Note: Descriptions are shown in the official language in which they were submitted.
CA 022~0102 1998-09-2~
W097/40041 PCT~P97/01733
1,3-OXAZIN-4ONE DERIVATES AS HF~BICTr)FC. PROCESS AND INTERI'/IEDIATES FOR THEiR- PREPARAnON
This invention relates to novel 1,3-oxazin-
4-one derivatives, processes and intermediates
for their preparation, compositions containing
the same, and their use as herbicides.
According to the present invention, there is
provided a l,3-oxazin-4-one derivative of the
formula (I):
V(i~ OJ
(I)
wherein
W represents -NR;
R1 represents thiophene optionally
substituted by one to three groups which may be
the same or different selected from halogen,
hydroxy,lower alkyl, lower haloalkyl, lower
alkoxy, lower haloalkoxy, -S(O) nR, -CO2R, COR,
cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower
haloalkyl, alkoxyalkyl, lower alkenyl, lower
haloalkenyl, alkoxyalkenyl, -CHO, -CoR7, -Co2R7,
-CH2NO2, and lower alkyl which is substituted by
a group selected from -S(O) mR and -OCOR;
R3 represents phenyl optionally substituted
by one to five groups which may be the same or
different selected from halogen, lower alkyl,
~lower haloalkyl, lower alkoxy, lower haloalkoxy,
3 0 ~ S (O ) nR, - CO2R, - COR, cyano, nitro, -OH,
phenoxy, -NR8R9 and -SF5; or
CA 022~0102 1998-09-2~
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-- 2
a cycloalkyl group containing from three to
six carbon atoms, optionally substituted by
lower alkyl, lower haloalkyl or one or more
halogen atoms which may be the same or
different;
R4 and R5 independently represent lower
alkyl;
R6 represents hydrogen;
R represents lower alkyl or lower
haloalkyl;
R3 and R9 independently represent hydrogen
or R ; and
m and n independently represent zero, one or
two;
or an agriculturally acceptable salt
thereof, which possesses valuable properties.
It will be appreciated that certain
substituents in the compounds of the invention
may contribute to optical and/or
stereoisomerism. All such forms are embraced by
the present in~ention.
By the term 'agriculturally acceptable
salts' is meant salts the cations or anions of
which are known and accepted in the art for the
formation of salts for agricultural or
horticultural use. Preferably the salts are
water-soluble. Suitable salts with bases
include alkali metal (e.g. sodium and
potassium), alkaline earth metal (e.g. calcium
and magnesium), ~mmo~;um and amine (e.g.
diethanolamine, triethanolamine, octylamine,
morpholine and dioctylmethylamine) salts.
Suitable acid addition salts, e.g. formed by
compounds of formula (I) containing an amino
group, include salts with inorganic acids, for
example hydrochlorides, sulphates, phosphates
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WO97/40041 PCT~P97/01733
- 3
and nitrates and salts with organic acids for
example acetic acid.
In the description the following terms are
generally defined thus:-
s ~lower alkyl' means a straight- or branched-
chain alkyl group having one to six carbon
atoms.
'lower haloalkyl' means a straight- or
branched- chain alkyl group having one to six
carbon atoms, substituted by one or more
halogens.
'lower alkoxy' means a straight- or
branched- chain alkoxy group having one to six
carbon atoms.
lS 'lower haloalkoxy' means a straight- or
branched- chain alkoxy group having one to six
carbon atoms, substituted by one or more
halogens.
~halogen' means a fluorine, chlorine,
bromine or iodine atom.
~lower alkenyl' means an alkenyl group
containing two to six carbon atoms.
~lower haloalkenyl' means an alkenyl group
containing from two to six carbon atoms,
substituted by one or more halogen atoms.
~alkoxyalkyl' means a lower alkyl group
substituted by a lower alkoxy group.
~alkoxyalkenyl' means a lower alkenyl group
substituted by a lower alkoxy group.
The compounds of the invention, in certain
aspects of their properties, for example their
control of the grass species Alopecurus
mYosuroides, Avena fatua and Echinochloa crus-
qalli and their selectivity in wheat, show
advantages over known compounds.
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WO 97/40041 PCT/EP97/01733
-- 4
.
Preferred compounds of formula (I) above
include those in which:-
R1 represents thiophene optionally
substituted by one to three groups which may be
the same or different selected from halogen,
hydroxy, lower alkyl, lower haloalkyl, lower
alkoxy, lower haloalkoxy, ~S(O)nR , -C02R , COR ,
cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower
haloaikyl, alkoxyalkyl, lower alkenyl, lower
haloalkenyl, alkoxyalkenyl, -CHO, -COR and
-Co2R7;
R3 represents phenyl optionally substituted
by one to five groups which may be the same or
different selected from halogen, lower alkyl,
lower haloalkyl, lower alkoxy, lower haloalkoxy,
-S(O)nR , -CO2R , -COR , cyano, nitro, -OH,
phenoxy and -NR8R9; or
a cycloalkyl group containing from three to
six carbon atoms, optionally substituted by
lower alkyl, lower haloalkyl or one or more
halogen atoms which may be the same or
different;
R4 and R5 independently represent lower
alkyl;
W represents -NR6;
R6 represents hydrogen;
R represents lower alkyl or lower
haloalkyl;
R8 and R9 independently represent hydrogen
or R ; and n is zero, one or two.
Compounds of formula (I) above in which
represents an unsubstltuted thiophene are
preferred.
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-- 5
Compounds of formula (I) above in which R4
and R5 each represent methyl are particularly
preferred.
Particularly preferred compounds of formula
(I) above are those in which R2 is lower alkyl,
most preferably methyl.
