or
alkoxycarbonyl group having 1 to 6 carbon atoms and R.sup.a
represents a group represented by any of the following (A1) to
(A12): 53wherein, R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group-or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9) , (A10) or (A11), R.sup.5 is not a
halogen atom.
23. The 3-aminothiophene derivative according to claim 22 wherein
R.sup.a represents (A1), (A2), (A3), (A4) or (A9).
24. The 3-aminothiophene derivative according to claim 23 wherein
R.sup.a represents (A1), (A2), (A3) or (A4).
25. The 3-aminothiophene derivative according to claim 24 wherein
R.sup.a represents (A1).
26. The 3-aminothiophene derivative according to claim 25 wherein
R.sup.5 represents a trifluoromethyl group and R.sup.7 represents a
hydrogen atom.
27. A mixture of 2-alkenyl-3-aminothiophene derivatives containing
compounds represented by the formulae (4a)', (4b)', (4c)' and (4d)'
respectively: 54wherein, R.sup.b represents a hydrogen atom, alkyl
group or alkoxy group which may be substituted, aromatic or
non-aromatic hydrocarbon ring which may be substituted or aromatic
or non-aromatic heterocyclic ring which may be substituted, and
each of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a independently
represents a hydrogen atom, straight or branched alkyl group having
1 to 12 carbon 5 atoms or straight or branched alkenyl group having
1 to 12 carbon atoms, and R.sup.1a and R.sup.2a, R.sup.3a and
R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a and R.sup.4a R.sup.2a and
R.sup.3a or R.sup.2a and R.sup.4a may together form a cycloalkyl
group or cycloalkenyl group, excepting the case in which R.sup.b
represents a group represented by any of the following (A1) to
(A12): 55wherein, R.sup.5represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom, and the case in which R.sup.b represents a
tert-butoxy group and R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a all
represent a hydrogen atom being excluded.
28. The mixture according to claim 27 wherein R.sup.b represents a
hydrogen atom, alkyl group or alkoxy group which may be substituted
or phenyl group which may be substituted.
29. The mixture according to claim 28 wherein each of R.sup.1a,
R.sup.2a and R.sup.3a represents a hydrogen atom and R.sup.4a
represent an isopropyl group.
30. A 2-alkyl-3-aminothiophene derivative represented by the
formula (1b): 56wherein, R.sup.b represents a hydrogen atom, alkyl
group or alkoxy group which may be substituted, aromatic or
non-aromatic hydrocarbon ring which may be substituted or aromatic
or non-aromatic heterocyclic ring which may be substituted, and
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently
represents a hydrogen atom or straight or branched alkyl group
having 1 to 12 carbon atoms, and R.sup.1 and R.sup.2, R.sup.3 and
R.sup.4, R.sup.1 and R.sup.3, R.sup.1 and R, R.sup.2 and R.sup.3 or
R.sup.2 and R.sup.4 may together form a cycloalkyl group, excepting
the case in which R.sup.b represents a group represented by any of
the following (A1) to (A12): 57wherein, R.sup.5 represents a
trifluoromethyl group, difluoromethyl group, methyl group, ethyl
group or halogen atom, R.sup.1 represent a hydrogen atom, methyl
group, trifluoromethyl group, halogen atom, methoxy group or amino
group, R.sup.7 represents a hydrogen atom, halogen atom, methyl
group or methoxy group, R.sup.8represents a hydrogen atom, methyl
group, ethyl group or halogen atom, and n represents an integer
from 0 to 2, and herein, in the case of (A9), (A10) or (A11),
R.sup.5 is not a halogen atom.
31. The 2-alkenyl-3-aminothiophene derivative according to claim 30
wherein R.sup.b represents a hydrogen atom, alkyl group or alkoxy
group which may be substituted or phenyl group which may be
substituted.
32. The mixture according to claim 31 wherein each of R.sup.1,
R.sup.2 and R.sup.3 represents a hydrogen atom and R.sup.4
represent an isopropyl group.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relate to a process for preparing a
2-alkyl-3-aminothiophene derivative useful as an agricultural
fungicide or intermediate thereof, and novel 3-aminothiophene
derivatives.
[0003] 2. Description of the Related Art
[0004] Japanese Patent Application Laid-Open (JP-A) No. 9-235282
(EP-A 0737682 A1) describes that a certain kind of
2-alkyl-3-aminothiophene derivative has strong control effect
against various plant disease damages. For producing this
2-alkyl-3-aminothiophene derivative, there is envisaged a method in
which an alkyl group is directly introduced into 2-position of a
3-aminothiophene derivative. For example, Tetrahedron Letters, 34,
5715 to 5718 (1993) teaches that 2-alkyl-3-aminothiophene is
obtained by reacting 3-aminothiophene with various aldehydes in the
presence of p-toluenesulfonic acid and selenophenol. 2
[0005] (wherein, R' represents an alkyl group.)
[0006] However, in this literature, there is utterly no description
in which 2-alkyl-3-aminothiophene having a secondary alkyl group is
synthesized. For obtaining a 2-alkyl-3-aminothiophene derivative
having a secondary alkyl group using a synthesis method described
in this literature, 3-aminothiophene derivative has to be reacted
with ketones. However, when the present inventors substituted an
aldehyde for the ketone and conducted this reaction,
3-aminothiophene was decomposed and the intended
2-alkyl-3-aminothiophene derivative or 2-alkenyl-3-aminothiophene
derivative could not be obtained (Reference Example 1). Further,
this literature includes a problem as an industrial production
method since the reaction uses as a reducing agent selenophenol
which is not easily obtained industrially.
[0007] Further, Tetrahedron 5, 9055 to 9066 (1998) teaches that
when an aldehyde having branching at a-position is reacted with
3-aminothiophene or 3-aminothiophene derivative, an primary alkenyl
group is introduced. However, this literature includes utterly no
description regarding reactions using a ketone.
SUMMARY OF THE INVENTION
[0008] The object of the present invention is to provide a process
for industrially preparing a compound having a secondary alkyl
group among 2-alkyl-3-aminothiophene derivatives useful as an
agricultural and horticultural fungicide or intermediate thereof by
reacting a 3-aminothiophene derivative with a ketone.
[0009] The present inventors have studied for solving the
above-described problems and found that when a 3-aminothiophene
derivative in which an amino group at 3-position is substituted
with an amide bond or carbamate bond is reacted with various
ketones in the presence of an acid, a secondary alkenyl group is
introduced into 2-position of the 3-aminothiophene derivative, and
when this alkenyl group is reduced by an industrially possible
method, it can be converted to an alkyl group easily, completing
the invention.
[0010] Namely, the aspect of the present invention relates to
following (1) to (6).
[0011] (1) A process for preparing a 2-alkyl-3-aminothiophene
derivative represented by the formula (1): 3
[0012] wherein, R represents a hydrogen atom, alkyl group or alkoxy
group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted, aromatic or non-aromatic
heterocyclic ring which may be substituted, each of R', R.sup.2,
R.sup.3 and R.sup.4 independently represents a hydrogen atom or
straight or branched alkyl group having 1 to 12 carbon atoms, and
R' and R.sup.2, R.sup.3 and R.sup.4, R.sup.1 and R.sup.3, R.sup.1
and R.sup.4, R.sup.2 and R.sup.3 or R.sup.2 and R.sup.4 may
together form a cycloalkyl group, comprising reacting a compound
represented by the formula (2): 4
[0013] wherein, R is as defined above, with a compound represented
by the formula (3): 5
[0014] wherein, each of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a
independently represents a hydrogen atom, straight or branched
alkyl group having 1 to 12 carbon atoms or straight or branched
alkenyl group having 1 to 12 carbon atoms, and R.sup.1a and
R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a
and R.sup.4a, R.sup.2a and R.sup.3a or R.sup.2a and R.sup.4a may
together form a cycloalkyl group or cycloalkenyl group,
[0015] in the presence of an acid, and reducing the resulted
reaction mixture.
[0016] (2) A process for preparing a mixture of
2-alkenyl-3-aminothiophene derivatives containing compounds
represented by the formulae (4a), (4b), (4c) and (4d) respectively:
6
[0017] wherein, R represents a hydrogen atom, alkyl group or alkoxy
group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted, aromatic or non-aromatic
heterocyclic ring which may be substituted, each of R.sup.1a,
R.sup.2a, R.sup.3a and R.sup.4a independently represents a hydrogen
atom, straight or branched alkyl group having 1 to 12 carbon atoms
or straight or branched alkenyl group having 1 to 12 carbon atoms,
and R.sup.1a and R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and
R.sup.3a, R.sup.1a and R.sup.4a, R.sup.1a and R.sup.3a or R.sup.2a
and R.sup.4a may together form a cycloalkyl group or cycloalkenyl
group,
[0018] comprising reacting a compound represented by the formula
(2): 7
[0019] wherein, R is as defined above, with a compound represented
by the formula (3): 8
[0020] wherein, R.sup.1a to R.sup.4a are as define above, in the
presence of an acid.
[0021] (3) A process for preparing 2-alkyl-3-aminothiophene
represented by the formula (1a): 9
[0022] wherein, R.sup.a represents a group represented by any of
the following (A1) to (A12): 10
[0023] wherein, R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom, R
represent a hydrogen atom, methyl group, trifluoromethyl group,
halogen atom, methoxy group or amino group, R.sup.7 represents a
hydrogen atom, halogen atom, methyl group or methoxy group,
R.sup.8represents a hydrogen atom, methyl group, ethyl group or
halogen atom, and n represents an integer from 0 to 2, and herein,
in the case of (A9), (A10) or (A11), R.sup.5 is not a halogen atom,
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently
represents a hydrogen atom or straight or branched alkyl group
having 1 to 12 carbon atoms, and R.sup.1 and R.sup.2, R.sup.3 and
R.sup.4, R.sup.1 and R.sup.3, R.sup.1 and R.sup.4, R.sup.2 and
R.sup.3 or R.sup.2 and R.sup.4 may together form a cycloalkyl
group, comprising reacting a compound represented by the formula
(2): 11
[0024] wherein, R represents a hydrogen atom, alkyl group or alkoxy
group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted or aromatic or
non-aromatic heterocyclic ring which may be substituted, with a
compound represented by the formula (3): 12
[0025] wherein, each of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a
independently represents a hydrogen atom, straight or branched
alkyl group having 1 to 12 carbon atoms or straight or branched
alkenyl group having 1 to 12 carbon atoms, and R.sup.1a and
R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a
and R.sup.4a, R.sup.2a and R.sup.3a or R.sup.2a and R.sup.4a may
together form a cycloalkyl group or cycloalkenyl group, in the
presence of an acid, reducing the resulted reaction mixture to
obtain a compound represented by the formula (1): 13
[0026] wherein, R, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined above, further hydrolyzing the resultant compound under
acidic or alkaline condition to obtain a compound represented by
the formula (5): 14
[0027] wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
defined above, and reacting this compound with a compound
represented by the formula (8a): 15
[0028] wherein, R.sup.a is as defined above.
[0029] (4) A 3-aminothiophene derivative represented by the formula
(6a): 16
[0030] wherein, R.sup.9 represents a hydrogen atom, carboxyl group
or alkoxycarbonyl group having 1 to 6 carbon atoms and R.sup.a
represents a group represented by any of the following (A1) to
(A12): 17
[0031] wherein, R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom.
[0032] (5) A mixture of 2-alkenyl-3-aminothiophene derivatives
containing compounds represented by the formulae (4a)', (4b)',
(4c)' and (4d)' respectively: 18
[0033] wherein, R.sup.b represents a hydrogen atom, alkyl group or
alkoxy group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted or aromatic or
non-aromatic heterocyclic ring which may be substituted, and each
of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a independently
represents a hydrogen atom, straight or branched alkyl group having
1 to 12 carbon atoms or straight or branched alkenyl group having 1
to 12 carbon atoms, and R.sup.1a and R.sup.2a, R.sup.3a and
R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a and .sup.4a R.sup.2a and
R.sup.3a or R.sup.2a and R.sup.4a may together form a cycloalkyl
group or cycloalkenyl group, excepting the case in which R.sup.b
represents a group represented by any of the following (A1) to
(A12): 19
[0034] wherein, R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom, R'
represent a hydrogen atom, methyl group, trifluoromethyl group,
halogen atom, methoxy group or amino group, R.sup.7 represents a
hydrogen atom, halogen atom, methyl group or methoxy group,
R.sup.8represents a hydrogen atom, methyl group, ethyl group or
halogen atom, and n represents an integer from 0 to 2, and herein,
in the case of (A9), (A10) or (A11), R.sup.5 is not a halogen atom,
and the case in which R.sup.b represents a tert-butoxy group and
R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a all represent a hydrogen
atom being excluded. (6) A 2-alkyl-3-aminothiophene derivative
represented by the formula (1b): 20
[0035] wherein, R.sup.b represents a hydrogen atom, alkyl group or
alkoxy group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted or aromatic or
non-aromatic heterocyclic ring which may be substituted, and each
of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently represents a
hydrogen atom or straight or branched alkyl group having 1 to 12
carbon atoms, and R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.1
and R.sup.3, R.sup.1 and R.sup.4, R.sup.2 and R.sup.3 or R.sup.2
and R.sup.4 may together form a cycloalkyl group, excepting the
case in which R.sup.b represents a group represented by any of the
following (A1) to (A12): 21
[0036] wherein, R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0037] In the present invention, R may represent a hydrogen atom,
and examples of an unsubstituted or substituted alkyl group
represented by R include alkyl groups such as a methyl group, ethyl
group, propyl group, isopropyl group, butyl group, isobutyl group,
sec-butyl group, tert-butyl group, hexyl group, decyl group,
methoxymethyl group, ethoxymethyl group, phenylmethyl group and the
like, examples of an unsubstituted or substituted alkoxy group
represented by R include alkoxy groups such as a methoxy group,
ethoxy group, propoxy group, isopropoxy group, cyclopropoxy group,
butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group,
cyclohexyloxy group, hexyloxy group, benzyloxy group and the like,
examples of an unsubstituted or substituted aromatic hydrocarbon
ring represented by R include a phenyl group and substituted phenyl
groups, the substituent on the substituted phenyl groups being, for
example, an alkyl group such as a methyl group, ethyl group, propyl
group, isopropyl group and the like, an alkoxy group such as a
methoxy group, ethoxy group, propoxy group, isopropoxy group and
the like, a halogen atom such as- chlorine atom, bromine atom,
fluorine atom and iodine atom, or a nitro group, cyano group, amino
group or the like; examples of an unsubstituted or substituted
non-aromatic hydrocarbon ring represented by R include non-aromatic
hydrocarbon rings such as a cyclopropyl group, cyclopentyl group,
cyclohexyl group, cyclohexenyl group and the like, examples of an
unsubstituted or substituted aromatic heterocyclic ring represented
by R include a pyrazolyl group, thiazolyl group, isothiazolyl
group, furyl group, thienyl group, pyridyl group, pyrazinyl group,
oxazolyl group, pyrrolyl group, substituted pyrazolyl group,
substituted thiazolyl group, substituted isothiazolyl group,
substituted furyl group, substituted thienyl group, substituted
pyridyl group, substituted pyrazinyl group, substituted oxazolyl
group, substituted pyrrolyl group and the like, the substituent on
the substituted pyrazolyl group, substituted thiazolyl group,
substituted isothiazolyl group, substituted furyl group,
substituted thienyl group, substituted pyridyl group, substituted
pyrazinyl group, substituted oxazolyl group and substituted
pyrrolyl group being, for example, an alkyl group such as a methyl
group, ethyl group, propyl group, isopropyl group and the like, a
haloalkyl group such as a trifluoromethyl group, difluoromethyl
group and the like, a halogen atom such as fluorine atom, chlorine
atom, bromine atom and iodine atom, or an amino group, cyano group
or the like; and examples of an unsubstituted or substituted
non-aromatic heterocyclic ring represented by R include a
dihydropyranyl group, dihydrofuryl group, tetrahydrofuryl group,
2,3-dihydro-1,4-oxathii- n-5-yl group, substituted dihydropyranyl
group, substituted dihydrofuryl group, substituted tetrahydrofuryl
group, substituted 2,3-dihydro-1,4-oxathiin-5-yl group and the
like, the substituent on the substituted dihydropyranyl group,
substituted dihydrofuryl group, substituted tetrahydrofuryl group
and substituted 2,3-dihydro-1,4-oxathii- n-5-yl group being, for
example, an alkyl group such as a methyl group, ethyl group, propyl
group, isopropyl group and the like, a haloalkyl group such as a
trifluoromethyl group, difluoromethyl group and the like, a halogen
atom such as fluorine atom, chlorine atom, iodine atom and the
like, or an amino group, cyano group or the like. When R represents
(A1), 4-pyrazolyl groups in which R.sup.5 at 3-position represents
a trifluoromethyl group, difluoromethyl group, methyl group, ethyl
group or halogen atom and R.sup.7 at 5-position represents a
hydrogen atom, halogen atom, methyl group or methoxy group and
methyl is substituted on 1-position are listed, examples thereof
including a 1,3-dimethyl-4-pyrazolyl group,
5-chloro-1,3-dimethyl-4-pyrazolyl group,
5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl group,
1-methyl-3-trifluoromethyl-4-pyrazolyl group,
1-methyl-3-difluoromethyl-4- -pyrazolyl group,
1-methyl-3-ethyl-4-pyrazolyl group, 1-methyl-3-chloro-4-pyrazolyl
group, 1-methyl-3-trifluoromethyl-5-methoxy- -4-pyrazolyl group and
the like, when R represents (A2), 5-thiazolyl groups in which
R.sup.5 at 4-position represents a trifluoromethyl group,
difluoromethyl group; methyl group, ethyl group or halogen atom and
R.sup.6 at 2-position represents a hydrogen atom, methyl group,
trifluoromethyl group, halogen atom, methoxy group or amino group
are listed, examples thereof including a
2-methyl-4-trifluoromethyl-5-thiazol- yl group,
2-methyl-4-difluoromethyl-5-thiazolyl group,
4-trifluoromethyl-5-thiazolyl group, 2,4-dimethyl-5-thiazolyl
group, 2-methyl-4-ethyl-5-thiazolyl group,
2-amino-4-methyl-5-thiazolyl group, 2-methoxy-4-methyl-5-thiazolyl
group, 2-chloro-4-methyl-5-thiazolyl group and the like, when R
represents (A3), 3-furyl groups in which R.sup.5 at 2-position
represents a trifluoromethyl group, difluoromethyl group, methyl
group, ethyl group or halogen atom and R.sup.8 at 5-position
represents a hydrogen atom, methyl group, ethyl group or halogen
atom are listed, examples thereof including a 2-methyl-3-furyl
group, 2,5-dimethyl-3-furyl group, 2-chloro-3-furyl group,
2-trifluoromethyl-3-furyl group and the like, when R represents
(A4), 2-thienyl groups in which R.sup.5 at 3-position represents a
trifluoromethyl group, difluoromethyl group, methyl group, ethyl
group or halogen atom and R.sup.8 at 5-position represents a
hydrogen atom, methyl group or halogen atom are listed, examples
thereof including a 3-methyl-2-thienyl group,
3,5-dimethyl-2-thienyl group, 3-chloro-2-thienyl group,
3-iodo-2-thienyl group and the like, when R represents (A5), phenyl
groups in which R.sup.5 at 2-position represents a trifluoromethyl
group, difluoromethyl group, methyl group, ethyl group or halogen
atom are listed, examples thereof including a
2-trifluoromethylphenyl group, 2-difluoromethylphenyl group,
2-methylphenyl group, 2-ethylphenyl group, 2-fluorophenyl group,
2-chlorophenyl group, 2-bromophenyl group, 2-iodophenyl group, when
R represents (A6), 3-pyridyl groups in which R.sup.5 at 2-position
represents a trifluoromethyl group, difluoromethyl group, methyl
group, ethyl group or halogen atom are listed, examples thereof
including a 2-trifluoromethyl-3-pyridyl group,
2-difluoromethyl-3-pyridyl group, 2-methyl-3-pyridyl group,
2-ethyl-3-pyridyl group, 2-fluoro-3-pyridyl group,
2-chloro-3-pydiryl group, 2-bromo-3-pyridyl group and
2-iodo-3-pyridyl group, when R represents (A7), examples thereof
include a 2-chloro-3-pyradinyl group, when R represents (A8),
4-thienyl groups in which R.sup.5 at 3-position represents a
trifluoromethyl group, difluoromethyl group, methyl group, ethyl
group or halogen atom are listed, examples thereof including a
3-trifluoromethyl-4-thienyl group, 3-difluoromethyl-4-thienyl
group, 3-methyl-4-thienyl group, 3-ethyl-4-thienyl group,
3-fluoro-4-thienyl group, 3-chloro-4-thienyl group,
3-bromo-4-thienyl group and 3-iodo-4-thienyl group, when R
represents (A9), 3,4-dihydro-2H-pyran-5-yl groups in which R.sup.5
at 6-position represents a trifluoromethyl group, difluoromethyl
group, methyl group or ethyl group are listed, examples thereof
including a 6-trifluoromethyl-3,4-dihydro-2H-pyran-5-yl group,
6-difluoromethyl-3,4-dihydro-2H-pyran-5-yl group,
6-methyl-3,4-dihydro-2H- -pyran-5-yl group and
2-ethyl-3,4-dihydro-2H-pyran-5-yl group, and when R represents
(A10), 2,3-dihydro-1,4-oxathiin-5-yl groups,
2,3-dihydro-1,4-oxathiin-4-oxide-5-yl groups or
2,3-dihydro-1,4-oxathiin-- 4,4-dioxide-5-yl groups in which R.sup.5
at 6-position represents a trifluoromethyl group, difluoromethyl
group, methyl group or ethyl group are listed, examples thereof
including a 6-methyl-2,3-dihydro-1,4-oxathii- n-5-yl group,
6-methyl-2,3-dihydro-1,4-oxathiin-4-oxide-5-yl group,
6-methyl-2,3-dihydro-1,4-oxathiin-4,4-dioxide-5-yl group and the
like. When R represents (All), 2,3-dihydro-4-furyl groups in which
R.sup.5 at 5-position represents a trifluoromethyl group,
difluoromethyl group, methyl -group or ethyl group are listed,
examples thereof including a 5-trifluoromethyl-2,3-dihydro-4-furyl
group, 5-difluoromethyl-2,3-dihydro- -4-furyl group,
5-methyl-2,3-dihydro-4-furl group and 5-ethyl-2,3-dihydro-4-furyl
group, and when R represents (A12), 4-isothiazolyl groups in which
R.sup.5 at 3-position represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom are
listed, examples thereof including a
3-trifluoromethyl-4-isothiazolyl group,
3-difluoromethyl-4-isothiazolyl group, 3-methyl-4-isothiazolyl
group, 3-ethyl-4-isothiazolyl group, 3-fluoro-4-isothiazolyl group,
3-chloro-4-isothiazolyl group, 3-bromo-4-isothiazolyl group and
3-iodo-4-isothiazolyl group.