Compounds of formula (I) in which R3
represents phenyl which is 3-monosubstituted,
3,5-disubstituted or 2,5-disubstituted are
preferred (3,5-disubstituted or
2,5-disubstituted being particularly preferred).
Compounds of formula (I) in which R3
represents phenyl optionally substituted by one
to three groups which may be the same or
different selected from halogen, or a straight-
or branched- chain alkyl group containing from
one to three carbon atoms optionally substituted
by one or more halogen atoms, are preferred.
Compounds of formula (I) in which R3
represents phenyl substituted by one or two
groups which may be the same or different
selected from halogen (especially chlorine or
fluorine), Cl 3 alkyl (especially methyl) and
Cl 3 haloalkyl (especially -CF3), are
particularly preferred.
A preferred class of compounds of formula
(I) are those wherein:
R represents methyl, halogenated methyl or
methoxymethyl;
R3 represents phenyl optionally substituted
by one to three groups which may be the same or
different selected from halogen, a straight- or
branched- chain optionally halogenated alkyl
group containing from one to four carbon atoms,
a straight- or branched- chain optionally
CA 022~0l02 l998-09-25
W O97/40041 PCT~EP97/01733
- 6
halogenated alkoxy group containing from one to
four carbon atoms, or -S(O) nR ; or
cyclobutyl;
R4 and R5 each represent methyl; and
R7 represents a straight- or branched- chain
optionally halogenated alkyl group containing
from one to four carbon atoms.
A particularly preferred class of compounds
of formula (I) are those wherein:
R1 represents thiophene optionally
substituted by one or two groups which may be
the same or different selected from halogen, a
straight- or branched- chain optionally
halogenated alkyl group containing from one to
four carbon atoms, a straight- or branched-
chain optionally halogenated alkoxy group
containing from one to four carbon atoms, or
-S(o)nR7;
R2, R4 and R5 each represent methyl;
R3 represents phenyl optionally substituted
by one or two groups which may be the same or
different selected from halogen and optionally
halogenated methyl; or
cyclobutyl; and
R7 represents a straight- or branched- chain
optionally halogenated alkyl group containing
from one to four carbon atoms.
A further particularly preferred class of
compounds of formula (I) are those wherein:
Rl represents thiophene;
R2, R4 and R5 each represent methyl; and
R3 represents phenyl optionally substituted
by one or two groups which may be the same or
different selected from halogen, optionally
halogenated methyl; or cyclobutyl.
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WO97/4~41 PCT~P97/01733
-- 7
-
A further particularly preferred class of
compounds of formula (I) are those wherein:
Rl represents thiophene optionally
substituted by lower alkyl, lower alkoxy or
halogen;
R represents methyl or ethyl;
R4 and Rs each represent methyl; and
R3 represents phenyl optionally substituted
by one, two or three groups which may be the
same or different selected from halogen,
optionally halogenated methyl, nitro or -SF5; or
cyclobutyl or cyclopropyl.
Another preferred class of compounds of
formula (I) above are those having one or more
lS of the following features:
Rl represents 2-thienyl; 3-thienyl; 3-
methoxy-2-thienyl; 5-methyl-2-thienyl or 5-
chloro-2-thienyl;
R2 represents methyl; ethyl or fluoromethyl;
R4 and R5 each represent methyl; and
R3 represents
cyclopropyl; cyclobutyl; 3,5-difluorophenyl;
3,5-dichlorophenyl; 2-fluoro-
5-trifluoromethylphenyl; 2-fluoro-
5-methylphenyl; 3-chlorophenyl;
2,5-difluorophenyl; 3-trifluoromethylphenyl;
5-chloro-2-methylphenyl;
3-pentafluorosulphanylphenyl; 2-chloro-
3,5-difluorophenyl; 3,4,5-trifluorophenyl;
2-chloro-5.fluorophenyl; 5-chloro-2-fluorophenyl
or 5-chloro-3-fluorophenyl .
Particularly important compounds of formula
(I) include the following:-
l. N-(3,5-difluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(2-thienyl)-4H-l,3-oxazin-3-
yl]-2-methylpropanamide;
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-- 8
- 2. N-(3~5-dichlorophenyl)-2-[2~3-dihydro
6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
3. N-(2-fluoro-5-trifluoromethylphenyl)-2-
[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-
~,3-oxazin-3-yl]-2-~ethylpropanamide;
4. N-(2-fluoro-5-methylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
5. N-(3-chlorophenyl)-2-~2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide;
6. N-(2,5-difluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
7. N-(3-trifluoromethylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
8. N-(3-chlorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide;
9. N-(3-trifluoromethylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
10. N-(5-chloro-2-methylphenyl)-2-[2,3-
dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-
4H-1,3-oxazin-3-yl]-2-methylpropanamide;
11. N-(cyclobutyl)-2-[2,3-dihydro-6-methyl-
4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide;
19. N-(3-trifluoromethylphenyl)-2-[2,3-
dihydro-5-~3-methoxy-2-thienyl)-6-methyl-4-oxo-
4H-1,3-oxazin-3-yl]-2-methylpropanamide;
20. N-(2,5-difluorophenyl)-2-[2,3-dihydro-
5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
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WO97/40041 PCT~P97/01733
g
40. N-(3-trifluoromethylphenyl)-2-f2,3-
dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-
4H-1,3-oxazin-3-yl]-2-methylpropanamide;
41. N-(2,5-difluorophenyl)-2-[2,3-dihydro-
6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
42. N-(3-chlorophenyl)-2-[2,3-dihydro-6-
methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
47. N-(2,5-difluorophenyl)-2-{2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
48. N-(3,5-dichlorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
49. N-(3,5-difluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
50. N-(5-chloro-2-methylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
53. N-(2,5-difluorophenyl)-2-[5-(5-chloro-
2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
54. N-(3-chlorophenyl)-2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
55. N-(3,5-dichlorophenyl)-2-{5-(5-chloro-
2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
~ 56. N-(3,5-difluorophenyl)-2-[5-(5-chloro-
2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
57. N-(5-chloro-2-methylphenyl)-2-[5-(5-
chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-
1,3-oxazin-3-yl]-2-methylpropanamide;
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WO97/40041 PCT~P97/01733
- 10
136. N-(2-fluoro-5-trifluoromethylphenyl)-2-
[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-
oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
137. N-(3-trifluoromethylphenyl)-2-[2,3-
dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
138. N-(3-chlorophenyl)-2-[2,3-dihydro-6-
ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide;
139. N-(2,5-difluorophenyl)-2-[2,3-dihydro-
6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide;
140. N-(2-fluoro-5-trifluoromethylphenyl)-2-
[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
141. N-(5-chloro-2-methylphenyl)-2-[2,3-
dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
142. N-(3,5-dichlorophenyl)-2-[2,3-dihydro-
6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
.-methylpropanamide;
143. N-(3,5-difluorophenyl)-2-[2,3-dihydro-
6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide;
144. N-(2,4-difluorophenyl)-2-[5-(5-chloro-
2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
145. N-(2-fluoro-5-trifluoromethylphenyl)-2-
[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-
oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
146. N-(3-pentafluorosulphanylphenyl)-2-
[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-
1,3-oxazin-3-yl]-2-methylpropanamide;
147. N-(2-chloro-3,5-difluorophenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
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148. N-(2-fluoro-5-trifluoromethylphenyl)-2-
[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-
oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
149. N-(3,4,5-trifluorophenyl)-2-~2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
150. N-(2-methyl-5-nitrophenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
151. N-(cyclopropyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide;
152. N-(2-chloro-5-fluorophenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide;
153. N-(3-chloro-5-trifluoromethylphenyl)-2-
[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-
1,3-oxazin-3-yl]-2-methylpropanamide;
154. N-(2,4-difluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide;
155. N-(2-fluoro-5-trifluoromethylphenyl)-2-
~2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-
1,3-oxazin-3-yl]-2-methylpropanamide; and
156. N-(2-chloro-5-fluorophenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-~3-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide.
The following compounds of formula (I)
wherein R4 and R5 represents methyl and W
represents -NH- form part of the present
invention.
In the Table that follows Me means methyl,
cBu means cyclobutyl, cPr means cyclopropyl, Ph
means phenyl and Et means ethyl. Where
subscripts do not occur in the Table it is
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WO97/40041
- 12 -
understood that in appropriate cases they are
present (for example CF3 is understood to mean
CF3)
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- 13 -
-
Cpd no Rl R2 R~
- 1 2-thienyl Me3,5-F2 Ph
2 2-thienyl Me3,5-C12 Ph
3 2-thlenyl Me2-F-5-CF3 Ph
4 2-thienyl Me2-F-5-CH3 Ph
2-thienyl Me 3-Cl Ph
6 2-thienyl Me2,5-F2 Ph
7 2-thienyl Me 3-CF3 Ph
8 3-thienyl Me 3-Cl Ph
9 3-thienyl Me 3-CF3 Ph
2-thienyl Me2-Me-5-Cl Ph
11 2-thienyl Me cBu
12 5-OMe-2-thienyl Me 3-CF3 Ph
13 5-OMe-2-thienyl Me2,5-F2 Ph
14 5-OMe-2-thienyl Me 3-Cl Ph
15 5-OMe-2-thienyl Me3,5-C12 Ph
16 5-OMe-2-thienyl Me3,5-F2 Ph
17 5-OMe-2-thienyl Me2-Me-5-Cl Ph
18 5-OMe-2-thienyl Me cBu
19 3-OMe-2-thienyl Me 3-CF3 Ph
20 3-OMe-2-thienyl Me2,5-F2 Ph
21 3-OMe-2-thienyl Me 3-Cl Ph
22 3-OMe-2-thienyl Me3,5-C12 Ph
23 3-OMe-2-thienyl Me3,5-F2 Ph
24 3-OMe-2-thienyl Me2-Me-5-Cl Ph
25 3-OMe-2-thienyl Me cBu
26 5-SMe-2-thienyl Me 3-CF3 Ph
27 5-SMe-2-thienyl Me2,5-F2 Ph
28 5-SMe-2-thienyl Me 3-Cl Ph
29 5-SMe-2-thienyl Me3,5-C12 Ph
30 5-SMe-2-thienyl Me3,5-F2 Ph
31 5-SMe-2-thienyl Me2-Me-5-Cl Ph
32 5-SMe-2-thienyl Me cBu
33 3-SMe-2-thienyl Me 3-CF3 Ph
34 3-SMe-2-thienyl Me2,5-F2 Ph
35 3-SMe-2-thienyl Me 3-Cl Ph
36 3-SMe-2-thienyl Me3,5-C12 Ph
37 3-SMe-2-thienyl Me3,5-F2 Ph
38 3-SMe-2-thienyl Me2-Me-5-Cl Ph
39 3-SMe-2-thienyl Me cBu
5-Me-2-thienyl Me 3-CF3 Ph
41 5-Me-2-thienyl Me2,5-F2 Ph
42 5-Me-2-thienyl Me 3-Cl Ph
43 5-Me-2-thienyl Me3,5-C12 Ph
44 5-Me-2-thienyl Me3,5-F2 Ph
5-Me-2-thienyl Me2-Me-5-Cl Ph
.