[0038] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may represent a
hydrogen atom, and examples of an alkyl group represented by
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 include straight or branched
alkyl groups having 1 to 12 carbon atoms such as a methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, sec-butyl group, tert-butyl group, hexyl group, decyl group,
dodecyl group and the like.
[0039] R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a may represent a
hydrogen atom, and examples of an alkyl group represented by
R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a include straight or
branched alkyl groups having 1 to 12 carbon atoms such as a methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
isobutyl group, sec-butyl group, tert-butyl group, hexyl group,
decyl group, dodecyl group and the like, and examples of an alkenyl
group represented by R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a
include straight or branched alkenyl groups having 1 to 12 carbon
atoms such as an ethenyl group, 1-propenyl group, 2-propenyl group,
isopropenyl group, 1-butenyl group, 2-butenyl group, 1-hexenyl
group, 2-dodecenyl group and the like.
[0040] R.sup.9 may represent a hydrogen atom or carboxyl group, and
examples of an alkoxycarbonyl group represented by R.sup.9 include
alkoxycarbonyl groups having 1 to 6 carbon atoms such as a
methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl
group, hexyloxycarbonyl group and the like.
[0041] When R.sup.a represents (A1), 4-pyrazolyl groups in which
R.sup.5 at 3-position represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom and
R.sup.7 at 5-position represents a hydrogen atom, halogen atom,
methyl group or methoxy group and methyl is substituted on
1-position are listed, examples thereof including a
1,3-dimethyl-4-pyrazolyl group, 5-chloro-1,3-dimethyl-4-pyraz- olyl
group, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl group,
1-methyl-3-trifluoromethyl-4-pyrazolyl group,
1-methyl-3-difluoromethyl-4- -pyrazolyl group,
1-methyl-3-ethyl-4-pyrazolyl group, 1-methyl-3-chloro-4-pyrazolyl
group, 1-methyl-3-trifluoromethyl-5-methoxy- -4-pyrazolyl group and
the like, when R.sup.a represents (A2), 5-thiazolyl groups in which
R.sup.5 at 4-position represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom and
R.sup.6 at 2-position represents a hydrogen atom, methyl group,
trifluoromethyl group, halogen atom, methoxy group or amino group
are listed, examples thereof including a
2-methyl-4-trifluoromethyl-5-thiazol- yl group,
2-methyl-4-difluoromethyl-5-thiazolyl group,
4-trifluoromethyl-5-thiazolyl group, 2, 4-dimethyl-5-thiazolyl
group, 2-methyl-4-ethyl-5-thiazolyl group,
2-amino-4-methyl-5-thiazolyl group, 2-methoxy-4-methyl-5-thiazolyl
group, 2-chloro-4-methyl-5-thiazolyl group and the like, when
R.sup.a represents (A3), 3-furyl groups in which R.sup.5 at
2-position represents a trifluoromethyl group, difluoromethyl
group, methyl group, ethyl group or halogen atom and R.sup.3 at
5-position represents a hydrogen atom, methyl group, ethyl group or
halogen atom are listed, examples thereof including a
2-methyl-3-furyl group, 2,5-dimethyl-3-furyl group,
2-chloro-3-furyl group, 2-trifluoromethyl-3-furyl group and the
like, when R.sup.a represents (A4), 2-thienyl groups in which
R.sup.5 at 3-position represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom and
R.sup.8 at 5-position represents a hydrogen atom, methyl group or
halogen atom are listed, examples thereof including a
3-methyl-2-thienyl group, 3,5-dimethyl-2-thienyl group,
3-chloro-2-thienyl group, 3-iodo-2-thienyl group and the like, when
R.sup.a represents (A5), phenyl groups in which R.sup.5 at
2-position represents a trifluoromethyl group, difluoromethyl
group, methyl group, ethyl group or halogen atom are listed,
examples thereof including a 2-trifluoromethylphenyl group,
2-difluoromethylphenyl group, 2-methylphenyl group, 2-ethylphenyl
group, 2-fluorophenyl group, 2-chlorophenyl group, 2-bromophenyl
group, 2-iodophenyl group, when R.sup.a represents (A6), 3-pyridyl
groups in which R.sup.5 at 2-position represents a trifluoromethyl
group, difluoromethyl group, methyl group, ethyl group or halogen
atom are listed, examples thereof including a
2-trifluoromethyl-3-pyridyl group, 2-difluoromethyl-3-pyridyl
group, 2-methyl-3-pyridyl group, 2-ethyl-3-pyridyl group,
2-fluoro-3-pyridyl group, 2-chloro-3-pydiryl group,
2-bromo-3-pyridyl group and 2-iodo-3-pyridyl group, when R.sup.a
represents (A7), examples thereof include a
2-chloromethyl-3-pyradinyl group, when R.sup.a represents (A8),
4-thienyl groups in which R' at 3-position represents a
trifluoromethyl group, difluoromethyl group, methyl group, ethyl
group or halogen atom are listed, examples thereof including a
3-trifluoromethyl-4-thienyl group, 3-difluoromethyl-4-thienyl
group, 3-methyl-4-thienyl group, 3-ethyl-4-thienyl group,
3-fluoro-4-thienyl group, 3-chloro-4-thienyl group,
3-bromo-4-thienyl group and 3-iodo-4-thienyl group, when R.sup.a
represents (A9), 3,4-dihydro-2H-pyran-5-yl groups in which R.sup.5
at 6-position represents a trifluoromethyl group, difluoromethyl
group, methyl group or ethyl group are listed, examples thereof
including a 6-trifluoromethyl-3,4-dihydro-2H-pyran-5-yl group,
6-difluoromethyl-3,4-dihydro-2H-pyran-5-yl group,
6-methyl-3,4-dihydro-2H- -pyran-5-yl group and
2-ethyl-3,4-dihydro-2H-pyran-5-yl group, and when R.sup.a
represents (A10), 2,3-dihydro-1,4-oxathiin-5-yl groups,
2,3-dihydro-1,4-oxathiin-4-oxide-5-yl groups or
2,3-dihydro-1,4-oxathiin-- 4,4-dioxide-5-yl groups in which R.sup.5
at 6-position represents a trifluoromethyl group, difluoromethyl
group, methyl group or ethyl group are listed, examples thereof
including a 6-methyl-2,3-dihydro-1,4-oxathii- n-5-yl group,
6-methyl-2,3-dihydro-1,4-oxathiin-4-oxide-5-yl group,
6-methyl-2,3-dihydro-1,4-oxathiin-4,4-dioxide-5-yl group and the
like. When R.sup.a represents (A11), 2,3-dihydro-4-furyl groups in
which R.sup.5 at 5-position represents a trifluoromethyl group,
difluoromethyl group, methyl group or ethyl group are listed,
examples thereof including a 5-trifluoromethyl-2,3-dihydro-4-furyl
group, 5-difluoromethyl-2,3-dihyd- ro-4-furyl group,
5-methyl-2,3-dihydro-4-furl group and 5-ethyl-2,3-dihydro-4-furyl
group, and when R.sup.a represents (A12), 4-isothiazolyl groups in
which R.sup.5 at 3-position represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom are
listed, examples thereof including a
3-trifluoromethyl-4-isothiazolyl group,
3-difluoromethyl-4-isothiazolyl group, 3-methyl-4-isothiazolyl
group, 3-ethyl-4-isothiazolyl group, 3-fluoro-4-isothiazolyl group,
3-chloro-4-isothiazolyl group, 3-bromo-4-isothiazolyl group and
3-iodo-4-isothiazolyl group.
[0042] R.sup.b is a substituent in which R.sup.a is excluded from
R.
[0043] A process for preparing a 2-alkyl-3-aminothiophene
derivative and a method for producing a 3-aminothiophene derivative
of the present invention will be described in detail below.
[0044] First, a reaction in which a secondary alkenyl group is
introduced into 2-position of a 3-aminothiophene derivative and
further this alkenyl group is converted to an alkyl group will be
explained. For explaining this reaction in detail, it is divided
into two steps and explained. However, the first step and the
second step can also be conducted continuously, and the two-step
reaction is not necessarily required.
[0045] In the first step reaction, a compound of the formula (2) is
reacted with a compound of the formula (3) in the presence of an
acid to produce a mixture of 2-alkenyl-3-aminothiophenes typified
by the formulae (4a) to (4d). 22
[0046] wherein, R, R.sup.1a to R.sup.4a are as defined above.
[0047] The mixture of 2-alkenyl-3-aminothiophenes typified by the
formulae (4a) to (4d) is constituted by the 4 species of compounds
at the maximum. For example, when R.sup.1a to R.sup.4a are all
different in the compound represented by the formula (3), the
mixture includes four compounds. When the compound represented by
the formula (3) is 4-methyl-2-pentanone, the mixture comprises
three compounds. And when the compound represented by the formula
(3) is cyclohexanone, only one compound typified by the formulae
(4a) to (4d) is obtained.
[0048] The use amount of a compound represented by the formula (3)
in the first step reaction is usually from 0.5 to 100.0 mol,
preferably from 1.0 to 30.0 mol, particularly preferable from 1.0
to 10.0 per 1 mol of a compound of the formula (2).
[0049] Examples of a solvent used if necessary in the first step
reaction include aliphatic hydrocarbons such as hexane, petroleum
ether and the like, aromatics such as benzene, toluene,
chlorobenzene, anisole and the like, alcohols such as methanol,
ethanol and the like, ethers such as dioxane, tetrahydrofuran,
diethyl ether and the like, nitriles such as acetonitrile,
propionitrile and the like, esters such as ethyl acetate and the
like, and halogenated hydrocarbons such as dichloromethane,
chloroform, 1,2-dichloroethane and the like, and mixed solvents
thereof are also used. Also, a compound represented by the formula
(3) can be used as a solvent. The use amount of a solvent in the
first step reaction is usually from 0.1 to 200 ml, preferably from
1 to 50 ml, more preferably from 1 to 20 ml based on 1 g of a
compound typified by the formula (2).
[0050] The first step reaction is conducted in the presence of an
acid, and examples of the acid include mineral acids such as
sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic
acid, phosphoric acid and the like, organic weak acids such as
acetic acid, propionic acid and the like, organic strong acids such
as p-toluenesulfonic acid, methanesulfonic acid and the like, solid
acids such as zeolite and the like, Lewis acids such as aluminum
chloride, zinc chloride and the like, ion-exchanged resins and the
like. Preferable are a mineral acid such as sulfuric acid,
hydrobromic acid and the like and an organic acid such as
p-toluenesulfonic acid, methanesulfonic acid and the like, and
particularly preferable are sulfuric acid and p-toluenesulfonic
acid. The use amount of these acids is usually from 0.001 to 10
mol, preferably from 0.01 to 1 mol based on 1 mol of a compound
represented by the formula (2).
[0051] The reaction temperature in the first step reaction is
usually from 0 to 300.degree. C., preferably from 40 to 180.degree.
C., more preferably from 70 to 130.degree. C., and the reaction
time is usually from 0.1 to 100 hours, preferably from 1 to 36
hours.
[0052] Regarding various conditions in the first step reaction,
namely, the use amounts of compounds of the general formulae (2)
and (3), the kind and use amount of a solvent, the kind and use
amount of an acid, the reaction temperature and the reaction time,
numerical values within usual ranges, preferable ranges and more or
particularly preferable ranges for respective conditions may be
appropriately selected and combined.
[0053] Further, in the first step reaction water is formed with the
compounds represented by the formulae (4a) to (4d). Removing the
formed water, if necessary, can promote the progress of the
reaction. Removing the formed water can be conducted by adding a
drying agent such as magnesium sulfate anhydride, sodium sulfate
anhydride or the like, or by carrying out azeotropic
dehydration.
[0054] The reaction temperature in the first step reaction should
beset at a temperature wherein the reaction can progress, and a
catalyst used in the first step reaction should also be
appropriately selected and used so that the reaction can progress.
Further, as the catalyst used in the first step reaction, catalysts
which can be used without problems at reaction temperatures at
which the reaction can progress should be appropriately selected
for use.
[0055] Among mixtures of 2-alkenyl-3-aminothiophene derivatives
represented by the general formulae (4a) to (4d) which can be
obtained in this first step reaction, the following is a mixture
composed of novel compounds. 23
[0056] wherein, R.sup.b represents a hydrogen atom, alkyl group or
alkoxy group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted or aromatic or
non-aromatic heterocyclic ring which may be substituted, and each
of R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a independently
represents a hydrogen atom, straight or branched alkyl group having
1 to 12 carbon atoms or straight or branched alkenyl group having 1
to 12 carbon atoms, and R.sup.1a and R.sup.2a, R.sup.3a and
R.sup.4a, R.sup.1a and R.sup.3a, R.sup.1a and R.sup.4a, R.sup.2a
and R.sup.3a or R.sup.2a and R.sup.4a may together form a
cycloalkyl group, excepting the case in which R represents a group
represented by any of the following (A1) to (A12): 24
[0057] wherein, R.sup.5represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2,and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom, and the case in which R represents a tert-butoxy
group and R.sup.1a, R.sup.2a, R.sup.3a and R.sup.4a all represent a
hydrogen atom being excluded.
[0058] In the second step reaction, a mixture composed of compounds
typified by the formulae (4a) to (4d) is reduced to produce a
2-alkyl-3-aminothiophene derivative represented by the formula (1).
25
[0059] group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted, aromatic or non-aromatic
heterocyclic ring which may be substituted, each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 independently represents a hydrogen
atom or straight or branched alkyl group having 1 to 12 carbon
atoms, and R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.1 and
R.sup.3, R.sup.1 and R.sup.4, R.sup.2 and R.sup.3 or R.sup.2 and
R.sup.4 may together form a cycloalkyl group, each of R.sup.1a,
R.sup.2a, R.sup.3a and R.sup.4a independently represents a hydrogen
atom, straight or branched alkyl group having 1 to 12 carbon atoms
or straight or branched alkenyl group having 1 to 12 carbon atoms,
and R.sup.1a and R.sup.2a, R.sup.3a and R.sup.4a, R.sup.1a and
R.sup.3a, R.sup.1a and R.sup.4a, R.sup.2a and R.sup.3a or R.sup.2a
and R.sup.4a may together form a cycloalkyl group or cycloalkenyl
group.
[0060] The reduction method is not particularly restricted, and
there is usually applied a method in which a double bond is reduced
to a single bond (for example, Shin Jikken Kagaku Koza, vol. 15,
Oxidation and Reduction [II], Maruzen (1977)), and catalytic
reduction is industrially preferable.
[0061] As a catalyst used in catalytic reaction, there can be used
metal catalyst usually used in catalytic reduction, for example,
nickel, palladium, platinum, rhodium, ruthenium, cobalt, chromium,
copper, lead and the like. And these metals can be used as mixture.
While these catalysts can be used in the form of metal, they are
usually supported on a carrier such as carbon, barium sulfate,
silica gel, aluminum, celite and the like, and alternatively,
nickel, cobalt, copper and the like can be used in the form of a
Raney catalyst.
[0062] The content of a catalyst used in catalytic reduction is
usually from 3 to 20%, and the use amount is not particularly
restricted and the catalyst is used in an amount of usually from 1
to 100% by weight, preferably from 1 to 30% by weight based on a
mixture composed of compounds typified by the formulae (4a) to
(4d).
[0063] Examples of a solvent used if necessary in the catalytic
reduction reaction of the second step include alcohols such as
methanol, ethanol and the like, aliphatic hydrocarbons such as
hexane, petroleum ether and the like, aromatics such as benzene,
toluene, anisole and the like, ethers such as dioxane,
tetrahydrofuran, diethyl ether and the like, esters such as ethyl
acetate and the like, aliphatic carboxylic acids such as acetic
acid, propionic acid and the like, aprotic polar solvents such as
dimethylformamide, dimethylsulfoxide and the like, and mixed
solvents thereof are also used. The use amount of a solvent in the
second step reaction is usually from 0.1 to 200 ml, preferably from
2 to 20 ml based on 1 g of a mixture composed of compounds typified
by the formulae (4a) to (4d).
[0064] The reaction temperature in the catalytic reduction of the
second step reaction is usually from 0 to 300.degree. C.,
preferably from 20 to 180.degree. C., and the reaction time is
usually from 0.5 to 100 hours, preferably from 1 to 48 hours.