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- - 14 -
- Cpd no Rl ~2 R~
465-Me-2-thienyl Me cBu
473-thienyl Me 2,5-F2 Ph
483-thienyl Me 3,5-Cl2 Ph
493-thienyl Me 3,5-F2 Ph
503-thienyl Me 2-Me-5-Cl Ph
513-thienyl Me cBu
525-Cl-2-thienyl Me 3-CF3 Ph
535-Cl-2-thienyl Me 2,5-F2 Ph
545-Cl-2-thienyl Me 3-Cl Ph
555-Cl-2-thienyl Me 3,5-Cl2 Ph
565-Cl-2-thienyl Me 3,5-F2 Ph
575-Cl-2-thienyl Me 2-Me-5-Cl Ph
585-Cl-2-thienyl Me cBu
593-Cl-2-thienyl Me 3-CF3 Ph
603-Cl-2-thienyl Me 2,5-F2 Ph
613-Cl-2-thienyl Me 3-Cl Ph
623-Cl-2-tnienyl Me 3,5-Cl2 Ph
633-Cl-2-thienyl Me 3,5-F2 Ph
643-C1-2-thienyl Me 2-Me-5-Cl Ph
653-Cl-2-thienyl Me cBu
665-F-2-thienyl Me 3-CF3 Ph
675-F-2-thienyl Me 2,5-F2 Ph
685-F-2-thienyl Me 3-Cl Ph
695-F-2-thienyl Me 3,5-Cl2 Ph
705-F-2-thienyl Me 3,5-F2 Ph
715-F-2-thienyl Me 2-Me-5-Cl Ph
725-F-2-thienyl Me cBu
733-F-2-thienyl Me 3-CF3 Ph
743-F-2-thienyl Me 2,5-F2 Ph
753-F-2-thienyl Me 3-Cl Ph
763-F-2-thienyl Me 3,5-Cl2 Ph
773-F-2-thienyl Me 3,5-F2 Ph
783-F-2-thienyl Me 2-Me-5-Cl Ph
793-F-2-thienyl Me cBu
802-thienyl CH2F 3-CF3 Ph
812-thienyl CH2F 2,5-F2 Ph
822-thienyl CH2F 3-Cl Ph
832-thienyl CH2F 3,5-Cl2 Ph
842-thienyl CH2F 3,5-F2 Ph
852-thienyl CH2F 2-Me-5-Cl Ph
862-thienyl CH2F cBu
873-thienyl CH2F 3-CF3 Ph
883-thienyl CH2F 2,5-F2 Ph
893-thienyl CH2F 3-Cl Ph
go3-thienyl CH2F 3,5-Cl2 Ph
913-thienyl CH2F 3,5-F2 Ph
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- 15 -
Cpd no Rl R2 R3
92 3-thienyl CH2F 2-Me-5-Cl Ph
93 3-thienyl CH2F cBu
94 2-thienyl CH20Me 3-CF3 Ph
2-thienyl CH20Me 2,5-F2 Ph
96 2-thienyl CH20Me 3-Cl Ph
97 2-thienyl CH20Me 3,5-C12 Ph
98 2-thienyl CH20Me 3,5-F2 Ph
99 2-thienyl CH20Me 2-Me-5-Cl Ph
100 2-thienyl CH20Me cBu
lO1 3-thienyl CH20Me 3-CF3 Ph
102 3-thienyl CH20Me 2,5-F2 Ph
103 3-thienyl CH20Me 3-Cl Ph
104 3-thienyl CH20Me 3,5-Cl2 Ph
105 3-thienyl CH20Me 3,5-F2 Ph
106 3-thienyl CH20Me 2-Me-5-Cl Ph
107 3-thienyl CH20Me cBu
108 3-N02-2-thienyl Me .3-CF3 Ph
109 3-N02-2-thienyl Me 2,5-F2 Ph
110 3-N02-2-thienyl Me 3-Cl Ph
111 3-N02-2-thienyl Me 3,5-C12 Ph
112 3-N02-2-thienyl Me 3,5-F2 Ph
113 3-N02-2-thienyl Me 2-Me-5-Cl Ph
114 3-N02-2-thienyl Me cBu
115 5-N02-2-thienyl Me 3-CF3 Ph
116 5-N02-2-thienyl Me 2,5-F2 Ph
117 5-N02-2-thienyl Me 3-Cl Ph
118 5-N02-2-thienyl Me 3,5-Cl2 Ph
119 5-N02-2-thienyl Me 3,5-F2 Ph
120 5-N02-2-thienyl Me 2-Me-5-Cl Ph
121 5-N02-2-thienyl Me cBu
122 3-CN-2-thienyl Me 3-CF3 Ph
123 3-CN-2-thienyl Me 2,5-F2 Ph
124 3-CN-2-thienyl Me 3-Cl Ph
125 3-CN-2-thienyl Me 3,5-Cl2 Ph
126 3-CN-2-thienyl Me 3,5-F2 Ph
127 3-CN-2-thienyl Me 2-Me-5-Cl Ph
128 3-CN-2-thienyl Me cBu
129 5-CN-2-thienyl Me 3-CF3 Ph
130 5-CN-2-thienyl Me 2,5-F2 Ph
131 5-CN-2-thienyl Me 3-Cl Ph
132 5-CN-2-thienyl Me 3,5-Cl2 Ph
133 5-CN-2-thienyl Me 3,5-F2 Ph
134 5-CN-2-thienyl Me 2-Me-5-Cl Ph
135 5-CN-2-thienyl Me cBu
136 5-Me-2-thienyl Me 2-F-5-CF3 Ph
137 2-thienyl Et 3-CF3 Ph
CA 022~0l02 l998-09-2~
WO 97/40041 rCT/EP97/01733
- 16 -
Cpd no Rl R2 R3
138 2-thienyl Et 3-Cl Ph
139 2-thienyl Et2,5-F2 Ph
140 2-thienyl Et2-F-5-CF3 Ph
141 2-thienyl Et2-Me-5-Cl Ph
142 2-thienyl Et3,5-C12 Ph
143 2-thienyl Et3,5-F2 Ph
1445-Cl-2-thienyl Me2,4-F2 Ph
1455-Cl-2-thienyl Me2-F-5-CF3 Ph
146 2-thienyl Me 3-SF5 Ph
147 2-thienyl Me2-Cl-3,5-F2 Ph
1483-OMe-2-thienyl Me2-F-5-CF3 Ph
149 2-thienyl Me3,4,5-F3 Ph
150 2-thienyl Me2-Me-5-NO2 Ph
151 2-thienyl Me cPr
152 2-thienyl Me2-Cl-5-F Ph
153 2-thienyl Me3-Cl-5-CF3 Ph
154 3-thienyl Me2,4-F2 Ph
155 3-thienyl Me2-F-5-CF3 Ph
156 3-thienyl Me2-Cl-5-F Ph
157 3-thienyl Et2-Cl-5-F Ph
158 2-thienyl ~t2-Cl-5--F Ph
1595-Me-2-thienyl Me2-Cl-5-F Ph
1603-SMe-2-thienyl Me2-Cl-5-F Ph
1615-Cl-2-thienyl Me2-Cl-5-F Ph
1623-Cl-2-thienyl Me2-Cl-5-F Ph
1635-F-2-thienyl Me2-Cl-5-F Ph
1643-F-2-thienyl Me2-Cl-5-F Ph
Compounds of formula (I) above may be
prepared by the application or adaptation of
known methods (i.e. methods heretofore used or
described in the literature).