[0065] The catalytic reduction reaction in the second step can be
carried out under atmospheric pressure of hydrogen or under
pressure of hydrogen. If the reaction is carried out under
pressure, the pressure of hydrogen is from 0.098 to 30 MPa,
preferably from 0.098 to 5.0 MPa.
[0066] Regarding various conditions in the catalytic reduction of
the second step reaction, namely, the kind and use amount of a
catalyst, the kind and use amount of a solvent, the reaction
temperature and the reaction time, and the reaction pressure,
numerical values within usual ranges and preferable ranges for
respective conditions may be appropriately selected and
combined.
[0067] Among mixtures of 2-alkyl-3-aminothiophene derivatives
represented by the general formula (1b) which can be obtained in
this second step reaction, the following is a novel compound.
26
[0068] wherein R.sup.b represents a hydrogen atom, alkyl group or
alkoxy group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted or aromatic or
non-aromatic heterocyclic ring which may be substituted. Each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 independently represents a
hydrogen atom or straight or branched alkyl group having 1 to 12
carbon atoms, and R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.1
and R.sup.3, R.sup.1 and R.sup.4, R.sup.2 and R.sup.3 or R.sup.2
and R.sup.4may together form a cycloalkyl group, excepting the case
in which R.sup.b represents a group represented by any of the
following (A1) to (A12): 27
[0069] wherein R.sup.5 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8 represents a hydrogen atom, methyl group, ethyl
group or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom.
[0070] Then, a method for synthesizing a 3-aminothiophene
derivative represented by the following formula (6): 28
[0071] wherein R.sup.9 represents a hydrogen atom, carboxyl group
or alkoxycarbonyl group having 1 to 6 carbon atoms, R represents a
hydrogen atom, alkyl group or alkoxy group which may be
substituted, aromatic or non-aromatic hydrocarbon ring which may be
substituted or aromatic or non-aromatic heterocyclic ring which may
be substituted, which is an intermediate in the present invention
will be described.
[0072] These compounds can be prepared for example by a method
shown in the following reaction formula 1, and examples of the
preparation method are not limited to this. The compound of the
formula (6) includes compounds of formulae (2), (9) and (10).
29
[0073] wherein R is as defined above, the formula (9) means the
case in which R.sup.9 in the formula (6) is an alkoxycarboyl group
having 1 to 6 carbon atoms, the formula (10) means the case in
which R.sup.9 in the formula (6) is a carboxyl group, the formula
(2) means the case in which R.sup.9 in the formula (6) is a
hydrogen atom, and R.sup.10 represents an alkyl group having 1 to 6
carbon atoms. Examples of the alkyl group represented by R.sup.10
include alkyl groups having 1 to 6 carbon atoms such as a methyl
group, ethyl group, propyl group, isopropyl group, butyl group,
tert-butyl group, hexyl group and the like.
[0074] A compound represented by the formula (9) can be prepared by
reacting 3-aminothiophene-2-carboxylates represented by the formula
(7) with a carboxylic acid halide represented by the formula (8) in
melted condition or in a solvent. Raw materials,
3-aminothiophene-2-carboxylates represented by the formula (7) can
be prepared by a known method, for example, a method described in
SYNTHETIC COMMUNICATION, 9(8), 731 to 734 (1979).
[0075] The use amount of a compound represented by the formula (8)
in this reaction is usually from 0.2 to 20.0 mol, preferably from
0.5 to 5 mol per 1 mol of a compound of the formula (7).
[0076] Examples of a solvent used if necessary in this reaction
include aliphatic hydrocarbons such as hexane, petroleum ether and
the like, aromatics such as benzene, toluene, chlorobenzene,
anisole and the like, ethers such as dioxane, tetrahydrofuran,
diethyl ether and the like, nitriles such as acetonitrile,
propionitrile and the like, esters such as ethyl acetate and the
like, halogenated hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane and the like, and aprotic polar solvents such as
dimethylformamide, dimethylsulfoxide,
1,3-dimethyl-2-imidazolidinone and the like, and mixed solvents
thereof are also used. The use amount of a solvent in this reaction
is usually from 0.1 to 200 ml, preferably from 1 to 20 ml based on
1 g of a compound represented by the formula (7)
[0077] This reaction may also be conducted in the presence of a
base, and examples of the base include hydroxides of alkali metals
and alkaline earth metals such as sodium hydroxide, potassium
hydroxide, calcium hydroxide and the like, oxides of alkali metals
and alkaline earth metals such as calcium oxide, magnesium oxide
and the like, metal hydride of alkali metals and alkaline earth
metals such as sodium hydride, calcium hydride and the like, alkali
metal amides such as lithium amide, sodium amide and the like,
carbonates of alkali metals and alkaline earth metals such as
sodium carbonate, calcium carbonate, magnesium carbonate and the
like, hydrogen carbonates of alkali metals and alkaline earth
metals such as sodium hydrogen carbonate, potassium hydrogen
carbonate and the like, alkylated alkali metals and alkaline earth
metals such as methyl lithium, phenyl lithium, methyl magnesium
chloride and the like, alkoxides of alkali metals and alkaline
earth metals such as sodium methoxide, sodium ethoxide,
potassium-t-butoxide, dimethoxy magnesium and the like, and various
organic bases such as triethylamine, pyridine and the like. The use
amount of these bases is usually from 0.1 to 20.0 mol, preferably
from 1 to 5.0 mol per 1 mol of carboxylic acid chlorides
represented by the formula (8).
[0078] The reaction temperature is usually from -70 to 250.degree.
C., preferably from 0 to 150.degree. C., and the reaction time is
usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.
[0079] Regarding various conditions in this reaction, namely, the
use amounts of compounds of the formulae (7) and (8), the kind and
use amount of a solvent, the kind and use amount of a base, the
reaction temperature and the reaction time, numerical values within
usual ranges and preferable ranges for respective conditions may be
appropriately selected and combined.
[0080] A compound represented by the formula (10) can be prepared
by hydrolyzing an ester of a compound represented by the formula
(9). The hydrolysis method is not particularly restricted, and
there is usually applied a method in which an ester is hydrolyzed
into a carboxylic acid (for example, Shin Jikken Kagaku Koza, vol.
14, Synthesis and Reaction of Organic Compound (II), Maruzen
(1977)).
[0081] (Method A):
[0082] A compound represented by the formula (2) can be prepared by
decarboxylating a compound represented by the formula (10).
[0083] This reaction can be conducted in a solvent or without
solvent. Examples of a solvent used if necessary include alcohols
such as methanol, ethanol, propanol, butanol, pentanol and the
like, aromatic hydrocarbons such as benzene, toluene, xylene and
the like, aprotic polar solvents such as dimethylformamide,
dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone and the like, and
basic solvents such as pyridine, quinoline and the like, and mixed
solvents thereof are also used. The use amount of a solvent in this
reaction is usually from 0.1 to 200 ml, preferably from 1 to 20 ml
based on 1 g of a compound represented by the general formula
(10).
[0084] This reaction may also be conducted in the presence of a
catalyst, and examples of the catalyst include mineral acids such
as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic
acid, phosphoric acid and the like, organic weak acids such as
acetic acid, propionic acid and the like, organic strong acids such
as p-toluenesulfonic acid, methanesulfonic acid and the like,
metals such as copper and the like, and metal oxides such as copper
oxide and the like. The use amount of these catalysts is usually
from 0.1 to 100% by mol, preferably from 1 to 20% by mol based on a
compound represented by the formula (10).
[0085] The reaction temperature of this reaction is usually from 0
to 400.degree. C., preferably from 40 to 250.degree. C., and the
reaction time is usually from 0.01 to 240 hours, preferably from
0.1 to 72 hours.
[0086] Regarding various conditions in this reaction, namely, the
use amount of a compound represented by the formula (10), the kind
and use amount of a solvent, the kind and use amount of a catalyst,
the reaction temperature and the reaction time, numerical values
within usual ranges and preferable ranges for respective conditions
may be appropriately selected and combined.
[0087] (Method B):
[0088] A compound represented by the formula (2) can also be
prepared from a compound represented by the formula (9) in one step
by a known method, for example, a method described in SYNTHESIS,
487(1981).
[0089] (Method C):
[0090] A compound represented by the formula (2) can also be
prepared by reacting 3-aminothiophene with a carboxylic acid halide
represented by the formula (8) under melted condition or in a
solvent. Raw materials, 3-aminothiophene can be prepared by a known
method, for example, a method described in SYNTHETIC COMMUNICATION,
25(23), 3729 to 3734 (1995).
[0091] Regarding 3-aminothiophene, an amino derivative may be
reacted in the free form intact, and may also be reacted in the
form of an acidic salt. Examples of the salt used include salts of
mineral acids such as hydrochlorides, sulfates, hydrobromides,
hydroiodides, phosphates and the like, and organic acids such as
acetates, oxalates and the like.
[0092] The use amount of a compound represented by the formula (8)
is usually from 0.2 to 20.0 mol, preferably from 0.5 to 5 mol per 1
mol of 3-aminothiophene.
[0093] Examples of a solvent used if necessary include aliphatic
hydrocarbons such as hexane, petroleum ether and the like,
aromatics such as benzene, toluene, chlorobenzene, anisole and the
like, ethers such as dioxane, tetrahydrofuran, diethyl ether and
the like, nitriles such as acetonitrile, propionitrile and the
like, esters such as ethyl acetate and the like, halogenated
hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane and the like and aprotic polar solvents such as
dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidin-
one and the like, and mixed solvents thereof are also used. The use
amount of a solvent in this reaction is usually from 0.1 to 200 ml,
preferably from 1 to 20 ml based on 1 g of 3-aminothiophene.
[0094] This reaction may also be conducted in the presence of a
base, and examples of the base include hydroxides of alkali metals
and alkaline earth metals such as sodium hydroxide, potassium
hydroxide, calcium hydroxide and the like, oxides of alkali metals
and alkaline earth metals such as calcium oxide, magnesium oxide
and the like, hydrides of alkali metals and alkaline earth metals
such as sodium hydride, calcium hydride and the like, alkali metal
amides such as lithium amide, sodium amide and the like, carbonates
of alkali metals and alkaline earth metals such as sodium
carbonate, calcium carbonate, magnesium carbonate and the like,
hydrogen carbonates of alkali metals and alkaline earth metals such
as sodium hydrogen carbonate, potassium hydrogen carbonate and the
like, alkylated alkali metals and alkaline earth metals such as
methyl lithium, phenyl lithium, methyl magnesium chloride and the
like, alkoxides of alkali metals and alkaline earth metals such as
sodium methoxide, sodium ethoxide, potassium-t-butoxide, dimethoxy
magnesium and the like, and various organic bases such as
triethylamine, pyridine and the like. The use amount of these bases
is usually from 0.1 to 20.0 mol, preferably from 1 to 5.0 mol per 1
mol of carboxylic acid chlorides represented by the formula
(8).
[0095] The reaction temperature is usually from -70 to 250.degree.
C., preferably from 0 to 150.degree. C., and the reaction time is
usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.
[0096] Regarding various conditions in this reaction, namely, the
use amounts of 3-aminothiophene and compounds represented by the
general formula (8), the kind and use amount of a solvent, the kind
and use amount of a base, the reaction temperature and the reaction
time, numerical values within usual ranges and preferable ranges
for respective conditions may be appropriately selected and
combined.
[0097] Among 3-aminothiophene derivatives represented by the
formula (6) which can be obtained by the above-described method
shown in the reaction formula 1, the following is a novel compound.
30
[0098] wherein R.sup.9 represents a hydrogen atom, carboxyl group
or alkoxycarbonyl group having 1 to 6 carbon atoms, and R.sup.a
represents a group represented by any of the following (A1) to
(A12): 31
[0099] wherein R.sup.1 represents a trifluoromethyl group,
difluoromethyl group, methyl group, ethyl group or halogen atom,
R.sup.6 represent a hydrogen atom, methyl group, trifluoromethyl
group, halogen atom, methoxy group or amino group, R.sup.7
represents a hydrogen atom, halogen atom, methyl group or methoxy
group, R.sup.8represents a hydrogen atom, methyl group, ethyl group
or halogen atom, and n represents an integer from 0 to 2, and
herein, in the case of (A9), (A10) or (A11), R.sup.5 is not a
halogen atom.
[0100] Then, a method for preparing 2-alkyl-3-aminothiophene
represented by the formula (5) will be described. 32
[0101] wherein R represents a hydrogen atom, alkyl group or alkoxy
group which may be substituted, aromatic or non-aromatic
hydrocarbon ring which may be substituted, aromatic or non-aromatic
heterocyclic ring which may be substituted, each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 independently represents a hydrogen
atom or straight or branched alkyl group having 1 to 12 carbon
atoms, and R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.1 and
R.sup.3, R.sup.1 and R.sup.4, R.sup.2 and R.sup.3 or R.sup.2 and
R.sup.4 may together form a cycloalkyl group.
[0102] A compound represented by the formula (5) can be produced by
hydrolyzing a compound represented by the formula (1) with an acid
or alkali. The hydrolysis method is not particularly restricted,
and there is usually applied a method in which an amide is
hydrolyzed into amine (for example, Shin Jikken Kagaku Koza, vol.
14, Synthesis and Reaction of Organic Compound (II), Maruzen
(1977)).
[0103] Then, a method for producing 2-alkyl-3-aminothiophene
derivative represented by the general formula (1a) will be
described. 33
[0104] wherein R.sup.1 to R.sup.4, R.sup.a are as defined
above.
[0105] A compound represented by the general formula (1a) can be
prepared by reacting a compound represented by the formula (5) with
a carboxylic acid halide represented by the formula (8a) under
melted condition or in a solvent.
[0106] The use amount of a compound represented by the formula (8a)
is usually from 0.2 to 20.0 mol, preferably from 0.5 to 5 mol per 1
mol of a compound represented by the formula (5).
[0107] Examples of a solvent used if necessary include aliphatic
hydrocarbons such as hexane, petroleum ether and the like,
aromatics such as benzene, toluene, chlorobenzene, anisole and the
like, ethers such as dioxane, tetrahydrofuran, diethyl ether and
the like, nitriles such as acetonitrile, propionitrile and the
like, esters such as ethyl acetate and the like, halogenated
hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane and the like and aprotic polar solvents such as
dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidin-
one and the like, and mixed solvents thereof are also used. The use
amount of a solvent in this reaction is usually from 0.1 to 200 ml,
preferably from 1 to 20 ml based on 1 g of a compound represented
by the formula (5).
[0108] This reaction may also be conducted in the presence of a
base, and examples of the base include hydroxides of alkali metals
and alkaline earth metals such as sodium hydroxide, potassium
hydroxide, calcium hydroxide and the like, oxides of alkali metals
and alkaline earth metals such as calcium oxide, magnesium oxide
and the like, hydrides of alkali metals and alkaline earth metals
such as sodium hydride, calcium hydride and the like, alkali metal
amides such as lithium amide, sodium amide and the like, carbonates
of alkali metals and alkaline earth metals such as sodium
carbonate, calcium carbonate, magnesium carbonate and the like,
hydrogen carbonates of alkali metals and alkaline earth metals such
as sodium hydrogen carbonate, potassium hydrogen carbonate and the
like, alkylated alkali metals and alkaline earth metals such as
methyl lithium, phenyl lithium, methyl magnesium chloride and the
like, alkoxides of alkali metals and alkaline earth metals such as
sodium methoxide, sodium ethoxide, potassium-t-butoxide, dimethoxy
magnesium and the like, and various organic bases such as
triethylamine, pyridine and the like. The use amount of these bases
is usually from 0.1 to 20.0 mol, preferably from 1 to 5.0 mol per 1
mol of carboxylic acid chlorides represented by the formula
(8a).
[0109] The reaction temperature is usually from -70 to 250.degree.
C., preferably from 0 to 150.degree. C., and the reaction time is
usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.
[0110] Regarding various conditions in this reaction, namely, the
use amounts of compounds represented by the formulae (5) and (8a),
the kind and use amount of a solvent, the kind and use amount of a
base, the reaction temperature and the reaction time, numerical
values within usual ranges and preferable ranges for respective
conditions may be appropriately selected and combined.
EXAMPLE
[0111] The following examples further specifically illustrate the
present invention but do not limit the scope of the present
invention.
[0112] Reference Example 1
[0113] Reaction of 3-aminothiophene with 4-methyl-2-pentanone
[0114] 0.15 g of p-toluenesulfonic acid monohydrate and 1.61 g
(16.1 mmol) of 4-methyl-2-pentanone were charged into 5 ml of
methylene chloride, cooled to 5.degree. C., then, 0.53 g (5.35
mmol) of 3-aminothiophene was added dropwise. The mixture was
stirred for 1 hour at 5.degree. C. to find no progress of the
reaction. Therefore, the reaction temperature was raised to
25.degree. C. and the mixture was stirred for 1 hour. Since the
reaction did not progress at all, stirring under reflux was
conducted to find decomposition of 3-aminothiophene.
Example 1
[0115] Synthesis of
N-{3-(2-methoxycarbonyl)-thienyl}-3-trifluoromethyl-1--
methylpyrazole-4-carboxamide amide (compound 1.1)
[0116] 9.53 g (60.7 mmol) of methyl 3-aminothiophene-2-carboxylate
and 9.60 g (121.4 mmol) of pyridine were charged into 63 ml of
tetrahydrofuran, then the mixture was cooled to 10.degree. C., and
to the mixture was added 12.9 g (60.7 mmol) of
3-trifluoromethyl-1-methylpyrazol- e-4-carbonyl chloride dropwise
at a temperature of 18.degree. C. or lower. After stirring the
mixture at 25.degree. C. for 3 hours, ethyl acetate was added, and
the mixture was washed sequentially with a 5% aqueous hydrochloric
acid solution, saturated aqueous sodium hydrogen carbonate-solution
and saturated sodium chloride solution. After drying over anhydrous
sodium sulfate, the solvent was distilled off under reduced
pressure, and the resultant residue was crystallized out from
hexane to obtain 20.1 g of the intended compound as a colorless
crystal (yield: 99%). The
3-trifluoromethyl-1-methylpyrazole-4-carbonyl chloride herein used
had been obtained by preparing ethyl 3-trifluoromethyl-1-meth-
ylpyrazole-4-carboxylate by a method -described in DE4231517,-
then, hydrolyzing it by an ordinary method and acid-chlorinating
the hydrolysate.
Example 2
[0117] Synthesis of
N-{3-(2-carboxy)thienyl}-3-trifluoromethyl-1-methylpyr-
azole-4-carboxamide (compound 8.1)
[0118] 15.6 g (46.8 mmol) of the
N-{3-(2-methoxycarbonyl)-thienyl}-3-trifl-
uoromethyl-1-methylpyrazole-4-carboxamide obtained in Example 1 and
3.74 g (93.7 mmol) of sodium hydroxide were charged into a mixed
solvent comprising 60 ml of methanol, 40 ml of water and 10 ml of
dioxane, and the mixture was stirred at 25.degree. C. for 5 hours.
To this was added 7.8 ml of concentrated hydrochloric acid to
control pH at about 4, then, methanol and dioxane were distilled
off under reduced pressure, and 1 ml of concentrated hydrochloric
acid was added to control pH at 1. The deposited crystal was
filtrated, then, washed with 30 ml of -water three times and dried
under reduced pressure to obtain 14.7 g of the intended compound
(yield: 99%).