It is to be understood that in the
descriptions of the following processes the
sequences may be performed in different orders,
and that suitable protecting groups may be
required to achieve the compounds sought.
According to a feature of the present
invention compounds of formula (I) wherein R1,
R2, R3, R4, R5 and W are as defined above may be
prepared by the reaction of a compound of
general formula (II):
CA 022~0102 1998-09-2~
WO97/40041 pcT~ps7lol733
- 17
R2 o
(II)
h i Rl R2 R3 R4 and R5 are as defined
above, with an amine of formula (III):
R6NH- R3 (III)
wherein R3 and R6 are as defined above. The
reaction is generally performed in the presence
of a base, for example a tertiary amine such as
triethylamine and in an inert solvent such as
dichloromethane at a temperature from 0~C to the
reflux temperature of the solvent.
According to a further feature of the
present invention compounds of formula (I)
wherein R , R , R , R , R and W are as defined
above may also ~e prepared by the reaction of a
compound of formula tIV):
~ R~R5
R2 o
(IV)
wherein Rl, R2, R4 and R5 are as defined
above, with an amine of formula (III) above
wherein R3 is as defined above, and in which R6
is hydrogen. The reaction is performed in the
presence of a coupling reagent for example
N,N'-dicyclohexylcarbodiimide (DCCI) optionally
in the presence of a base for example 4-
dimethylaminopyridine (DMAP) and in an inert
solvent such as dichloromethane at a temperature
from 0 to 60~C.
CA 022~0102 1998-09-2~
WO97140041 PCT~P97/01733
- 18 -
Accordin~ to a further feature of the
present invention compounds of formula (I)
wherein R , R , R , R , R and W are as defined
above, may also be prepared by the reaction of a
carboxylic acid of formula (IV) above with a
phenyl carbamate of formula PhO2C-N~R , wherein
R is as defined above. The reaction is
generally performed in the presence of a base,
preferably l,8-diazabicyclo[5.4.0] undec-7-ene,
in an inert solvent for example l,4-dioxan and
at a temperature from 20-100~C.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R2, R3, R4, R5 and W are as defined
above may also be prepared by the reaction of a
trimethylsilyl ester of formula (V):
~ R,<R5
R2 o
(V)
wherein Rl, R2, R4 and R5 are as defined
above and TMS means trimethylsilyl, with an
amine of formula NH2R3, wherein R3 is as defined
above. The reaction is generally performed in
the presence of a catalytic amount of a titanium
(IV) salt, preferably prepared in situ from the
reaction of titanium (IV) chloride and silver
(I) trifluoromethanesulphonate, and in the
presence of an anhydride, preferably 4-
trifluoromethylbenzoic anhydride and in an inert
solvent for example dichloromethane at a
temperature from 0 to 60~C. This procedure is
useful for weakly nucleophilic amines and is
described in Chem. Letters (1993), 1053-1054 by
M. Miyashita, I. Shirna and T. Mukaiyama.
CA 022~0102 1998-09-2~
WO97/40041 PCT~P97/01733
- 19 -
According to a further feature of the
present invention compounds of formula (I) in
which Rl, R3, R4, R5 and W are as defined above
and R2 represents lower alkenyl optionally
substituted by halogen or lower alkoxy and
wherein the double bond of the alkenyl group is
located between the two carbon atoms closest to
the l,3-oxazin-4-one ring may be prepared by
reaction of the corresponding compound of
formula (I) in which R is -CHO or -COR in
which R is defined above, with a phosphorane,
typically generated by reaction of a phosphonium
salt of formula Ph3P+-CHRl0Rll_X- in which X
represents chlorine, bromine or iodine, Rl~
represents hydrogen, alkoxy, or alkyl containing
from one to four carbon atoms optionally
substituted by halogen or alkoxy, and Rll
represents hydrogen or alkyl containing from one
to four carbon atoms optionally substituted by
halogen with the proviso that the total number
of carbon atoms in the combined alkyl groups R7,
Rl0 and Rll does not exceed four. The reaction
is generally performed in the presence of a
strong base for example n-butyl lithium and in
an inert solvent for example tetrahydrofuran at
a temperature from 0~C to the reflux
temperature, the reaction being conducted under
an inert atmosphere.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents chloromethyl, bromomethyl or
iodomethyl may be prepared by reaction of the
correspon~;~g compound of formula (I) in which
R2 is methyl with a chlorinating, brominating or
iodinating agent, preferably the appropriate N-
CA 022~0102 1998-09-2~
WO 97140041 P~ 57/01733
- 20 -
halosuccinimide, for example N-bromosuccinimide
in an inert solvent e.g. carbon tetrachloride,
optionally in the presence of a radical
initiator e.g. azobis-isobutyronitrile or by
irradiation with a tungsten light source, and at
a temperature from ambient to the reflux
temperature of the solvent.