Example 3
[0119] Synthesis of
N-(3-thienyl)-3-trifluoromethyl-1-methyl-pyrazole-4-ca- rboxamide
(compound 15.1)(Method A)
[0120] 2.0 g (6.27 mmol) of the
N-{3-(2-carboxy)thienyl}-3-trifluoromethyl-
-1-methylpyrazole-4-carboxamide obtained in Example 2 was heated to
215.degree. C. without using a solvent, and stirred for 10 minutes
in the same condition. It was cooled to room temperature to obtain
1.57 g of the intended compound as a brown crystal (yield: 91%)
Example 4
[0121] Synthesis of
N-(3-thienyl)-3-trifluoromethyl-1-methyl-pyrazole-4-ca- rboxamide
(compound 15.1)(Method C)
[0122] 65.0 g (0.451 mol) of 3-aminothiophene 1/2 oxalate was
charged into 455 ml of tetrahydrofuran, and the mixture was cooled
to 10.degree. C. under nitrogen flow. 74.9 g (0.948 mol) of
pyridine and 67.2 g (0.316 mol) of
3-trifluoromethyl-1-methylpyrazole-4-carbonyl chloride were added
dropwise sequentially at 18.degree. C., and the mixture was stirred
for 2 hours at 25.degree. C. The reaction solution was discharged
into 1500 ml of water, then, tetrahydrofuran was distilled off
under reduced pressure. The deposited crystal was filtrated, then,
washed with 100 ml of water three times and dried under reduced
pressure to obtain 73.9 g of the intended compound (yield: 85%
(based on carbonyl chloride)) as a crystal. The
3-trifluoromethyl-1-methylpyrazole-4-carbonyl chloride herein used
had been obtained by producing ethyl
3-trifluoromethyl-1-methylpyrazole-4- -carboxylate by a method
described in DE4231517, then, hydrolyzing it by an ordinary method
and acid-chlorinating the hydrolysate.
Example 5
[0123] Synthesis of
N-(3-thienyl)-3-trifluoromethyl-1-methyl-pyrazole-4-ca- rboxamide
(compound. 15.1)(Method B)
[0124] 5.0 g (15.0 mmol) of the
N-{3-(2-methoxycarbonyl)-thienyl}-3-triflu-
oromethyl-1-methylpyrazole-4-carboxamide obtained in Example 1 and
1.91 g (16.5 mmol) of pyridine hydrochloride were charged into 25
ml of pyridine, and the mixture was stirred for 42 hours at
120.degree. C. The mixture was cooled to room temperature, then,
pyridine was distilled off under reduced pressure to obtain 12.1 g
of an oil. This oil was discharged into 200 ml of water, and the
deposited crystal was filtrated. This crystal was washed with 10 ml
of water three times and dried under reduced pressure to obtain
3.88 g of the intended compound (yield: 94%) as a crystal.
Example 6
[0125] Synthesis of
N-[3-{2-(1,3-dimethylbutyl)}thienyl]-3-trifluoromethyl-
-1-methylpyrazole-4-carboxamide
[0126] 20.0 g (72.7 mmol) of the
N-(3-thienyl)-3-trifluoro-methyl-1-methyl- pyrazole-4-carboxamide
obtained in Example 4, 21.9 g (218.2 mmol) of 4-methyl-2-pentanone
and 1.0 g of p-toluenesulfonic acid monohydrate were charged into
160 ml of toluene, and the mixture was stirred with heating at
112.degree. C. for 8 hours while extracting water producing in the
reaction out of the system. After cooling to 50.degree. C., the
solution was washed with a saturated aqueous sodium hydrogen
carbonate solution and dried over sodium sulfate. The solvent was
distilled off under reduced pressure, then, the resulted residue
was purified by silica gel column chromatography (eluent:
hexane/ethyl acetate=6/4) to obtain 24.1 g of a mixture as a
colorless crystal.
[0127] 1.0 g (2.80 mmol) of this mixture and 0.2 g of 5% palladium
carbon (Degussa chemical catalyst E106R/W) were charged into 10 ml
of methanol, and catalytic reduction was conducted at 25.degree. C.
for 9 hours at normal pressure. The palladium carbon was filtrated,
and methanol in the filtrate was distilled off under reduced
pressure, then, ethyl acetate was added to the residue. After
washing with water, the organic layer was dried over anhydrous
sodium sulfate, and the solvent was distilled off under reduced
pressure to obtain 1.0 g of the intended compound as a colorless
crystal (yield: 91%).
[0128] .sup.1H-NMR (CDCl.sub.3, .sigma. value, J=Hz): 0.86 (6H, d,
J=6.8), 1.25 (3H, d, J=6.8), 1.43-1.64 (3H, m), 3.08 (1H, sext,
J=6.8), 3.99 (3H, s), 7.12 (1H, d, J=5.1), 7.43 (1H, d, J=5.1),
7.53 (1H, brs), 8.05 (1H, s).
[0129] m.p.: 107 to 108.degree. C.
Example 7
[0130] Synthesis of
N-[3-[2-(1-methylpropyl)}thienyl]-3-trifluoromethyl-1--
methylpyrazole-4-carboxamide
[0131] The title compound was synthesized in the same manner as in
Example 6 except that methyl ethyl ketone was used instead of
4-methyl-2-pentanone (yield: 76%).
[0132] .sup.1H-NMR (CDCl.sub.3, .sigma. value, J=Hz): 0.89 (3H,-d,
J=7.3), 1.30 (3H, d, J=7.3), 1.59-1.69 (2H, m), 2.85-2.93 (1H, m),
3.99 (3H, s), 7.13 (1H, d, J=5.1), 7.46 (1H, d, J=5.1), 7.54 (1H,
brs), 8.05 (1H, s).
[0133] m.p.: 112 to 114.degree. C.
Example 8
[0134] Synthesis of
N-{3-(2-cyclohexyl)thienyl}-3-trifluoromethyl-1-methyl-
pyrazole-4-carboxamide
[0135] The title compound was synthesized in the same manner as in
Example 6 except that cyclohexanone was used instead of
4-methyl-2-pentanone (yield: 68%).
[0136] .sup.1H-NMR (CDCl.sub.3, .sigma. value, J=Hz): 1.22-1.49
(5H, m), 1.72-1.94 (5H, m), 2.72-2.79 (1H, m), 3.99 (3H, s), 7.10
(1H, d, J=5.1), 7.51 (1H, d, J=5.1), 7.60 (1H, brs), 8.06 (1H,
s).
[0137] m.p.: 128.7 to 129.5.degree. C.
Reference Example 2
[0138] Synthesis of N-{3-(2-methoxycarbonyl)thienyl}-benzamide
[0139] 31.4 g (0.200 mol) of methyl 3-aminothiophene-2-carboxylate
was charged into 97.2 g of toluene, and the mixture was heated to
90.degree. C. 29.5 g (0.210 mol) of benzoyl chloride was added
dropwise over 20 minutes while keeping the reflux temperature, and
the mixture was stirred for 4 hours under reflux. After cooling to
room temperature, 100 ml of toluene was added, and the mixture was
washed sequentially with a saturated aqueous sodium hydrogen
carbonate solution and a saturated sodium chloride solution. The
solution was dried over anhydrous magnesium sulfate, then, the
solvent was distilled off under reduced pressure to obtain 52.0 g
of the intended compound as a crystal (yield: 100%).
[0140] .sup.1H-NMR (CDCl.sub.3, ppm, J=Hz): 3.94 (3H, s), 7.49-7.61
(5H.sub.1 m), 8.00-8.05 (2H, m), 8.31 (1H, d, J=5.3)
[0141] m.p.: 101.4 to 102.3.degree. C.
Reference Example 3
[0142] Synthesis of N-{3-(2-carboxy)thienyl}-benzamide
[0143] 50.0 g (0.192 mol) of the
N-{3-(2-methoxycarbonyl)-thienyl}-benzami- de obtained in Reference
Example 2 was charged into 300 ml of ethanol, and to this was added
dropwise 15.4 g (0.385 mol) of sodium hydroxide dissolved in 150 ml
of water. The mixture was stirred for 4 hours at room temperature,
then, cooled to 10.degree. C., and 30 ml of concentrated
hydrochloric acid was added dropwise to control pH at about 6.
Methanol was distilled off under reduced pressure, then, 100 ml of
water was charged into the resulted residue, and 10 ml of
concentrated hydrochloric acid was added to control pH at 1. The
deposited crystal was filtrated, and washed with 50 ml of water
three times. The resulted crystal was dried under reduced pressure
to obtain 45.0 g of the intended compound as a colorless crystal
(yield: 95%).
[0144] .sup.1H-NMR (DMSO-d.sub.6l ppm, J=Hz): 7.56-7.69- (3H, m),
7.91-7.94 (3H, m), 8.09 (1H, d, J=5.7), 11.2 (1H, brs)
[0145] m.p.: 214.6 to 214.9.degree. C.
Reference Example 4
[0146] Synthesis of N-(3-thienyl)-benzamide (Method A)
[0147] 30.0 g (12.1 mmol) of the
N-{3-(2-carbonyl)thienyl}-benzamide obtained in Reference Example 3
and 1.5 g of p--toluenesulfonic acid monohydrate were charged into
120 ml of 1,3-dimethyl-2-imidazolydinone, and the mixture was
stirred at 130.degree. C. for 27 hours. After cooled to room
temperature, the solution was discharged into 1000 ml of water. The
deposited crystal-was filtrated, and washed with 30 ml of water
three times. The resulted crystal was dried under reduced pressure
to obtain 20.8 g of the intended compound as a crystal (yield:
85%).
[0148] .sup.1H-NMR (CDCl.sub.3, ppm, J=Hz): 7.12-7.14 (1H, m),
7.28-7.29 (1H, m), 7.44-7.58 (3H, m), 7.73 (1H, dd, J=2.9, 0.6),
7.84-7.88 (2H, m), 8.20 (1H, brs)
[0149] m.p.: 155.4 to 156.2.degree. C.
Example 9
[0150] Synthesis of mixture of
N-[3-{2-(E)-(4-methyl-2-penten-2-yl)}thieny- l]-benzamide,
N-[3-{2-(Z)-(4-methyl-2-penten-2-yl)}thienyl]-benzamide, and
N-[3-{2-(4-methyl-1-penten-2-yl)}thienyl]-benzamide (mixture
115.3)
[0151] 20.0 g (0.0985 mol) of the N-(3-thienyl)-benzamide obtained
in Reference Example 4, 29.6 g (0.296 mol) of 4-methyl-2-pentanone
and 1.0 g of p-toluenesulfonic acid monohydrate were charged into
200 ml of toluene, and the mixture was stirred with heating at
111.degree. C. for 9.5 hours while extracting water producing in
the reaction out of the system. After cooling to room temperature,
the solution was washed with a 1N aqueous sodium hydroxide solution
and saturated sodium chloride solution sequentially, then, dried
over sodium sulfate. The solvent was distilled off under reduced
pressure, then, the resulted residue was purified by silica gel
column chromatography (eluent: hexane:ethyl acetate=9:1) to obtain
26.1 g of the intended mixture as a colorless crystal (yield:
93%).
Example 10
[0152] Synthesis of N- [3-{2- (1,3-dimethylbutyl)}thienyl-benzamide
(compound 114.3)
[0153] 24.0 g (84.2 mmol) of the mixture
N-[3-{2-(E)-(4-methyl-2-penten-2-- yl)}thienyl]-benzamide,
N-[3-{2-(Z)-(4-methyl-2-penten-2-yl)}thienyl]-benz- amide, and
N-[3-{2-(4-methyl-1-penten-2-yl) }thienyl] -benzamide obtained in
Example 9, 4.8 g of 5% palladium carbon (Degussa chemical catalyst
E106R/W) and 120 ml of methanol were charged into 200 ml autoclave,
purged with nitrogen, then, a hydrogenation reaction was conducted
for 11 hours under conditions of a temperature of 40.degree. C. and
a hydrogen pressure of 1.96 MPa. After purging with nitrogen, the
catalyst was filtrated off, and the filtrate was distilled off
under reduced pressure to obtain 23.5 g of the intended compound as
a colorless crystal (yield: 97%).
Example 11
[0154] Synthesis of 3-amino-2-(1,3-dimethylbutyl)thiophene 21.8 g
(76.0 mmol) of the N-[3-{2-(1,3-dimethyl-butyl) }thienyl]-benzamide
obtained in Example 10 was charged into a mixed solution composed
of 100 ml of concentrated hydrochloric acid and 70 ml of acetic
acid, and the reaction was conducted with heating under reflux at
97.degree. C. for 27 hours. After cooling to room temperature, the
solution was neutralized with a 10N aqueous sodium hydroxide
solution while charging ice. After extracting with ethyl acetate
twice, the solution was washed with a saturated sodium chloride
solution, and dried over magnesium sulfate. The solvent was
distilled off under reduced pressure to obtain 13.3 g of the
intended compound as an oil (yield: 96%).
[0155] .sup.1H-NMR (CDCl.sub.3, .sigma. value, J=Hz): 0.89 (3H, d,
J=6.6), 0.90 (3H, d, J=6.6), 1.23 (3H, d, J=6.6), 1.35-1.65 (3H,
m), 2.95 (1H, sext, J=6.6), 3.35 (2H, brs), 6.55 (1H, d, J=5.1),
6.95 (1H, d, J=5.1)
[0156] Physical condition: oil
Example 12
[0157] Synthesis of
N-(3-{2-(1,3-dimethylbutyl)}thienyl]-3-trifluoromethyl-
-1-methylpyrazole-4-carboxamide
[0158] 0.50 g (2.73 mmol) of the
3-amino-2-(1,3-dimethyl-butyl)thiophene obtained in Example 11 and
0.26 g (3.28 mmol) of pyridine were charged into 3 ml of
tetrahydrofuran, and the mixture was cooled to 10.degree. C. 0.64 g
(3.00 mmol) of 3-trifluoromethyl-1-methylpyrazole-4-carbonyl
chloride was added dropwise while keeping the reaction temperature
under 18.degree. C. The mixture was stirred for2 hours at room
temperature, then, discharged into a 5% aqueous hydrochloric acid
solution and extracted with ethyl acetate. The ethyl acetate layer
was washed with a saturated aqueous sodium hydrogen carbonate
solution and a saturated sodium chloride solution, then, dried over
anhydrous magnesium sulfate. The solvent was distilled off under
reduced pressure, then, the resulted residue was crystallized out
from hexane to obtain 0.93 g of the intended compound as a crystal
(yield: 95%). The 3-trifluoromethyl-1-methylpyrazol- e-4-carbonyl
chloride herein used had been obtained by producing ethyl
3-trifluoromethyl-1-methylpyrazole-4-carboxylate by a method
described in DE4231517, then, hydrolyzing it by an ordinary method
and acid-chlorinating the hydrolysate.
[0159] .sup.1H-NMR (CDCl.sub.3, .sigma. value, J=Hz): 0.86 (6H, d,
J=6.8), 1.25 (3H, d, J=6.8), 1.43-1.64 (3H, m), 3.08 (1H, sext,
J=6.8), 3.99 (3H, s), 7.12 (1H, d, J=5.1), 7.43 (1H, d, J=5.1),
7.53 (1H, brs), 8.05 (1H, s).
[0160] m.p.: 107 to 108.degree. C.
Reference Example 5
[0161] Synthesis of methyl
3-isopropoxycarbonylaminothiophene-2-carboxylat- e
[0162] 22.1 g (0.141 mol) of methyl 3-aminothiophene-2-carboxylate
was dissolved in 100 ml of ethyl acetate, and to this was added
11.7 g (0.148 mol) of pyridine. 18.1 g (0.148 mol) of isopropyl
chloroformate was added dropwise while cooling with ice over 30
minutes. After completion of the addition, the solution was heated
to 60.degree. C. and stirred with heating for 3 hours. After
completion of the reaction, the reaction solution was washed
sequentially with a 5% aqueous hydrochloric acid solution,
saturated aqueous sodium hydrogen carbonate solution and saturated
sodium chloride solution, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulted residue was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate=7/3) to obtain 30.6 g of the intended
compound as a crystal (yield: 85%). The crystal herein obtained was
not analyzed and used for the next reaction. Reference Example 6
Synthesis of 3-isopropoxycarbonyl-aminothiophene (Method B)
[0163] 30.8 g (0.126 mol) of the methyl
3-isopropoxy-carbonylaminothiophen- e-2-carboxylate obtained in
Reference Example 5 and 16.1 g (0.139 mol) of pyridine
hydrochloride were charged into 70 ml of pyridine, and the mixture
was heated to 130.degree. C., and stirred with heating for 45
hours. After cooling to room temperature, pyridine was distilled
off under reduced pressure, and into the resulted residue was
charged 300 ml of ethyl acetate. The ethyl acetate layer was washed
with water, then, dried over magnesium sulfate. The solvent was
distilled off under reduced pressure, and the resulted residue was
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate=2/1) to obtain 21.0 g of the intended compound as a
colorless crystal (yield: 90%).
[0164] .sup.1H-NMR (CDCl.sub.3, ppm, J=Hz): 1.29 (6H, d, J=6.3),
5.01 (1H, sept, J=6.3), 6.80 (1H, brs), 6.92-6.94 (1H, m),
7.19-7.26 (2H, m).
[0165] m.p.: 105.0 to 107.2.degree. C.
Example 13
[0166] Synthesis of mixture of
3-isopropoxycarbonylamino-{2-(E)-(4-methyl-- 2-penten-2-yl)
}thiophene, 3-isopropoxycarbonylamino-{2-(Z)-(4-methyl-2-pe-
nten-2-yl)}thiophene, and
3-isopropoxycarbonylamino-{2-(4-methyl-1-penten-- 2-yl)}thiophene
(mixture 115.5)
[0167] (15.4 mmol) of the 3-isopropoxycarbonylaminothiophene
obtained in Reference Example 6, 4.60 g (46.0 mmol) of
4-methyl-2-pentanone and 0.14 g of p-toluenesulfonic acid
monohydrate were charged into 20 ml of toluene, and the mixture was
heated under reflux for 7 hours while extracting water producing in
the reaction out of the system. After cooling to room temperature,
the solution was washed with a saturated aqueous sodium hydrogen
carbonate solution, and dried over sodium sulfate. The solvent was
distilled off under reduced pressure, then, the resulted residue
was purified by silica gel column chromatography (eluent/hexane:
ethyl acetate=20/1) to obtain 3.68 g of the intended mixture as an
oil (yield: 89%).
Example 14
[0168] Synthesis
of-3-isopropoxycarbonyl-{2-(1,3-dimethylbutyl)}-thiophene (compound
114.5)
[0169] 2.06 g (7.72 mmol) of the mixture of
3-isopropoxy-carbonylamino-{2--
(E)-(4-methyl-2-penten-2-yl)}thiophene,
3-isopropoxycarbonylamino-(2-(Z) (4-methyl-2-penten-2-yl)
}thiophene, and 3-isopropoxycarbonylamino-{2-(4--
methyl-1-penten-2-yl) }thiophene obtained in Example 13 and 0.41 g
of 5% palladium carbon (Degussa chemical catalyst E106R/W) were
charged into 20 ml of methanol, and after nitrogen purge, a
hydrogenation reaction was conducted at normal pressure under
hydrogen atmosphere for 9 hours. After nitrogen purge, the catalyst
was filtrated off, and the solvent was distilled off under reduced
pressure. The resulted residue was purified by silica gel column
chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1.61 g
of the intended compound as a colorless crystal (yield: 70%).
Example 15
[0170] Synthesis of 3-amino-2-(1,3-dimethylbutyl)thiophene
[0171] 1.24 g (4.61 mmol) of the
3-isopropoxycarbonyl-{2-(1,3-dimethylbuty- l) }thiophene obtained
in Example 14 and 1.36 g (34.0 mmol) of sodium hydroxide were
charged into a mixture of 5 ml of methanol, 4 ml of water and-5 ml
of dioxane, and the mixture was heated under reflux for 8 hours.
The solvent was distilled off under reduced pressure, then,
extracted with diethyl ether twice, and washed with a saturated
sodium chloride solution. The solvent was distilled off under
reduced pressure, and the resulted residue was purified by silica
gel column chromatography (eluent: hexane/ethyl acetate=9/1) to
obtain 0.42 g of the intended compound as a brown oil (yield:
50%).
[0172] .sup.1H-NMR (CDCl.sub.3, a value, J=Hz): 0.89 (3H, d,
J=6.6), 0.90 (3H, d, J=6.6), 1.23 (3H, d, J=6.6), 1.35-1.65 (3H,
m), 2.95 (1H, sext, J=6.6), 3.35 (2H, brs), 6.55 (1H, d, J=5.1),
6.95 (1H, d, J=5.1).
[0173] Physical condition: oil
Example 16
[0174] Synthesis of
N-[3-{2-(1,3-dimethylbutyl)thienyl}]-3-trifluoromethyl-
-1-methylpyrazole-4.-carboxylic amide
[0175] 0.25 g (1.36 mmol) of the 3-amino-2-(1,3-dimethylbutyl)
thiophene obtained in Example 15 and 0.13 g (1.64 mmol) were
charged into 3 ml of tetrahydrofuran, and the mixture was cooled to
10.degree. C. 0.32 g (1.50 mmol) of
3-trifluoromethyl-1-methylpyrazole-4-carbonyl chloride was added
dropwise while keeping the reaction temperature under 18.degree. C.
The mixture was stirred for2 hours at room temperature, then,
discharged into a 5% aqueous hydrochloric acid solution and
extracted with ethyl acetate. The ethyl acetate layer was washed
with a saturated aqueous sodium hydrogen carbonate solution and a
saturated sodium chloride solution, then, dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, then, the resulted residue was crystallized out from
hexane to obtain 0.46 g of the intended compound as a crystal
(yield: 94%). The 3-trifluoromethyl-1-methylpyrazole-4-carbonyl
chloride herein used had been obtained by producing ethyl
3-trifluoromethyl-1-meth- ylpyrazole-4-carboxylate by a method
described in DE4231517, then, hydrolyzing it by an ordinary method
and acid-chlorinating the hydrolysate. .sup.1H-NMR (CDCl.sub.3, a
value, J=Hz): 0.86 (6H, d, J-6.8), 1.25 (3H, d, J=6.8), 1.43-1.64
(3H, m), 3.08 (1H, sext, J=6.8), 3.99 (3H, s), 7.12 (1H, d, J=5.1),
7.43 (1H, d, J=5.1), 7.53 (1H, brs), 8.05 (1H, s).
[0176] m.p.: 107 to 108.degree. C.
[0177] Examples of a compound of the formula (6a) which is an
intermediate of the present invention are summarized in the
following Tables 1.
[0178] In table 1, a solvent for measurement of NMR is DMSO-d6,
when R.sup.9 is carboxy group. 34
1TABLE 1 Compound m.p. .sup.1H--NMR (270 MHz) No. R.sup.9 Ar
(.degree. C.) (CDCl.sub.3, .delta. value, J:Hz) 1.1
CO.sub.2CH.sub.3 A1 (R.sup.5 = CF.sub.3, 144.1.about. 3.92 (3H, s),
4.03 (3H, s), 7.51 (1H, d, R.sup.7 = H) 144.9 J = 5.6), 7.96 (1H,
s), 8.19(1H, d, J = 5. 6), 10.68 (1H, brs) 1.2 CO.sub.2CH.sub.3 A1
(R.sup.5 = CHF.sub.2, R.sup.7 = H) 1.3 CO.sub.2CH.sub.3 A1 (R.sup.5
= CH.sub.3, R.sup.7 = H) 1.4 CO.sub.2CH.sub.3 A1 (R.sup.5 =
C.sub.2H.sub.5, R.sup.7 = H) 1.5 CO.sub.2CH.sub.3 A1 (R.sup.5 = F,
R.sup.7 = H) 1.6 CO.sub.2CH.sub.3 A1 (R.sup.5 Cl, R.sup.7 = H) 1.7
CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = H) 1.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = H) 2.1 CO.sub.2CH.sub.3
A1 (R.sup.5 = CF.sub.3, R.sup.7 = F) 2.2 CO.sub.2CH.sub.3 A1
(R.sup.5 = CHF.sub.2, R.sup.7 = F) 2.3 CO.sub.2CH.sub.3 A1 (R.sup.5
= CH.sub.3, R.sup.7 = F) 2.4 CO.sub.2CH.sub.3 A1 (R.sup.5 =
C.sub.2H.sub.5, R.sup.7 = F) 2.5 CO.sub.2CH.sub.3 A1 (R.sup.5 = F,
R.sup.7 = F) 2.6 CO.sub.2CH.sub.3 A1 (R.sup.5 = Cl, R.sup.7 = F)
2.7 CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = F) 2.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = F) 3.1 CO.sub.2CH.sub.3
A1 (R.sup.5 = CF.sub.3, R.sup.7 = Cl) 3.2 CO.sub.2CH.sub.3 A1
(R.sup.5 = CHF.sub.2, R.sup.7 = Cl) 3.3 CO.sub.2CH.sub.3 A1
(R.sup.5 = CH.sub.3, R.sup.7 = Cl) 3.4 CO.sub.2CH.sub.3 A1 (R.sub.5
= C.sub.2H.sub.5, R.sup.7 = Cl) 3.5 CO.sub.2CH.sub.3 A1 (R.sup.5 =
F, R.sup.7 = Cl) 3.6 CO.sub.2CH.sub.3 A1 (R.sup.5 = Cl, R.sup.7 =
Cl) 3.7 CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = Cl) 3.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = Cl) 4.1
CO.sub.2CH.sub.3 A1 (R.sup.5 = CF.sub.3, R.sup.7 = Br) 4.2
CO.sub.2CH.sub.3 A1 (R.sup.5 = CHF.sub.2, R.sup.7 = Br) 4.3
CO.sub.2CH.sub.3 A1 (R.sup.5 = CH.sub.3, R.sup.7 = Br) 4.4
CO.sub.2CH.sub.3 A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = Br) 4.5
CO.sub.2CH.sub.3 A1 (R.sup.5 = F, R.sup.7 = Br) 4.6
CO.sub.2CH.sub.3 A1 (R.sup.5 = Cl, R.sup.7 = Br) 4.7
CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = Br) 4.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = Br) 5.1
CO.sub.2CH.sub.3 A1 (R.sup.5 = CF.sub.3, R.sup.7 = I) 5.2
CO.sub.2CH.sub.3 A1 (R.sup.5 = CHF.sub.2, R.sup.7 = I) 5.3
CO.sub.2CH.sub.3 A1 (R.sup.5 = CH.sub.3, R.sup.7 = I) 5.4
CO.sub.2CH.sub.3 A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = I) 5.5
CO.sub.2CH.sub.3 A1 (R.sup.5 = F, R.sup.7 = I) 5.6 CO.sub.2CH.sub.3
A1 (R.sup.5 = Cl, R.sup.7 = I) 5.7 CO.sub.2CH.sub.3 A1 (R.sup.5 =
Br, R.sup.7 = I) 5.8 CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = I)
6.1 CO.sub.2CH.sub.3 A1 (R.sup.5 = CF.sub.3, R.sup.7 = CH.sub.3)
6.2 CO.sub.2CH.sub.3 A1 (R.sup.5 = CHF.sub.2, R.sup.7 = CH.sub.3)
6.3 CO.sub.2CH.sub.3 A1 (R.sup.5 = CH.sub.3, R.sup.7 = CH.sub.3)
6.4 CO.sub.2CH.sub.3 A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 =
CH.sub.3) 6.5 CO.sub.2CH.sub.3 A1 (R.sup.5 = F, R.sup.7 = CH.sub.3)
6.6 CO.sub.2CH.sub.3 A1 (R.sup.5 = Cl, R.sup.7 = CH.sub.3) 6.7
CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = CH.sup.3) 6.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = CH.sup.3) 7.1
CO.sub.2CH.sub.3 A1 (R.sup.5 = CF.sup.3, R.sup.7 = OCH.sub.3) 7.2
CO.sub.2CH.sub.3 A1 (R.sup.5 = CHF.sub.2, R.sup.7 = OCH.sub.3) 7.3
CO.sub.2CH.sub.3 A1 (R.sup.5 = CH.sup.3, R.sup.7 = OCH.sub.3) 7.4
CO.sub.2CH.sub.3 A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = OCH.sub.3)
7.5 CO.sub.2CH.sub.3 A1 (R.sup.5 = F, R.sup.7 = OCH.sup.3) 7.6
CO.sub.2CH.sub.3 A1 (R.sup.5 = Cl, R.sup.7 = OCH.sub.3) 7.7
CO.sub.2CH.sub.3 A1 (R.sup.5 = Br, R.sup.7 = OCH.sub.3) 7.8
CO.sub.2CH.sub.3 A1 (R.sup.5 = I, R.sup.7 = OCH.sub.3) 8.1
CO.sub.2H A1 (R.sup.5 = CF.sub.3, 221.6.about. 4.03 (3H, s), 7.53
(1H, d, J = 5.6), 8.09 R.sup.7 = H 222 (1H, s), 8.13 (1H, d, J =
5.6) 8.2 CO.sub.2H A1 (R.sup.5 = CHF.sub.2, R.sup.7 = H) 8.3
CO.sub.2H A1 (R.sup.5 = CH.sub.3, R.sup.7 = H) 8.4 CO.sub.2H A1
(R.sup.5 = C.sub.2H.sub.5, R.sup.7 = H) 8.5 CO.sub.2H A1 (R.sup.5 =
F, R.sup.7 = H) 8.6 CO.sub.2H A1 (R.sup.5 = Cl, R.sup.7 = H) 8.7
CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = H) 8.8 CO.sub.2H A1 (R.sup.5
= I, R.sup.7 = H) 9.1 CO.sub.2H A1 (R.sup.5 = CF.sub.3, R.sup.7 =
F) 9.2 CO.sub.2H A1 (R.sup.5 = CHF.sub.2, R.sup.7 = F) 9.3
CO.sub.2H A1 (R.sup.5 = CH.sub.3, R.sup.7 = F) 9.4 CO.sub.2H A1
(R.sup.5 = C.sub.2H.sub.5, R.sup.7 = F) 9.5 CO.sub.2H A1 (R.sup.5 =
F, R.sup.7 = F) 9.6 CO.sub.2H A1 (R.sup.5 = Cl, R.sup.7 = F) 9.7
CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = F) 9.8 CO.sub.2H A1 (R.sup.5
= I, R.sup.7 = F) 10.1 CO.sub.2H A1 (R.sup.5 = CF.sub.3, R.sup.7 =
Cl) 10.2 CO.sub.2H A1 (R.sup.5 = CHF.sub.2, R.sup.7 = Cl) 10.3
CO.sub.2H A1 (R.sup.5 = CH.sub.3, R.sup.7 = Cl) 10.4 CO.sub.2H A1
(R.sup.5 = C.sub.2H.sub.5, R.sup.7 = Cl) 10.5 CO.sub.2H A1 (R.sup.5
= F, R.sup.7 = Cl) 10.6 CO.sub.2H A1 (R.sup.5 = Cl, R.sup.7 = Cl)
10.7 CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = Cl) 10.8 CO.sub.2H A1
(R.sup.5 = I, R.sup.7 = Cl) 11.1 CO.sub.2H A1 (R.sup.5 = CF.sub.3,
R.sup.7 = Br) 11.2 CO.sub.2H A1 (R.sup.5 = CHF.sub.2, R.sup.7 = Br)
11.3 CO.sub.2H A1 (R.sup.5 = CH.sup.3, R.sup.7 = Br) 11.4 CO.sub.2H
A1 (R.sup.5 = C.sup.2H.sup.5, R.sup.7 = Br) 11.5 CO.sub.2H A1
(R.sup.5 = F, R.sup.7 = Br) 11.6 CO.sub.2H A1 (R.sup.5 = Cl,
R.sup.7 = Br) 11.7 CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = Br) 11.8
CO.sub.2H A1 (R.sup.5 = I, R.sup.7 = Br) 12.1 CO.sub.2H A1 (R.sup.5
= CF.sup.3, R.sup.7 = I) 12.2 CO.sub.2H A1 (R.sup.5 = CHF.sub.2,
R.sup.7 = I) 12.3 CO.sub.2H A1 (R.sup.5 = CH.sub.3, R.sup.7 = I)
12.4 CO.sub.2H A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = I) 12.5
CO.sub.2H A1 (R.sup.5 = F, R.sup.7 = I) 12.6 CO.sub.2H A1 (R.sup.5
= Cl, R.sup.7 = I) 12.7 CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = I)
12.8 CO.sub.2H A1 (R.sup.5 = I, R.sup.7 = I) 13.1 CO.sub.2H A1
(R.sup.5 = CF.sub.3, R.sup.7 = CH.sub.3) 13.2 CO.sub.2H A1 (R.sup.5
= CHF.sub.2, R.sup.7 = CH.sub.3) 13.3 CO.sub.2H A1 (R.sup.5 =
CH.sub.3, R.sup.7 = CH.sub.3) 13.4 CO.sub.2H A1 (R.sup.5 =
C.sub.2H.sub.5, R.sup.7 = CH.sub.3) 13.5 CO.sub.2H A1 (R.sup.5 = F,
R.sup.7 = CH.sub.3) 13.6 CO.sub.2H A1 (R.sup.5 = Cl, R.sup.7 =
CH.sub.3) 13.7 CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = CH.sub.3) 13.8
CO.sub.2H A1 (R.sup.5 = I, R.sup.7 = CH.sub.3) 14.1 CO.sub.2H A1
(R.sup.5 = CF.sub.3, R.sup.7 = CH.sub.3) 14.2 CO.sub.2H A1 (R.sup.5
= CHF.sub.2, R.sup.7 = OCH.sub.3) 14.3 CO.sub.2H A1 (R.sup.5 =
CH.sub.3, R.sup.7 = OCH.sub.3) 14.4 CO.sub.2H A1 (R.sup.5 =
C.sub.2H.sub.5, R.sup.7 = OCH.sub.3) 14.5 CO.sub.2H A1 (R.sup.5 =
F, R.sup.7 = OCH.sub.3) 14.6 CO.sub.2H A1 (R.sup.5 = Cl, R.sup.7 =
OCH.sub.3) 14.7 CO.sub.2H A1 (R.sup.5 = Br, R.sup.7 = OCH.sub.3)
14.8 CO.sub.2H A1 (R.sup.5 = I, R.sup.7 = OCH.sub.3) 15.1 H A1
(R.sup.5 = CF.sub.3, 158.3.about. 3.98 (3H, s), 7.03 (1H, dd, J =
5.2, 1.3), R.sup.7 = H) 158.9 7.26 (1H, dd, J = 5.2, 3.3), 7.65
(1H, d d, J = 3.3, 1.3), 8.00 (1H, s), 8.01 (1H, brs) 15.2 H A1
(R.sup.5 = CHF.sub.2, R.sup.7 = H) 15.3 H A1 (R.sup.5 = CH.sub.3,
R.sup.7 = H) 15.4 H A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = H) 15.5
H A1 (R.sup.5 = F, R.sup.7 = H) 15.6 H A1 (R.sup.5 = Cl, R.sup.7 =
H) 15.7 H A1 (R.sup.5 = Br, R.sup.7 = H) 15.8 H A1 (R.sup.5 = I,
R.sup.7 = H) 16.1 H A1 (R.sup.5 = CF.sub.3, R.sup.7 = F) 16.2 H A1
(R.sup.5 = CHF.sub.2, R.sup.7 = F) 16.3 H A1 (R.sup.5 = CH.sub.3,
R.sup.7 = F) 16.4 H A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = F) 16.5
H A1 (R.sup.5 = F, R.sup.7 = F) 16.6 H A1 (R.sup.5 = Cl, R.sup.7 =
F) 16.7 H A1 (R.sup.5 = Br, R.sup.7 = F) 16.8 H A1 (R.sup.5 = I,
R.sup.7 = F) 17.1 H A1 (R.sup.5 = CF.sub.3, R.sup.7 = Cl) 17.2 H A1
(R.sup.5 = CHF.sub.2, R.sup.7 = Cl) 17.3 H A1 (R.sup.5 = CH.sub.3,
R.sup.7 = Cl) 17.4 H A1 (R.sup.5 = C.sub.2H.sub.5, R.sup.7 = Cl)
17.5 H A1 (R.sup.5 = F, R.sup.7 = Cl) 17.6 H A1 (R.sup.5 = Cl,
R.sup.7 = Cl) 17.7 H A1 (R.sup.5 = Br, R.sup.7 = Cl) 17.8 H A1
(R.sup.5 = I, R.sup.7 = Cl) 18.1 H A1 (R.sup.5 = CF.sub.3, R.sup.7
= Br) 18.2 H A1 (R.sup.5 = CHF.sub.2, R.sup.7 = Br) 18.3 H A1
(R.sup.5 = CH.sub.3, R.sup.7 = Br) 18.4 H A1 (R.sup.5 =
C.sub.2H.sub.5, R.sup.7 = Br) 18.5 H A1 (R.sup.5 = F, R.sup.7 = Br)
18.6 H A1 (R.sup.5 = Cl, R.sup.7 = Br) 18.7 H A1 (R.sup.5 = Br,
R.sup.7 = Br) 18.8 H A1 (R.sup.5 = I, R.sup.7 = Br) 19.1 H A1
(R.sup.5 = CF.sub.3, R.sup.7 = I) 19.2 H A1 (R.sup.5 = CHF.sub.2,
R.sup.7 = I) 19.3 H A1 (R.sup.5 = CH.sub.3, R.sup.7 = I) 19.4 H A1
(R.sup.5 = C.sub.2H.sub.5, R.sup.7 = I) 19.5 H A1 (R.sup.5 = F,
R.sup.7 = I) 19.6 H A1 (R.sup.5 = Cl, R.sup.7 = I) 19.7 H A1
(R.sup.5 = Br, R.sup.7 = I) 19.8 H A1 (R.sup.5 = I, R.sup.7 = I)
20.1 H A1 (R.sup.5 = CF.sub.3, R.sup.7 = CH.sub.3) 20.2 H A1
(R.sup.5 = CHF.sub.2, R.sup.7 = CH.sub.3) 20.3 H A1 (R.sup.5 =
CH.sub.3, R.sup.7 = CH.sub.3) 20.4 H A1 (R.sup.5 = C.sub.2H.sub.5,
R.sup.7 = CH.sub.3) 20.5 H A1 (R.sup.5 = F, R.sup.7 = CH.sub.3)
20.6 H A1 (R.sup.5 = Cl, R.sup.7 = CH.sub.3) 20.7 H A1 (R.sup.5 =
Br, R.sup.7 = CH.sub.3) 20.8 H A1 (R.sup.5 = I, R.sup.7 = CH.sub.3)
21.1 H A1 (R.sup.5 = CF.sub.3, R.sup.7 = OCH.sub.3) 21.2 H A1
(R.sup.5 = CHF.sub.2, R.sup.7 = OCH.sub.3) 21.3 H A1 (R.sup.5 =
CH.sub.3, R.sup.7 = OCH.sub.3) 21.4 H A1 (R.sup.5 = C.sub.2H.sub.5,
R.sup.7 = OCH.sub.3) 21.5 H A1 (R.sup.5 = F, R.sup.7 = OCH.sub.3)
21.6 H A1 (R.sup.5 = Cl, R.sup.7 = OCH.sub.3) 21.7 H A1 (R.sup.5 =
Br, R.sup.7 = OCH.sub.3) 21.8 H A1 (R.sup.5 = I, R.sup.7 =
OCH.sub.3) 22.1 CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 =
H) 22.2 CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = H) 22.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = H) 22.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = H) 22.5
CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = H) 22.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = H) 22.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = H) 22.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = H) 23.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = CH.sub.3) 23.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = CH.sub.3) 23.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = CH.sub.3) 23.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, 107.1.about. 1.35
(3H, t, J .+-. 7.6), 2.73 (3H, s), 3.18 R.sup.6 = CH.sub.3) 109.4
(2H, q, J = 7.6), 3.93 (3H, s), 7.52 (1H, d, J = 5.0), 8.19 (1H, d,
J = 5.0), 10.7 (1 H, brs) 23.5 CO.sub.2CH.sub.3 A2 (R.sup.5 = F,
R.sup.6 = CH.sub.3) 23.6 CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6
= CH.sub.3) 23.7 CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 =
CH.sub.3) 23.8 CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 =
CH.sub.3) 24.1 CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 =
CF.sub.3) 24.2 CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 =
CF.sub.3) 24.3 CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 =
CF.sub.3) 24.4 CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5,
R.sup.6 = CF.sub.3) 24.5 CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6
= CF.sub.3) 24.6 CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 =
CF.sub.3) 24.7 CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 =