According to a further feature of the
present invention compounds of formula (I) in
which R1, R3, R4, Rs and W are as defined above
and R2 is -CF2R12a wherein R12a is C1-C5 alkyl or
haloalkyl, may be prepared by reaction of the
corresponding compound of formula (I) in which
R2 is -COR12a with diethylaminosulphur
trifluoride in an inert solvent, e.g.
dichloromethane, at a temperature of 0 to 60~C.
According to a further feature of the
present invention compounds of formula (I) in
which R}, R3, R4, R5 and W are as defined above
and R2 is lower alkyl substituted by iodine may
be prepared by iodination of the corresponding
compound of formula (I) in which the iodine atom
in R2 is replaced by bromine or chlorine. The
transhalogenation reaction is generally
performed using sodium or potassium iodide in a
inert solvent preferably acetone at a
temperature from ambient to the reflux
temperature of the solvent.
According to a further feature of the
present invention compounds of formula (I)
wherein R2 represents a lower alkyl group
substituted by a group -SR7, and Rl, R3, R4, R5,
R7 and w are as defined abo~e, may be prepared
by the reaction of the corresponding compound of
formula (I) in which the -SR7 group is replaced
by a leaving group, preferably chloro or bromo,
.
CA 022~0102 1998-09-2~
WO 97/40041 PCr/Er97/01733
- 21 -
with a thiol of formula R7SH or alkali metal
salt of the thiol R SM wherein M represents
lithium or sodium. The reaction is generally
performed in an inert solvent e.g. N,N-
dimethylformamide at a temperature from 0 to
60~C.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents a lower alkyl group
substituted by -SCF3 may be prepared by the
reaction of the corresponding compound of
formula (I) in which the -SCF3 group is replaced
by an -SCN group, with
trifluoromethyltrimethylsilane according to the
procedure of B.R.Langlois et. al. as described
in Tetrahedron Letters, Volume 38 (l), pages 65-
68 (1997). The reaction is generally performed
in the presence of a catalyst preferably
tetrabutyl~mmo~lum fluoride in an inert solvent
for example tetrahydrofuran and at a temperature
of from -20 to 20~C.
According to a further feature of the
present invention compounds of formula (I)
wherein R1, R3, R4, R5 and W are as defined above
and R2 represents a lower alkyl group
substituted by -oC(o)R7 wherein R7 is as defined
above may be prepared by the reaction of the
corresponding compound of formula (I) in which
the -oC(o)R7 group is replaced by a leaving
group, with a salt of formula R7-Co2-M1+,
wherein M1 represents sodium or potassium. The
leaving group is preferably chlorine or bromine.
The reaction is typically performed in an inert
solvent preferably N,N-dimethylformamide, at a
temperature from ambient to 120~C.
CA 022~0102 1998-09-2~
WO97/40041 pcT~ps7lol733
- - 22 -
Compounds of formula (I) in which R2
represents a lower alkyl group substituted by
-oR7 and Rl, R3, R4, R5, R7 and W are as defined
above, may be prepared by reaction of the
correspondin~ compound of formula (I) in which
-oR7 is replaced by a hydroxy group, with an
alcohol of formula R OH in the presence of a
trialkylphosphine, e.g. tri-n-butylphosphine and
l,ll-(azodicarbonyl)piperidine, in an inert
solvent (e.g. toluene at a temperature from 20~C
to the reflux temperature). The general
procedure is described by J.R. Falck in
Tetrahedron Letters 35, 5997 (1994).
According to a further feature of the
present invention compounds of formula (I) in
which R2 is - CHFR7 and Rl, R3, R , R , R and W
are as defined above, may be prepared by
reaction of the corresponding compound of
formula (I) in which R is -CH(OH)R with
diethylaminosulphur trifluoride in an inert
solvent, e.g. dichloromethane at a temperature
from 0 to 60~C.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents a fluoromethyl group may be
prepared by the fluorination of the
corresponding compound of formula (I) in which
R2 is replaced by a hydroxymethyl group, most
preferably with diethylaminosulphur trifluoride
in an inert solvent for example dichloromethane
at a temperature from 0 to 60~C.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents a difluoromethyl group may be
CA 022~0102 1998-09-2~
WO97/4~41 PCT~P97/01733
- 23 -
prepared by the fluorination of the
corresponding compound of formula (I) in which
R2 is -CHO, most preferably with
diethylaminosulphur trifluoride in an inert
solvent for example dichloromethane at a
temperature from 0 to 60~C.
According to a further feature of the
present invention compounds of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents alkoxyalkyl may be prepared by
the reaction of the corresponding compound of
formula (I) in which R2 is replaced by
hydroxyalkyl, with an alkyl iodide in the
presence of silver (I) oxide and in an inert
solvent for example acetonitrile at a
temperature from ambient to the reflux
temperature. The general procedure is as
described in J. Org.Chem. 40, 206 (1975).
According to a further feature of the
present invention aldehydes of formula (I)
wherein Rl, R3, R4, R5 and W are as defined above
and R2 represents a -CHO group, may be prepared
by oxidation of the corresponding compounds of
formula (I) in which R2 is replaced by
hydroxymethyl using for example pyridinium
chlorochromate in dichloromethane at 0~C to the
reflux temperature.
According to a further feature of the
present invention compounds of formula (I) in
which R2 represents -COR and Rl, R3, R4, R5, R7
and W are as defined above, may be prepared by
oxidation of the corresponding compounds of
formula (I) in which R2 is replaced by -
CH(OH)R , using for example pyridinium
chlorochromate in dichloromethane at 0~C to the
reflux temperature.
CA 022~0102 1998-09-2~
WO97140041 PCT~P97/01733
- 24 -
According to a further feature of the
present invention compounds of formula (I) in
which R2 represents -CO2R and R , R3, R4, R5, R7
and W are as defined above, may be prepared by
esterification of the corresponding compound of
formula (I) in which R2 is replaced by -CO2H.
The reaction is preferably performed using an
alcohol of formula R OH and
diethylazodicarboxylate in an inert solvent for
exampie ether, at a temperature from 0~C to the
reflux temperature of the solvent.
Alternatively, the above conversion may be
performed by chlorination of the corresponding
compound of formula (I) in which R2 is replaced
lS by -CO2H using for example oxalyl chloride, in
an inert solvent for example dichloromethane or
l,2-dichloroethane, optionally in the presence
of a catalyst such as N,N-dimethylformamide at a
temperature from 20~C to the reflux temperature
of the mixture to give the corresponding acid
chloride, which is subsequently reacted with an
alcohol of formula R OH in an inert solvent for
example tetrahydrofuran at a temperature from
0~C to the reflux temperature of the solvent.
According to a further feature of the
present invention compounds of formula (I) in
which Rl, R3, R4, R5 and W are as defined above
and R2 represents -CH2NO2 may be prepared by
reaction of the corresponding compound in which
R2 is bromomethyl or iodomethyl, with an alkali
metal nitrite preferably sodium nitrite, or
silver nitrite in a solvent such as N,N-
dimethylformamide or dimethylsulphoxide, and at
a temperature from -20 to 50~C.
According to a further feature of the
present invention compounds in which m and/or n
CA 022~0102 1998-09-2~
WOg7/40041 PCT~P97/01733
- 25 -
- are one or two are generally prepared by the
oxidation of the sulphur atom of the
corresponding compounds in which m and/or n are
zero or one. The oxidation of the sulphur atom
is generally carried out using for example 3-
chloroperbenzoic acid in an inert solvent such
as dichloromethane at a temperature from -40~C
to room temperature.
Intermediates of formula (I) in which R is
replaced by -CH(OH)R7 and Rl, R3, R4, R5, R and
W are as defined above, may be prepared by the
reaction of the corresponding compounds of
formula (I) in which R represents -CHO with a
Grignard reagent of formula R7Mg-Xl wherein Xl
represents bromine or iodine. The reaction may
be performed in an inert solvent for example
ether or tetrahydrofuran at a temperature from
20 to 60~C.
Intermediates of formula (I) in which Rl,
R3, R4, R5 and W are as defined above and R2 is
replaced by a lower alkyl group substituted by
-SCN may be prepared by the reaction of the
corresponding compound of formula (I) in which
-SCN is replaced by a leaving group preferably
halogen such as chlorine, bromine or iodine,
with an alkali metal thiocyanate or ammonium
thiocyanate. The reaction is generally performed
in a solvent such as ethanol or N,N-
dimethylformamide and at a temperature from 0 to
60~C.
Intermediates of formula (I) in which Rl,
R3, R4, R5 and W are as defined above and R2 is
replaced by -CO2H, may be prepared by oxidation
of the corresponding compounds of formula (I) in
which R2 represents -CHO, which may be achieved
by procedures reported by R.C. Larock in
CA 022~0102 1998-09-2~
WO97/40041 PCT~P97/01733
- 26 -
Comprehensive Organic Transformations p.838, for
example by reaction with pyridinium dichromate
in N,N-dimethylformamide at a temperature from 0
to 60~C.
Acid chlorides of formula (II) may be
prepared by the reaction of an acid of formula
(IV) above with a chlorinating agent, for
example oxalyl chloride or a mixture of
triphenylphosphine and carbon tetrachloride.
The reaction with oxalyl chloride may be
performed in an inert solvent for example
dichloromethane optionally in the presence of a
catalyst, for example N,N-dimethylformamide, at
a temperature from 0 to 50~C. The reaction with
triphenylphosphine and carbon tetrachloride may
be performed in an inert solvent, for example
toluene or excess carbon tetrachloride, and at a
temperature from 20 to 120~C.
Carboxylic acids of formula (IV) may be
prepared by the hydrolysis of an ester of
formula (VI):
R1X~N~<CO R8a
R2 o
(VI)
wherein R , R , R and R are as defined
above and R8a represents an alkyl group,
preferably methyl or ethyl. The reaction is
performed in the presence of a base for example
sodium or potassium hydroxide and in a solvent,
e.g. aqueous alcohol at a temperature from 0~C
to the reflux temperature of the solvent.
CA 022~0102 1998-09-2~
WO97/40041 PCT~P97/01733
- 27 -
- Carboxylic acids of formula ~IV) may also be
prepared by the reaction of a benzyl ester of
formula (VII):
R1 ~ N ~ CO Bz
R2 o
(VII)
wherein Rl, R2, R4 and R5 are as defined
above and Bz is benzyl, with aluminium bromide
and anisole in the presence of nitromethane and
in an inert solvent e.g. dichloromethane at a
temperature from 0 to 50~C.