CF.sub.3) 24.8 CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 =
CF.sub.3) 25.1 CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 =
F) 25.2 CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = F) 25.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = F) 25.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = F) 25.5
CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = F) 25.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = F) 25.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = F) 25.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = F) 26.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = Cl) 26.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = Cl) 26.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = Cl) 26.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = Cl) 26.5
CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = Cl) 26.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = Cl) 26.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = Cl) 26.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = Cl) 27.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = Br) 27.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = Br) 27.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = Br) 27.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = Br) 27.5
CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = Br) 27.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = Br) 27.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = Br) 27.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = Br) 28.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = I) 28.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = I) 28.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = I) 28.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = I) 28.5
CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = I) 28.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = I) 28.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = I) 28.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = I) 29.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = OCH.sub.3) 29.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = OCH.sub.3) 29.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = OCH.sub.3) 29.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = OCH.sub.3)
29.5 CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = OCH.sub.3) 29.6
CO.sub.2CH.sub.3 A2(R.sup.5 = Cl, R.sup.6 = OCH.sub.3) 29.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = OCH.sub.3) 29.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = OCH.sub.3) 30.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.6 = NH.sub.2) 30.2
CO.sub.2CH.sub.3 A2 (R.sup.5 = CHF.sub.2, R.sup.6 = NH.sub.2) 30.3
CO.sub.2CH.sub.3 A2 (R.sup.5 = CH.sub.3, R.sup.6 = NH.sub.2) 30.4
CO.sub.2CH.sub.3 A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = NH.sub.2)
30.5 CO.sub.2CH.sub.3 A2 (R.sup.5 = F, R.sup.6 = NH.sub.2) 30.6
CO.sub.2CH.sub.3 A2 (R.sup.5 = Cl, R.sup.6 = NH.sub.2) 30.7
CO.sub.2CH.sub.3 A2 (R.sup.5 = Br, R.sup.6 = NH.sub.2) 30.8
CO.sub.2CH.sub.3 A2 (R.sup.5 = I, R.sup.6 = NH.sub.2) 31.1
CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6 = H) 31.2 CO.sub.2H A2
(R.sup.5 = CHF.sub.2, R.sup.6 = H) 31.3 CO.sub.2H A2 (R.sup.5 =
CH.sub.3, R.sup.6 = H) 31.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5,
R.sup.6 = H) 31.5 CO.sub.2H A2 (R.sup.5 =
F, R.sup.6 = H) 31.6 CO.sub.2H A2 (R.sup.5 = Cl, R.sup.6 = H) 31.7
CO.sub.2H A2 (R.sup.5 = Br, R.sup.6 = H) 31.8 CO.sub.2H A2 (R.sup.5
= I, R.sup.6 = H) 32.1 CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6 =
CH.sub.3) 32.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 =
CH.sub.3) 32.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 =
CH.sub.3) 32.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
CH.sub.3) 32.5 CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = CH.sub.3) 32.6
CO.sub.2H A2(R.sup.5 = Cl, R.sup.6 = CH.sub.3) 32.7 CO.sub.2H A2
(R.sup.5 = Br, R.sup.6 = CH.sub.3) 32.8 CO.sub.2H A2 (R.sup.5 = I,
R.sup.6 = CH.sub.3) 33.1 CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6
= CF.sub.3) 33.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 =
CF.sub.3) 33.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 =
CF.sub.3) 33.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
CF.sub.3) 33.5 CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = CF.sub.3) 33.6
CO.sub.2H A2 (R.sup.5 = Cl, R.sup.6 = CF.sub.3) 33.7 CO.sub.2H A2
(R.sup.5 = Br, R.sup.6 = CF.sub.3) 33.8 CO.sub.2H A2 (R.sup.5 = I,
R.sup.6 = CF.sub.3) 34.1 CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6
= F) 34.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 = F) 34.3
CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 = F) 34.4 CO.sub.2H A2
(R.sup.5 = C.sub.2H.sub.5, R.sup.6 = F) 34.5 CO.sub.2H A2 (R.sup.5
= F, R.sup.6 = F) 34.6 CO.sub.2H A2 (R.sup.5 = Cl, R.sup.6 = F)
34.7 CO.sub.2H A2 (R.sup.5 = Br, R.sup.6 = F) 34.8 CO.sub.2H A2
(R.sup.5 = I, R.sup.6 = F) 35.1 CO.sub.2H A2 (R.sup.5 = CF.sub.3,
R.sup.6 = Cl) 35.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 = Cl)
35.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 = Cl) 35.4 CO.sub.2H
A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = Cl) 35.5 CO.sub.2H A2
(R.sup.5 = F, R.sup.6 = Cl) 35.6 CO.sub.2H A2 (R.sup.5 = Cl,
R.sup.6 = Cl) 35.7 CO.sub.2H A2 (R.sup.5 = Br, R.sup.6 = Cl) 35.8
CO.sub.2H A2 (R.sup.5 = I, R.sup.6 = Cl) 36.1 CO.sub.2H A2 (R.sup.5
= CF.sub.3, R.sup.6 = Br) 36.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2,
R.sup.6 = Br) 36.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 = Br)
36.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = Br) 36.5
CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = Br) 36.6 CO.sub.2H A2 (R.sup.5
= Cl, R.sup.6 = Br) 36.7 CO.sub.2H A2 (R.sup.5 = Br, R.sup.6 = Br)
36.8 CO.sub.2H A2 (R.sup.5 = I, R.sup.6 = Br) 37.1 CO.sub.2H A2
(R.sup.5 = CF.sub.3, R.sup.6 = I) 37.2 CO.sub.2H A2 (R.sup.5 =
CHF.sub.2, R.sup.6 = I) 37.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3,
R.sup.6 = I) 37.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
I) 37.5 CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = I) 37.6 CO.sub.2H A2
(R.sup.5 = Cl, R.sup.6 = I) 37.7 CO.sub.2H A2 (R.sup.5 = Br,
R.sup.6 = I) 37.8 CO.sub.2H A2 (R.sup.5 = I, R.sup.6 = I) 38.1
CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6 = OCH.sub.3) 38.2
CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 = OCH.sub.3) 38.3
CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 = OCH.sub.3) 38.4
CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = OCH.sub.3) 38.5
CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = OCH.sub.3) 38.6 CO.sub.2H A2
(R.sup.5 = Cl, R.sup.6 = OCH.sub.3) 38.7 CO.sub.2H A2 (R.sup.5 =
Br, R.sup.6 = OCH.sub.3) 38.8 CO.sub.2H A2 (R.sup.5 = I, R.sup.6 =
OCH.sub.3) 39.1 CO.sub.2H A2 (R.sup.5 = CF.sub.3, R.sup.6 =
NH.sub.2) 39.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2, R.sup.6 =
NH.sub.2) 39.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 =
NH.sub.2) 39.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
NH.sub.2) 39.5 CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = NH.sub.2) 39.6
CO.sub.2H A2 (R.sup.5 = Cl, R.sup.6 = NH.sub.2) 39.7 CO.sub.2H A2
(R.sup.5 = Br, R.sup.6 = NH.sub.2) 39.8 CO.sub.2H A2 (R.sup.5 = I,
R.sup.6 = NH.sub.2) 40.1 H A2 (R.sup.5 = CF.sub.3, R.sup.6 = H)
40.2 H A2 (R.sup.5 = CHF.sub.2, R.sup.6 = H) 40.3 H A2 (R.sup.5 =
CH.sub.3, R.sup.6 = H) 40.4 H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6
= H) 40.5 H A2 (R.sup.5 = F, R.sup.6 = H) 40.6 H A2 (R.sup.5 = Cl,
R.sup.6 = H) 40.7 H A2 (R.sup.5 = Br, R.sup.6 = H) 40.8 H A2
(R.sup.5 = I, R.sup.6 = H) 41.1 H A2 (R.sup.5 = CF.sub.3, R.sup.6 =
CH.sub.3) 41.2 H A2 (R.sup.5 = CHF.sub.2, R.sup.6 = CH.sub.3) 41.3
H A2 (R.sup.5 = CH.sub.3, R.sup.6 = CH.sub.3) 41.4 H A2 (R.sup.5 =
C.sub.2H.sub.5, 119.6.about. 1.34 (3H, t, J = 7.3), 2.71 (3H, s),
3.10 R.sup.6 = CH.sub.3) 121.1 (2H, q, J = 7.3), 7.05 (1H, dd, J =
5.3, 1. 3), 7.26-7.29 (1H, m), 7.62 (1H, dd, J = 3.3, 1.3), 7.66
(1H, brs) 41.5 H A2 (R.sup.5 = F, R.sup.6 = CH.sub.3) 41.6 H A2
(R.sup.5 = Cl, R.sup.6 = CH.sub.3) 41.7 H A2 (R.sup.5 = Br, R.sup.6
= CH.sub.3) 41.8 H A2 (R.sup.5 = I, R.sup.6 = CH.sub.3) 42.1 H A2
(R.sup.5 = CF.sub.3, R.sup.6 = CF.sub.3) 42.2 H A2 (R.sup.5 =
CHF.sub.2, R.sup.6 = CF.sub.3) 42.3 H A2 (R.sup.5 = CH.sub.3,
R.sup.6 = CF.sub.3) 42.4 H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
CF.sub.3) 42.5 H A2 (R.sup.5 = F, R.sup.6 = CF.sub.3) 42.6 H A2
(R.sup.5 = Cl, R.sup.6 = CF.sub.3) 42.7 H A2 (R.sup.5 = Br, R.sup.6
= CF.sub.3) 42.8 H A2 (R.sup.5 = I, R.sup.6 = CF.sub.3) 43.1 H A2
(R.sup.5 = CF.sub.3, R.sup.6 = F) 43.2 H A2 (R.sup.5 = CHF.sub.2,
R.sup.6 = F) 43.3 H A2 (R.sup.5 = CH.sub.3, R.sup.6 = F) 43.4 H A2
(R.sup.5 = C.sub.2H.sub.5, R.sup.6 = F) 43.5 H A2 (R.sup.5 = F,
R.sup.6 = F) 43.6 H A2 (R.sup.5 = Cl, R.sup.6 = F) 43.7 H A2
(R.sup.5 = Br, R.sup.6 = F) 43.8 H A2 (R.sup.5 = I, R.sup.6 = F)
44.1 H A2 (R.sup.5 = CF.sub.3, R.sup.6 = Cl) 44.2 H A2 (R.sup.5 =
CHF.sub.2, R.sup.6 = Cl) 44.3 H A2 (R.sup.5 = CH.sub.3, R.sup.6 =
Cl) 44.4 H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = Cl) 44.5 H A2
(R.sup.5 = F, R.sup.6 = Cl) 44.6 H A2 (R.sup.5 = Cl, R.sup.6 = Cl)
44.7 H A2 (R.sup.5 = Br, R.sup.6 = Cl) 44.8 H A2 (R.sup.5 = I,
R.sup.6 = Cl) 45.1 H A2 (R.sup.5 = CF.sub.3, R.sup.6 = Br) 45.2 H
A2 (R.sup.5 = CHF.sub.2, R.sup.6 = Br) 45.3 H A2 (R.sup.5 =
CH.sub.3, R.sup.6 = Br) 45.4 H A2 (R.sup.5 = C.sub.2H.sub.5,
R.sup.6 = Br) 45.5 H A2 (R.sup.5 = F, R.sup.6 = Br) 45.6 H A2
(R.sup.5 = Cl, R.sup.6 = Br) 45.7 H A2 (R.sup.5 = Br, R.sup.6 = Br)
45.8 H A2 (R.sup.5 = I, R.sup.6 = Br) 46.1 CO.sub.2H A2 (R.sup.5 =
CF.sub.3, R.sup.6 = I) 46.2 CO.sub.2H A2 (R.sup.5 = CHF.sub.2,
R.sup.6 = I) 46.3 CO.sub.2H A2 (R.sup.5 = CH.sub.3, R.sup.6 = I)
46.4 CO.sub.2H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 = I) 46.5
CO.sub.2H A2 (R.sup.5 = F, R.sup.6 = I) 46.6 CO.sub.2H A2 (R.sup.5
= Cl, R.sup.6 = I) 46.7 CO.sub.2H A2 (R.sup.5 = Br, R.sup.6 = I)
46.8 CO.sub.2H A2 (R.sup.5 = I, R.sup.6 = I) 47.1 H A2 (R.sup.5 =
CF.sub.3, R.sup.6 = OCH.sub.3) 47.2 H A2 (R.sup.5 = CHF.sub.2,
R.sup.6 = OCH.sub.3) 47.3 H A2 (R.sup.5 = CH.sub.3, R.sup.6 =
OCH.sub.3) 47.4 H A2 (R.sup.5 = C.sub.2H.sub.5, R.sup.6 =
OCH.sub.3) 47.5 H A2 (R.sup.5 = F, R.sup.6 = OCH.sub.3) 47.6 H A2
(R.sup.5 = Cl, R.sup.6 = OCH.sub.3) 47.7 H A2 (R.sup.5 = Br,
R.sup.6 = OCH.sub.3) 47.8 H A2 (R.sup.5 = I, R.sup.6 = OCH.sub.3)
48.1 H A2 (R.sup.5 = CF.sub.3, R.sup.6 = NH.sub.2) 48.2 H A2
(R.sup.5 = CHF.sub.2, R.sup.6 = NH.sub.2) 48.3 H A2 (R.sup.5 =
CH.sub.3, R.sup.6 = NH.sub.2) 48.4 H A2 (R.sup.5 = C.sub.2H.sub.5,
R.sup.6 = NH.sub.2) 48.5 H A2 (R.sup.5 = F, R.sup.6 = NH.sub.2)
48.6 H A2 (R.sup.5 = Cl, R.sup.6 = NH.sub.2) 48.7 H A2 (R.sup.5 =
Br, R.sup.6 = NH.sub.2) 48.8 H A2 (R.sup.5 = I, R.sup.6 = NH.sub.2)
49.1 CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 = H) 49.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = H) 49.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, 135.3.about. 2.68 (3H, s),
3.92 (3H, s), 6.72 (1H, d, R.sup.8 = H) 136.2 J = 2.3), 7.31 (1H,
d, J = 2.3), 7.50 (1H, d, J = 5.3), 8.23 (1H, d, J = 5.3), 10.70
(1H, brs) 49.4 CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5,
R.sup.8 = H) 49.5 CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = H)
49.6 CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = H) 49.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = H) 49.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = H) 50.1
CO.sub.2CH.sub.3 A2 (R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3) 50.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = CH.sub.3) 50.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, R.sup.8 = CH.sub.3) 50.4
CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.3)
50.5 CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = CH.sub.3) 50.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = CH.sub.3) 50.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = CH.sub.3) 50.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = CH.sub.3) 51.1
CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 51.2 CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2,
R.sup.8 = CH.sub.2CH.sub.3) 51.3 CO.sub.2CH.sub.3 A3 (R.sup.5 =
CH.sub.3, R.sup.8 = CH.sub.2CH.sub.3) 51.4 CO.sub.2CH.sub.3 A3
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.2CH.sub.3) 51.5
CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = CH.sub.2CH.sub.3) 51.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = CH.sub.2CH.sub.3) 51.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = CH.sub.2CH.sub.3) 51.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = CH.sub.2CH.sub.3) 52.1
CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 = F) 52.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = F) 52.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, R.sup.8 = F) 52.4
CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = F) 52.5
CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = F) 52.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = F) 52.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = F) 52.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = F) 53.1
CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 = Cl) 53.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl) 53.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 53.4
CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 53.5
CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = Cl) 53.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = Cl) 53.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = Cl) 53.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = Cl) 54.1
CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 = Br) 54.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = Br) 54.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, R.sup.8 = Br) 54.4
CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Br) 54.5
CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = Br) 54.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = Br) 54.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = Br) 54.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = Br) 55.1
CO.sub.2CH.sub.3 A3 (R.sup.5 = CF.sub.3, R.sup.8 = I) 55.2
CO.sub.2CH.sub.3 A3 (R.sup.5 = CHF.sub.2, R.sup.8 = I) 55.3
CO.sub.2CH.sub.3 A3 (R.sup.5 = CH.sub.3, R.sup.8 = I) 55.4
CO.sub.2CH.sub.3 A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = I) 55.5
CO.sub.2CH.sub.3 A3 (R.sup.5 = F, R.sup.8 = I) 55.6
CO.sub.2CH.sub.3 A3 (R.sup.5 = Cl, R.sup.8 = I) 55.7
CO.sub.2CH.sub.3 A3 (R.sup.5 = Br, R.sup.8 = I) 55.8
CO.sub.2CH.sub.3 A3 (R.sup.5 = I, R.sup.8 = I) 56.1 CO.sub.2H A3
(R.sup.5 = CF.sub.3, R.sup.8 = H) 56.2 CO.sub.2H A3 (R.sup.5 =
CHF.sub.2, R.sup.8 = H) 56.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3,
R.sup.8 = H) 56.4 CO.sub.2H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
H) 56.5 CO.sub.2H A3 (R.sup.5 = F, R.sup.8 = H) 56.6 CO.sub.2H A3
(R.sup.5 = Cl, R.sup.8 = H) 56.7 CO.sub.2H A3 (R.sup.5 = Br,
R.sup.8 = H) 56.8 CO.sub.2H A3 (R.sup.5 = I, R.sup.8 = H) 57.1
CO.sub.2H A3 (R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3) 57.2
CO.sub.2H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = CH.sub.3) 57.3
CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 = CH.sub.3) 57.4
CO.sub.2H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.3) 57.5
CO.sub.2H A3 (R.sup.5 = F, R.sup.8 = CH.sub.3) 57.6 CO.sub.2H A3
(R.sup.5 = Cl, R.sup.8 = CH.sub.3) 57.7 CO.sub.2H A3 (R.sup.5 = Br,
R.sup.8 = CH.sub.3) 57.8 CO.sub.2H A3 (R.sup.5 = I, R.sup.8 =
CH.sub.3) 58.1 CO.sub.2H A3 (R.sup.5 = CF.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 58.2 CO.sub.2H A3 (R.sup.5 = CHF.sub.2, R.sup.8 =
CH.sub.2CH.sub.3) 58.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 58.4 CO.sub.2H A3 (R.sup.5 = C.sub.2H.sub.5,
R.sup.8 = CH.sub.2CH.sub.3) 58.5 CO.sub.2H A3 (R.sup.5 = F, R.sup.8
= CH.sub.2CH.sub.3) 58.6 CO.sub.2H A3 (R.sup.5 = Cl, R.sup.8 =
CH.sub.2CH.sub.3) 58.7 CO.sub.2H A3 (R.sup.5 = Br, R.sup.8 =
CH.sub.2CH.sub.3) 58.8 CO.sub.2H A3 (R.sup.5 = I, R.sup.8 =
CH.sub.2CH.sub.3) 59.1 CO.sub.2H A3 (R.sup.5 = CF.sub.3, R.sup.8 =
F) 59.2 CO.sub.2H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = F) 59.3
CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 = F) 59.4 CO.sub.2H A3
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = F) 59.5 CO.sub.2H A3 (R.sup.5
= F, R.sup.8 = F) 59.6 CO.sub.2H A3 (R.sup.5 = Cl, R.sup.8 = F)
59.7 CO.sub.2H A3 (R.sup.5 = Br, R.sup.8 = F) 59.8 CO.sub.2H A3
(R.sup.5 = I, R.sup.8 = F) 60.1 CO.sub.2H A3 (R.sup.5 = CF.sub.3,
R.sup.8 = Cl) 60.2 CO.sub.2H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl)
60.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 60.4 CO.sub.2H
A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 60.5 CO.sub.2H A3
(R.sup.5 = F, R.sup.8 = Cl) 60.6 CO.sub.2H A3 (R.sup.5 = Cl,
R.sup.8 = Cl) 60.7 CO.sub.2H A3 (R.sup.5 = Br, R.sup.8 = Cl) 60.8
CO.sub.2H A3 (R.sup.5 = I, R.sup.8 = Cl) 61.1 CO.sub.2H A3 (R.sup.5
= CF.sub.3, R.sup.8 = Br) 61.2 CO.sub.2H A3 (R.sup.5 = CHF.sub.2,
R.sup.8 = Br) 61.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 = Br)
61.4 CO.sub.2H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Br) 61.5
CO.sub.2H A3 (R.sup.5 = F, R.sup.8 = Br) 61.6 CO.sub.2H A3 (R.sup.5
= Cl, R.sup.8 = Br) 61.7 CO.sub.2H A3 (R.sup.5 = Br, R.sup.8 = Br)
61.8 CO.sub.2H A3 (R.sup.5 = I, R.sup.8 = Br) 62.1 CO.sub.2H A3
(R.sup.5 = CF.sub.3, R.sup.8 = I) 62.2 CO.sub.2H A3 (R.sup.5 =
CHF.sub.2, R.sup.8 = I) 62.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3,
R.sup.8 = I) 62.4 CO.sub.2H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
I) 62.5 CO.sub.2H A3 (R.sup.5 = F, R.sup.8 = I) 62.6 CO.sub.2H A3
(R.sup.5 = Cl, R.sup.8 = I) 62.7 CO.sub.2H A3 (R.sup.5 = Br,
R.sup.8 = I) 62.8 CO.sub.2H A3 (R.sup.5 = I, R.sup.8 = I) 63.1 H A3
(R.sup.5 = CF.sub.3, R.sup.8 = H) 63.2 H A3 (R.sup.5 = CHF.sub.2,
R.sup.8 = H) 63.3 H A3 (R.sup.5 = CH.sub.3, 118.4.about. 2.64 (3H,
s), 6.53 (1H, d, J = 2.3), 7.07
R.sup.8 = H) 120.4 (1H, dd, J = 5.3, 1.3), 7.25 (1H, dd, J = 5 .3,
3.3), 7.29 (1H, d, J = 2.3) 7.63 (1H, dd, J = 3.3, 1.3), 7.41 (1H,
brs) 63.4 H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = H) 63.5 H A3
(R.sup.5 = F, R.sup.8 = H) 63.6 H A3 (R.sup.5 = Cl, R.sup.8 = H)
63.7 H A3 (R.sup.5 = Br, R.sup.8 = H) 63.8 H A3 (R.sup.5 = I,
R.sup.8 = H) 64.1 H A3 (R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3)
64.2 H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = CH.sub.3) 64.3 H A3
(R.sup.5 = CH.sub.3, R.sup.8 = CH.sub.3) 64.4 H A3 (R.sup.5 =
C.sub.2H.sub.5, R.sup.8 = CH.sub.3) 64.5 H A3 (R.sup.5 = F, R.sup.8
= CH.sub.3) 64.6 H A3 (R.sup.5 = Cl, R.sup.8 = CH.sub.3) 64.7 H A3
(R.sup.5 = Br, R.sup.8 = CH.sub.3) 64.8 H A3 (R.sup.5 = I, R.sup.8
= CH.sub.3) 65.1 H A3 (R.sup.5 = CF.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 65.2 H A3 (R.sup.5 = CHF.sub.2, R.sup.8 =
CH.sub.2CH.sub.3) 65.3 H A3 (R.sup.5 = CH.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 65.4 H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
CH.sub.2CH.sub.3) 65.5 H A3 (R.sup.5 = F, R.sup.8 =
CH.sub.2CH.sub.3) 65.6 H A3 (R.sup.5 = Cl, R.sup.8 =
CH.sub.2CH.sub.3) 65.7 H A3 (R.sup.5 = Br, R.sup.8 =
CH.sub.2CH.sub.3) 65.8 H A3 (R.sup.5 = I, R.sup.8 =
CH.sub.2CH.sub.3) 66.1 H A3 (R.sup.5 = CF.sub.3, R.sup.8 = F) 66.2
H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = F) 66.3 H A3 (R.sup.5 =
CH.sub.3, R.sup.8 = F) 66.4 H A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8
= F) 66.5 H A3 (R.sup.5 = F, R.sup.8 = F) 66.6 H A3 (R.sup.5 = Cl,
R.sup.8 = F) 66.7 H A3 (R.sup.5 = Br, R.sup.8 = F) 66.8 H A3
(R.sup.5 = I, R.sup.8 = F) 67.1 CO.sub.2H A3 (R.sup.5 = CF.sub.3,
R.sup.8 = Cl) 67.2 CO.sub.2H A3 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl)
67.3 CO.sub.2H A3 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 67.4 CO.sub.2H
A3 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 67.5 CO.sub.2H A3
(R.sup.5 = F, R.sup.8 = Cl) 67.6 CO.sub.2H A3 (R.sup.5 = Cl,
R.sup.8 = Cl) 67.7 CO.sub.2H A3 (R.sup.5 = Br, R.sup.8 = Cl) 67.8
CO.sub.2H A3 (R.sup.5 = I, R.sup.8 = Cl) 68.1 H A3 (R.sup.5 =
CF.sub.3, R.sup.8 = Br) 68.2 H A3 (R.sup.5 = CHF.sub.2, R.sup.8 =
Br) 68.3 H A3 (R.sup.5 = CH.sub.3, R.sup.8 = Br) 68.4 H A3 (R.sup.5
= C.sub.2H.sub.5, R.sup.8 = Br) 68.5 H A3 (R.sup.5 = F, R.sup.8 =
Br) 68.6 H A3 (R.sup.5 = Cl, R.sup.8 = Br) 68.7 H A3 (R.sup.5 = Br,
R.sup.8 = Br) 68.8 H A3 (R.sup.5 = I, R.sup.8 = Br) 69.1 H A3
(R.sup.5 = CF.sub.3, R.sup.8 = I) 69.2 H A3 (R.sup.5 = CHF.sub.2,
R.sup.8 = I) 69.3 H A3 (R.sup.5 = CH.sub.3, R.sup.8 = I) 69.4 H A3
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = I) 69.5 H A3 (R.sup.5 = F,
R.sup.8 = I) 69.6 H A3 (R.sup.5 = Cl, R.sup.8 = I) 69.7 H A3
(R.sup.5 = Br, R.sup.8 = I) 69.8 H A3 (R.sup.5 = I, R.sup.8 = I)
70.1 CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = H) 70.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = H) 70.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, 157.8.about. 2.66 (3H, s),
3.92 (3H, s), 6.95 (1H, d, R.sup.8 = H) 158.7 J = 4.9), 7.38 (1H,
d, J = 4.9), 7.50 (1H, d, J = 5.3), 8.23 (1H, d, J = 5.3), 10.8 (1
H, brs) 70.4 CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8
= H) 70.5 CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = H) 70.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = H) 70.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = H) 70.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = H) 71.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3) 71.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = CH.sub.3) 71.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, R.sup.8 = CH.sub.3) 71.4
CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.3)
71.5 CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = CH.sub.3) 71.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = CH.sub.3) 71.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = CH.sub.3) 71.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = CH.sub.3) 72.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 72.2 CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2,
R.sup.8 = CH.sub.2CH.sub.3) 72.3 CO.sub.2CH.sub.3 A4 (R.sup.5 =
CH.sub.3, R.sup.8 = CH.sub.2CH.sub.3) 72.4 CO.sub.2CH.sub.3 A4
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.2CH.sub.3) 72.5
CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = CH.sub.2CH.sub.3) 72.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = CH.sub.2CH.sub.3) 72.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = CH.sub.2CH.sub.3) 72.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = CH.sub.2CH.sub.3) 73.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = F) 73.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = F) 73.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, R.sup.8 = F) 73.4
CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = F) 73.5
CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = F) 73.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = F) 73.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = F) 73.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = F) 74.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = Cl) 74.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl) 74.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 74.4
CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 74.5
CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = Cl) 74.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = Cl) 74.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = Cl) 74.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = Cl) 75.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = Br) 75.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = Br) 75.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, R.sup.8 = Br) 75.4
CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Br) 75.5
CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = Br) 75.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = Br) 75.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = Br) 75.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = Br) 76.1
CO.sub.2CH.sub.3 A4 (R.sup.5 = CF.sub.3, R.sup.8 = I) 76.2
CO.sub.2CH.sub.3 A4 (R.sup.5 = CHF.sub.2, R.sup.8 = I) 76.3
CO.sub.2CH.sub.3 A4 (R.sup.5 = CH.sub.3, R.sup.8 = I) 76.4
CO.sub.2CH.sub.3 A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = I) 76.5
CO.sub.2CH.sub.3 A4 (R.sup.5 = F, R.sup.8 = I) 76.6
CO.sub.2CH.sub.3 A4 (R.sup.5 = Cl, R.sup.8 = I) 76.7
CO.sub.2CH.sub.3 A4 (R.sup.5 = Br, R.sup.8 = I) 76.8
CO.sub.2CH.sub.3 A4 (R.sup.5 = I, R.sup.8 = I) 77.1 CO.sub.2H A4
(R.sup.5 = CF.sub.3, R.sup.8 = H) 77.2 CO.sub.2H A4 (R.sup.5 =
CHF.sub.2, R.sup.8 = H) 77.3 CO.sub.2H A4 (R.sup.5 = CH.sub.3,
R.sup.8 = H) 77.4 CO.sub.2H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
H) 77.5 CO.sub.2H A4 (R.sup.5 = F, R.sup.8 = H) 77.6 CO.sub.2H A4
(R.sup.5 = Cl, R.sup.8 = H) 77.7 CO.sub.2H A4 (R.sup.5 = Br,
R.sup.8 = H) 77.8 CO.sub.2H A4 (R.sup.5 = I, R.sup.8 = H) 78.1
CO.sub.2H A4 (R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3) 78.2
CO.sub.2H A4 (R.sup.5 = CHF.sub.2, R.sup.8 = CH.sub.3) 78.3
CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 = CH.sub.3) 78.4
CO.sub.2H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = CH.sub.3) 78.5
CO.sub.2H A4 (R.sup.5 = F, R.sup.8 = CH.sub.3) 78.6 CO.sub.2H A4
(R.sup.5 = Cl, R.sup.8 = CH.sub.3) 78.7 CO.sub.2H A4 (R.sup.5 = Br,
R.sup.8 = CH.sub.3) 78.8 CO.sub.2H A4 (R.sup.5 = I, R.sup.8 =
CH.sub.3) 79.1 CO.sub.2H A4 (R.sup.5 = CF.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 79.2 CO.sub.2H A4 (R.sup.5 = CHF.sub.2, R.sup.8 =
CH.sub.2CH.sub.3) 79.3 CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 =
CH.sub.2CH.sub.3) 79.4 CO.sub.2H A4 (R.sup.5 = C.sub.2H.sub.5,
R.sup.8 = CH.sub.2CH.sub.3) 79.5 CO.sub.2H A4 (R.sup.5 = F, R.sup.8
= CH.sub.2CH.sub.3) 79.6 CO.sub.2H A4 (R.sup.5 = Cl, R.sup.8 =
CH.sub.2CH.sub.3) 79.7 CO.sub.2H A4 (R.sup.5 = Br, R.sup.8 =
CH.sub.2CH.sub.3) 79.8 CO.sub.2H A4 (R.sup.5 = I, R.sup.8 =
CH.sub.2CH.sub.3) 80.1 CO.sub.2H A4 (R.sup.5 = CF.sub.3, R.sup.8 =
F) 80.2 CO.sub.2H A4 (R.sup.5 = CHF.sub.2, R.sup.8 = F) 80.3
CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 = F) 80.4 CO.sub.2H A4
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = F) 80.5 CO.sub.2H A4 (R.sup.5
= F, R.sup.8 = F) 80.6 CO.sub.2H A4 (R.sup.5 = Cl, R.sup.8 = F)
80.7 CO.sub.2H A4 (R.sup.5 = Br, R.sup.8 = F) 80.8 CO.sub.2H A4
(R.sup.5 = I, R.sup.8 = F) 81.1 CO.sub.2H A4 (R.sup.5 = CF.sub.3,
R.sup.8 = Cl) 81.2 CO.sub.2H A4 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl)
81.3 CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 81.4 CO.sub.2H
A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 81.5 CO.sub.2H A4
(R.sup.5 = F, R.sup.8 = Cl) 81.6 CO.sub.2H A4 (R.sup.5 = Cl,
R.sup.8 = Cl) 81.7 CO.sub.2H A4 (R.sup.5 = Br, R.sup.8 = Cl) 81.8
CO.sub.2H A4 (R.sup.5 = I, R.sup.8 = Cl) 82.1 CO.sub.2H A4 (R.sup.5
= CF.sub.3, R.sup.8 = Br) 82.2 CO.sub.2H A4 (R.sup.5 = CHF.sub.2,
R.sup.8 = Br) 82.3 CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 = Br)
82.4 CO.sub.2H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Br) 82.5
CO.sub.2H A4 (R.sup.5 = F, R.sup.8 = Br) 82.6 CO.sub.2H A4 (R.sup.5
= Cl, R.sup.8 = Br) 82.7 CO.sub.2H A4 (R.sup.5 = Br, R.sup.8 = Br)
82.8 CO.sub.2H A4 (R.sup.5 = I, R.sup.8 = Br) 83.1 CO.sub.2H A4
(R.sup.5 = CF.sub.3, R.sup.8 = I) 83.2 CO.sub.2H A4 (R.sup.5 =
CHF.sub.2, R.sup.8 = I) 83.3 CO.sub.2H A4 (R.sup.5 = CH.sub.3,
R.sup.8 = I) 83.4 CO.sub.2H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
I) 83.5 CO.sub.2H A4 (R.sup.5 = F, R.sup.8 = I) 83.6 CO.sub.2H A4
(R.sup.5 = Cl, R.sup.8 = I) 83.7 CO.sub.2H A4 (R.sup.5 = Br,
R.sup.8 = I) 83.8 CO.sub.2H A4 (R.sup.5 = I, R.sup.8 = I) 84.1 H A4
(R.sup.5 = CF.sub.3, R.sup.8 = H) 84.2 H A4 (R.sup.5 = CHF.sub.2,
R.sup.8 = H) 84.3 H A4 (R.sup.5 = CH.sub.3, 100.about. 2.58 (3H,
s), 6.93 (1H, d, J = 4.8), 7.07 R.sup.8 = H 100.8 (1H, dd, J = 5.1,
1.3), 7.26 (1H, dd, J = 5 .1, 3.1), 7.31 (1H, d, J = 4.8), 7.64 (1H
dd, J = 3.1, 1.3), 7.82 (1H, brs) 84.4 H A4 (R.sup.5 =
C.sub.2H.sub.5, R.sup.8 = H) 84.5 H A4 (R.sup.5 = F, R.sup.8 = H)
84.6 H A4 (R.sup.5 = Cl, R.sup.8 = H) 84.7 H A4 (R.sup.5 = Br,
R.sup.8 = H) 84.8 H A4 (R.sup.5 = I, R.sup.8 = H) 85.1 H A4
(R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.3) 85.2 H A4 (R.sup.5 =
CHF.sub.2, R.sup.8 = CH.sub.3) 85.3 H A4 (R.sup.5 = CH.sub.3,
R.sup.8 = CH.sub.3) 85.4 H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 =
CH.sub.3) 85.5 H A4 (R.sup.5 = F, R.sup.8 = CH.sub.3) 85.6 H A4
(R.sup.5 = Cl, R.sup.8 = CH.sub.3) 85.7 H A4 (R.sup.5 = Br, R.sup.8
= CH.sub.3) 85.8 H A4 (R.sup.5 = I, R.sup.8 = CH.sub.3) 86.1 H A4
(R.sup.5 = CF.sub.3, R.sup.8 = CH.sub.2CH.sub.3) 86.2 H A4 (R.sup.5
= CHF.sub.2, R.sup.8 = CH.sub.2CH.sub.3) 86.3 H A4 (R.sup.5 =
CH.sub.3, R.sup.8 = CH.sub.2CH.sub.3) 86.4 H A4 (R.sup.5 =
C.sub.2H.sub.5, R.sup.8 = CH.sub.2CH.sub.3) 86.5 H A4 (R.sup.5 = F,
R.sup.8 = CH.sub.2CH.sub.3) 86.6 H A4 (R.sup.5 = Cl, R.sup.8 =
CH.sub.2CH.sub.3) 86.7 H A4 (R.sup.5 = Br, R.sup.8 =
CH.sub.2CH.sub.3) 86.8 H A4 (R.sup.5 = I, R.sup.8 =
CH.sub.2CH.sub.3) 87.1 H A4 (R.sup.5 = CF3, R.sup.8 = F) 87.2 H A4
(R.sup.5 = CHF.sub.2, R.sup.8 = F) 87.3 H A4 (R.sup.5 = CH.sub.3,
R.sup.8 = F) 87.4 H A4 (R.sup.5 = C.sub.2H.sub.5, R.sup.8 = F) 87.5
H A4 (R.sup.5 = F, R.sup.8 = F) 87.6 H A4 (R.sup.5 = Cl, R.sup.8 =
F) 87.7 H A4 (R.sup.5 = Br, R.sup.8 = F) 87.8 H A4 (R.sup.5 = I,
R.sup.8 = F) 88.1 CO.sub.2H A4 (R.sup.5 = CF.sub.3, R.sup.8 = Cl)
88.2 CO.sub.2H A4 (R.sup.5 = CHF.sub.2, R.sup.8 = Cl) 88.3
CO.sub.2H A4 (R.sup.5 = CH.sub.3, R.sup.8 = Cl) 88.4 CO.sub.2H A4
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = Cl) 88.5 CO.sub.2H A4 (R.sup.5
= F, R.sup.8 = Cl) 88.6 CO.sub.2H A4 (R.sup.5 = Cl, R.sup.8 = Cl)
88.7 CO.sub.2H A4 (R.sup.5 = Br, R.sup.8 = Cl) 88.8 CO.sub.2H A4
(R.sup.5 = I, R.sup.8 = Cl) 89.1 H A4 (R.sup.5 = CF.sub.3, R.sup.8
= Br) 89.2 H A4 (R.sup.5 = CHF.sub.2, R.sup.8 = Br) 89.3 H A4
(R.sup.5 = CH.sub.3, R.sup.8 = Br) 89.4 H A4 (R.sup.5 =
C.sub.2H.sub.5, R.sup.8 = Br) 89.5 H A4 (R.sup.5 = F, R.sup.8 = Br)
89.6 H A4 (R.sup.5 = Cl, R.sup.8 = Br) 89.7 H A4 (R.sup.5 = Br,
R.sup.8 = Br) 89.8 H A4 (R.sup.5 = I, R.sup.8 = Br) 90.1 H A4
(R.sup.5 = CF.sub.3, R.sup.8 = I) 90.2 H A4 (R.sup.5 = CHF.sub.2,
R.sup.8 = I) 90.3 H A4 (R.sup.5 = CH.sub.3, R.sup.8 = I) 90.4 H A4
(R.sup.5 = C.sub.2H.sub.5, R.sup.8 = I) 90.5 H A4 (R.sup.5 = F,
R.sup.8 = I) 90.6 H A4 (R.sup.5 = Cl, R.sup.8 = I) 90.7 H A4
(R.sup.5 = Br, R.sup.8 = I) 90.8 H A4 (R.sup.5 = I, R.sup.8 = I)
91.1 CO.sub.2CH.sub.3 A5 (R.sup.5 = CF.sub.3) 91.2 CO.sub.2CH.sub.3
A5 (R.sup.5 = CHF.sub.2) 91.3 CO.sub.2CH.sub.3 A5 (R.sup.5 =
CH.sub.3) 122.4.about. 2.57 (3H, s), 3.88 (3H, s), 7.29.about.7.42
123.1 (3H, m), 7.53.about.7.55 (1H, m), 7.60.about. 7.63 (1H, m),
8.30 (1H, d, J = 5.3) 10.60 (1H, brs) 91.4 CO.sub.2CH.sub.3 A5
(R.sup.5 = C.sub.2H.sub.5) 91.5 CO.sub.2CH.sub.3 A5 (R.sup.5 = F)
91.6 CO.sub.2CH.sub.3 A5 (R.sup.5 = Cl) 91.7 CO.sub.2CH.sub.3 A5
(R.sup.5 = Br) 91.8 CO.sub.2CH.sub.3 A5 (R.sup.5 = I) 92.1
CO.sub.2H A5 (R.sup.5 = CF.sub.3) 92.2 CO.sub.2H A5 (R.sup.5 =
CHF.sub.2) 92.3 CO.sub.2H A5 (R.sup.5 = CH.sub.3) 200.9.about. 2.46
(3H, s), 7.33.about.7.38 (2H, m), 7.44.about. 201.4 7.50 (1H, m),
7.60.about.7.64 (1H, m), 7.93 (1H, d, J = 5.6), 8.11 (1H, d, J =
5.6), 10 .7 (1H, s) 92.4 CO.sub.2H A5 (R.sup.5 = C.sub.2H.sub.5)
92.5 CO.sub.2H A5 (R.sup.5 = F) 92.6 CO.sub.2H A5 (R.sup.5 = Cl)
92.7 CO.sub.2H A5 (R.sup.5 = Br) 92.8 CO.sub.2H A5 (R.sup.5 = I)
93.1 H A5 (R.sup.5 = CF.sub.3) 93.2 H A5 (R.sup.5 = CHF.sub.2) 93.3
H A5 (R.sup.5 = CH.sub.3) 162.2.about. 2.49 (3H, s), 7.05 (1H, dd,
J = 5.3, 1.3), 163.8 7.24.about.7.36 (5H, m), 7.70 (1H, dd, J =
2.9, 1.3) 7.84 (1H, brs) 93.4 H A5 (R.sup.5 = C.sub.2H.sub.5) 93.5
H A5 (R.sup.5 = F) 93.6 H A5 (R.sup.5 = Cl) 93.7 H A5 (R.sup.5 =
Br) 93.8 H A5 (R.sup.5 = I) 94.1 CO.sub.2CH.sub.3 A6 (R.sup.5 =
CF.sub.3) 94.2 CO.sub.2CH.sub.3 A6 (R.sup.5 = CHF.sub.2) 93.3
CO.sub.2CH.sub.3 A6 (R.sup.5 = CH.sub.3) 93.4 CO.sub.2CH.sub.3 A6
(R.sup.5 = C.sub.2H.sub.5) 94.5 CO.sub.2CH.sub.3 A6 (R.sup.5 = F)
94.6 CO.sub.2CH.sub.3 A6 (R.sup.5 = Cl) 152.5.about. 3.90 (3H, s),
7.40 (1H, dd, J = 7.6, 4.9), 153.4 7.56 (1H, d, J = 5.3), 8.09 (1H,
dd, J = 7 6, 2.0), 8.27 (1H, d, J = 5.3), 8.54 (1H, dd, J = 4.9,
2.0), 10.92 (1H, brs) 93.7 CO.sub.2CH.sub.3 A6 (R.sup.5 = Br) 94.8
CO.sub.2CH.sub.3 A6 (R.sup.5 = I) 95.1 CO.sub.2H A6 (R.sup.5 =
CF.sub.3) 95.2 CO.sub.2H A6 (R.sup.5 = CHF.sub.2) 95.3
CO.sub.2H A6 (R.sup.5 = CH.sub.3) 95.4 CO.sub.2H A6 (R.sup.5 =
C.sub.2H.sub.5) 95.5 CO.sub.2H A6 (R.sup.5 = F) 95.6 CO.sub.2H A6
(R.sup.5 = Cl) more 7.61 (1H, dd, J = 7.6, 4.9), 7.92 (1H, d, than
J = 5.3), 8.06 (1H, d, J = 5.3), 8.21 (1H, 200.degree. C. dd, J =
7.6, 2.0), 8.59 (1H, dd, J = 4.9, 2 .0), 10.84 (1H, s) 95.7
CO.sub.2H A6 (R.sup.5 = Br) 95.8 CO.sub.2H A6 (R.sup.5 = I) 96.1 H
A6 (R.sup.5 = CF.sub.3) 96.2 H A6 (R.sup.5 = CHF.sub.2) 96.3 H A6
(R.sup.5 = CH.sub.3) 96.4 H A6 (R.sup.5 = C.sub.2H.sub.5) 96.5 H A6
(R.sup.5 = F) 96.6 H A6 (R.sup.5 = Cl) semi- 7.11 (1H, dd, J = 5.3,
1.3), 7.30 (1H, dd, solid J = 5.3, 3.3), 7.41 (1H, dd, J = 7.9,
4.7), 7.76 (1H, dd, J = 3.3, 1.3), 8.20- 8.23 (1H, m), 8.50 (1H,
dd, J = 4.7, 2.0), 8.58 (1H, brs) 96.7 H A6 (R.sup.5 = Br) 96.8 H
A6 (R.sup.5 = I) 97.1 CO.sub.2CH.sub.3 A7 97.2 CO.sub.2H A7 97.3 H
A7 98.1 CO.sub.2CH.sub.3 A8 (R.sup.5 = CF.sub.3) 98.2
CO.sub.2CH.sub.3 A8 (R.sup.5 = CHF.sub.2) 98.3 CO.sub.2CH.sub.3 A8
(R.sup.5 = CH.sub.3) 98.4 CO.sub.2CH.sub.3 A8 (R.sup.5 =
C.sub.2H.sub.5) 98.5 CO.sub.2CH.sub.3 A8 (R.sup.5 = F) 98.6
CO.sub.2CH.sub.3 A8 (R.sup.5 = Cl) 98.7 CO.sub.2CH.sub.3 A8
(R.sup.5 = Br) 98.8 CO.sub.2CH.sub.3 A8 (R.sup.5 = I) 99.1
CO.sub.2H A8 (R.sup.5 = CF.sub.3) 99.2 CO.sub.2H A8 (R.sup.5 =
CHF.sub.2) 99.3 CO.sub.2H A8 (R.sup.5 = CH.sub.3) 99.4 CO.sub.2H A8
(R.sup.5 = C.sub.2H.sub.5) 99.5 CO.sub.2H A8 (R.sup.5 = F) 99.6
CO.sub.2H A8 (R.sup.5 = Cl) 99.7 CO.sub.2H A8 (R.sup.5 = Br) 99.8
CO.sub.2H A8 (R.sup.5 = I) 100.1 H A8 (R.sup.5 = CF.sub.3) 100.2 H
A8 (R.sup.5 = CHF.sub.2) 100.3 H A8 (R.sup.5 = CH.sub.3) 100.4 H A8
(R.sup.5 = C.sub.2H.sub.5) 100.5 H A8 (R.sup.5 = F) 100.6 H A8
(R.sup.5 = Cl) 100.7 H A8 (R.sup.5 = Br) 100.8 H A8 (R.sup.5 = I)
101.1 CO.sub.2CH.sub.3 A9 (R.sup.5 = CF.sub.3) 101.2
CO.sub.2CH.sub.3 A9 (R.sup.5 = CHF.sub.2) 101.3 CO.sub.2CH.sub.3 A9
(R.sup.5 = CH.sub.3) 101.4 CO.sub.2CH.sub.3 A9 (R.sup.5 =
C.sub.2H.sub.5) 102.1 CO.sub.2H A9 (R.sup.5 = CF.sub.3) 102.2
CO.sub.2H A9 (R.sup.5 = CHF2) 102.3 CO.sub.2H A9 (R.sup.5 =
CH.sub.3) 102.4 CO.sub.2H A9 (R.sup.5 = C.sub.2H.sub.5) 103.1 H A9
(R.sup.5 = CF.sub.3) 103.2 H A9 (R.sup.5 = CHF.sub.2) 103.3 H A9
(R.sup.5 = CH.sub.3) 151.1.about. 1.89.about.1.97 (2H, m), 2.19
(3H, s), 2.32 152.6 .about.2.37 (2H, m), 4.02.about.4.05 (2H, m),
6.99 (1H, dd, J = 5.3, 1.3), 7.23 (1H, dd, J = 5.3, 3.3), 7.40 (1H,
brs), 7.58 (1H, dd, J = 3.3, 1.3) 103.4 H A9 (R.sup.5 =
C.sub.2H.sub.5) 104.1 CO.sub.2CH.sub.3 A10 (R.sup.5 = CF.sub.3)
104.2 CO.sub.2CH.sub.3 A10 (R.sup.5 = CHF.sub.2) 104.3
CO.sub.2CH.sub.3 A10 (R.sup.5 = CH.sub.3) 104.4 CO.sub.2CH.sub.3
A10 (R.sup.5 = C.sub.2H.sub.5) 105.1 CO.sub.2H A10 (R.sup.5 =
CF.sub.3) 105.2 CO.sub.2H A10 (R.sup.5 = CHF.sub.2) 105.3 CO.sub.2H
A10 (R.sup.5 = CH.sub.3) 105.4 CO.sub.2H A10 (R.sup.5 =
C.sub.2H.sub.5) 106.1 H A10 (R.sup.5 = CF.sub.3) 106.2 H A10
(R.sup.5 = CHF.sub.2) 106.3 H A10 (R.sup.5 = CH.sub.3) 106.4 H A10
(R.sup.5 = C.sub.2H.sub.5) 107.1 CO.sub.2CH.sub.3 A11 (R.sup.5 =
CF.sub.3) 107.2 CO.sub.2CH.sub.3 A11 (R.sup.5 = CHF.sub.2) 107.3
CO.sub.2CH.sub.3 A11 (R.sup.5 = CH.sub.3) 107.4 CO.sub.2CH.sub.3
A11 (R.sup.5 = C.sub.2H.sub.5) 108.1 CO.sub.2H A11 (R.sup.5 =
CF.sub.3) 108.2 CO.sub.2H A11 (R.sup.5 = CHF.sub.2) 108.3 CO.sub.2H
A11 (R.sup.5 = CH.sub.3) 108.4 CO.sub.2H A11 (R.sup.5 =
C.sub.2H.sub.5) 109.1 H A11 (R.sup.5 = CF.sub.3) 109.2 H A11
(R.sup.5 = CHF.sub.2) 109.3 H A11 (R.sup.5 = CH.sub.3) 109.4 H A11
(R.sup.5 = C.sub.2H.sub.5) 110.1 CO.sub.2CH.sub.3 A12 (R.sup.5 =
CF.sub.3) 110.2 CO.sub.2CH.sub.3 A12 (R.sup.5 = CHF.sub.2) 110.3
CO.sub.2CH.sub.3 A12 (R.sup.5 = CH.sub.3) 110.4 CO.sub.2CH.sub.3
A12 (R.sup.5 = C.sub.2H.sub.5) 110.5 CO.sub.2CH.sub.3 A12 (R.sup.5
= F) 110.6 CO.sub.2CH.sub.3 A12 (R.sup.5 = Cl) 110.7
CO.sub.2CH.sub.3 A12 (R.sup.5 = Br) 110.8 CO.sub.2CH.sub.3 A12
(R.sup.5 = I) 111.1 CO.sub.2H A12 (R.sup.5 = CF.sub.3) 111.2
CO.sub.2H A12 (R.sup.5 = CHF.sub.2) 111.3 CO.sub.2H A12 (R.sup.5 =
CH.sub.3) 111.4 CO.sub.2H A12 (R.sup.5 = C.sub.2H.sub.5) 111.5
CO.sub.2H A12 (R.sup.5 = F) 111.6 CO.sub.2H A12 (R.sup.5 = Cl)
111.7 CO.sub.2H A12 (R.sup.5 = Br) 111.8 CO.sub.2H A12 (R.sup.5 =
I) 112.1 H A12 (R.sup.5 = CF.sub.3) 112.2 H A12 (R.sup.5 =
CHF.sub.2) 112.3 H A12 (R.sup.5 = CH.sub.3) 112.4 H A12 (R.sup.5 =
C.sub.2H.sub.5) 112.5 H A12 (R.sup.5 = F) 112.6 H A12 (R.sup.5 =
Cl) 112.7 H A12 (R.sup.5 = Br) 112.8 H A12 (R.sup.5 = I) 113.1
CO.sub.2C.sub.2H.sub.6 A1 (R.sup.5 = CF.sub.3, 144.8 1.40 (3H, t, J
= 7.3), 4.02 (3H, s), 4.36 R.sup.7 = 11) .about. (2H, q, J = 7.3),
7.50 (1H, d, J = 5.6), 146.2 7.95 (1H, s), 8.18 (1H, d, J = 5.6),
10.7 (1H, H, brs) 113.2 CO.sub.2.sup.iPr A1 (R.sup.5 = CF.sub.3,
159.6 1.37 (6H, d, J = 6.2), 4.03 (3H, s), 5.22 R.sup.7 = H)
.about. (1H, sept, J = 6.2), 7.49 (1H, d, J = 5.0), 161.5 7.96 (1H,
s), 8.18 (1H, d, J = 5.0), 10.8 8 (1H, brs) 113.3
CO.sub.2C.sub.2H.sub.5 A2 (R.sup.5 = CH.sub.3, R.sup.6 = CH.sub.3)
113.4 CO.sub.2.sup.nPr A3 (R.sup.5 = CH.sub.3, R.sup.8 = H) 113.5
CO.sub.2.sup.nBu A4 (R.sup.5 = CH.sub.3, R.sup.8 = H) 113.6
CO.sub.2.sup.sBu A5 (R.sup.5 = CF.sup.3 113.7 CO.sub.2.sup.tBu A6
(R.sup.5 = Cl) 113.8 CO.sub.2.sup.nPen A7 113.9 CO.sub.2.sup.nHex
A8 (R.sup.5 = CH.sub.3) 113.1 CO.sub.2.sup.cHex A9 (R.sup.5 =
CH.sub.3) 113.11 CO.sub.2.sup.nPr A10 (R.sup.5 = CH.sub.3) 113.12
CO.sub.2.sup.cPr A11 (R.sup.5 = CH.sub.3) 113.13
CO.sub.2C.sub.2H.sub.5 A12 (R.sup.5 = Cl)
[0179] Examples of a compound of the general formula (1b) which is
an intermediate of the present invention are summarized in the
following Table 2. 35
[0180] Examples of compounds of the general formulae (4a)' to (4d)'
which are intermediates of the present invention are summarized in
the following Table 3. 36
2TABLE 3 .sup.1H-NMR(270 Com- MHz) pound Physical (CDCl.sub.3
,.delta. value, No. R R.sup.1.about.R.sup.4 property J:Hz) 115.1 H
R.sup.1a=R.sup.2a=R.sup.3a=H, b.p. 0.89(6H, m),
R.sup.4a=i-C.sub.3H.sub.7 123.about.130.degree. C./ 1.94-2.01(3H, 4
mmHg m), 2.35(1H, m), 5.52(1H, m), 7.32(1H, m), 7.60 (1H, m),
8.30(1H, m), 5.26-5.43(1/20 .times. 2H, exo-meth- ylene protons)
115.2 CH.sub.3 R.sup.1a=R.sup.2a=R.sup.3a=H, b.p. 0.93-1.06(6H,
R.sup.4a=i-C.sub.3H.sub.7 123.about.137.degree. C./ m), 2 mmHg
1.96-1.99(3H, m), 2.12(3H, s), 2.25-2.70(1H, m), 5.47-5.55(1H, m),
7.11-7.19(1H, d, J=5.3), 7.33(1H, brs), 7.65-7.74(1H, m),
5.19-5.28(1/10 .times. 2H, exo-meth- ylene protons) 115.3 Ph
R.sup.1a=R.sup.2a=R.sup.3a=H, colorless 0.86-1.07(6H,
R.sup.4a=i-C.sub.3H.sub.7 crystal m), 2.00-2.05(3H, m),
2.24-2.82(1H, m), 5.55-5.63(1H, m), 7.18-7.27 (1H, m),
7.45-7.54(3H, m), 7.80-7.95(3H, m), 8.27(1H, brs), 5.27-5.36(1/5
.times. 2H, exo-meth- ylene protons) 115.4 OC.sub.2C.sub.5
R.sup.1a=R.sup.2a=R.sup.3a=H, oil 0.92-1.05 (6H, m), 1.27 (3H, m),
1.93-1.99(3H, R.sup.4a=i-C.sub.3H.sub.7 m), 2.24-2.67(1H, m), 4.21
(2H, q, J=7.2), 5.47-5.50(1H, m), 7.09(1H, d, J=5.3), 7.18(1H, d,
J=5.3), 5.19-5.27(1/10 .times. 2H, exo-meth- ylene protons) 115.5
i- R.sup.1a=R.sup.2a=R.sup.3a=H, colorless 0.91-1.05(6H,
OC.sub.3H.sub.7 R.sup.4a=i-C.sub.3H.sub.7 crystal m), 1.23-1.30(6H,
m), 1.94-1.98(3H, m), 2.12-2.74 (1H, m), 4.94-5.04 (1H, m),
5.44-5.53(1H, m), 6.38-6.57(1H, m), 7.08-7.17(1H, m), 7.49-7.57(1H,
m), 5.18-5.26(1/6 .times. 2H, exo-meth- ylene protons) 115.6 OBz
R.sup.1a=R.sup.2a=R.sup.3a=H, oil 0.89-1.02 (6H,
R.sup.4a=I-C.sub.3H.sub.7 m), 1.92-1.97 (3H, m), 2.18-2.70(1H, m),
5.18-5.19 (2H, m), 5.44-5.52 (1H, m), 6.51-6.70(1H, m),
7.09-7.18(1H, m), 7.33-7.41(5H, m), 7.50-7.60(1H, m), 5.21-5.25(1/4
.times. 2H, exo-meth- ylene protons)
[0181] According to the present invention, a
2-alkyl-3-aminothiophene derivative having a secondary alkyl group
represented by the formula (1) can be produced simply and at high
yield by reacting a compound of the formula (2) with a compound of
the formula (3) in the presence of an acid and reducing the
resultant reaction mixture.
* * * * *