Carboxylic acids of formula (IV) may also be
prepared from benzyl esters of formula (VII) by
catalytic hydrogenation. The reaction may be
performed at normal or elevated pressure in an
inert solvent, for example ethanol, preferably
at room temperature and in the presence of a
suitable catalyst, for example 5~ palladium or
activated carbon.
Compounds of formula (II), (IV), (V), (VI)
and (VII) are novel and as such constitute a
further feature of the present invention.
Esters of formula (VI) or (VII) may be
prepared by the reaction of a compound of
formula (VIII):
o
R1\~o
R2 ~ O ~ Me
(VIII)
wherein Rl-and R2 are as defined above, with
an imine of formula CH2=NC(R4)(R5)Co2R8a or of
CA 022~0102 1998-09-2~
.
WO97/4~41 pcT~ps7lol733
- 28 -
formula CH2=NC(R )~R )CO2Bz wherein R , R5, R8
and Bz are as defined above. The reaction is
generally performed in the presence or absence
of solvent and at a temperature from 90 to 200~C
or the boiling point of the sol~ent. The
solvent when used is inert, for example xylene,
and the acetone produced is preferably removed
by distillation.
Esters of formula (VI) or (VII) may also be
prepared by the reaction of a compound of
formula (IX):
R C(O)-CH(R )-CO2Rl2
(IX)
wherein Rl and R are as defined above and
Rl2 represents an alkyl group (preferably methyl
or ethyl), with an imine of formula
CH2=NC(R4)(R5)Co2R8a or CH2=NC(R4)(Rs)Co2Bz
respectively, wherein R4 RS R8a a d B
defined above. The reaction is performed
utilising similar conditions to those used for
the preparation of compounds of formula (VI) or
(VII) from compounds of formula (VIII) above and
preferably with removal of the alcohol Rl2OH
formed in the reaction.
Intermediate alcohols of formula (I) wherein
R is replaced by a hydroxymethyl group may be
prepared by hydrolysis of the corresponding
ester of formula (I) in which R2 is replaced by
a -CH2OCOR group in which Rl3 represents lower
alkyl preferably methyl. The reaction is
generally performed using a base for example
potassium carbonate in an aqueous alcohol
solution at 0 to 50~C.
Imines of formula C~2=NC(R )(R5)Co2R8a or of
formula CH2=NC(R )(RS)CO2Bz may be prepared by
the reaction of an aminoacid ester of formula
CA 022~0102 1998-09-2~
WO97/4~41 PCT~P97/01733
- 29 -
H,N-C(R4)(R5)Co2R8a or of formula
H2N-C(R )(R )CO2Bz respectively, wherein R , R ,
R8a and Bz are as defined above, with
formaldehyde, preferably as an aqueous solution
and at a temperature from ambient to 60~C.
Compounds of formulae (III), (VIII) and (IX)
are known or may be prepared using ~nown
methods, for example see International Patent
Publication No. WO 93/15064. The compounds of
formula (I) can be converted into salts which
can be prepared by known methods.
The following non-limiting Examples
illustrate the invention.
EXAMPLE 1
oxalyl chloride (0.17 ml) followed by N,N-
dimethylformamide (2 drops) were added to a
stirred solution of 2-[2,3-dihydro-6-methyl-4-
oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-
methylpropanoic acid (0.51 g) in dichloromethane
at ambient temperature. After 20 minutes the
solution was evaporated and redissolved in
dichloromethane. A solution of 3,5-
difluoroaniline (0.32 g) was added at 0~C,
stirring maintained at 0~C for 10 minutes, and
triethylamine (0.56 ml) added. The mixture was
stirred at room temperature for 2 hours, then
washed in turn with hydrochloric acid (2 M),
sodium carbonate solution (1 M) and brine, dried
(magnesium sulphate) and evaporated. The residue
was purified by column chromatography eluting
with cyclohexane/ethyl acetate to give N-(3,5-
difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-
(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
CA 022~0l02 l998-09-2~
WO 97/40041 PCTlEr97101733
- 30
methylpropanamide (compound 1, 0.2 g), m.p. 178-
179~C
By proceeding in a similar manner the
following compounds were prepared.
N-(3,5-dichlorophenyl)-2-~2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide (compound 2), m.p. 156-
158~C;
N-(2-fluoro-5-trifluoromethylphenyl)-2-~2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide (compound 3),
m.p. 113.5-115.5~C;
N-(2-fluoro-5-methylphenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide (compound 4), m.p.
144.5-146~C;
N-(3-chlorophenyl)-2-~2,3-dihydro-6-methyl-
4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-
methylpropanamide (compound 5), m.p. 125-
126.5~C;
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide (compound 6), m.p. 95-
96.5~C;
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-
yll-2-methylpropanamide (compound 7), m.p.
149.7-152.7~C;
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-
6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 40)
NMR 1.65(s,6H), 2.08(s,3H), 2.18(s,3H),
S.22(s,2H), 6.72(m,lH), 6.85(m,lH), 7.6(m,lH),
7.8(br m,2H), 7.8(m,lH), 8.68(br s,lH);
N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-
5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-
. .
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WO 97/40041 PCT/EP97/01733
- 31 -
- yl]-2-methylpropanamide,(compound 42) NMR
1.63(s,6H), 2.05(s,3H), 2.16(s,3H), 5.2(s,2H),
6.7(m,lH), 6.82(m,lH), 6.96(m,lH), 7.11(m,lH),
7.25(m,lH), 7.56(m,lH), 8.4(br s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-
methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 41)
NMR 1.6(s,6H), 2.07(s,3H), 2.12(s,3H),
5.2(s,2H), 6.6(m,1H), 6.72(m,1H), 6.8(m,1H),
6.9(m,lH), 8.08(m,2H);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-
dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-
4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 136) NMR 1.62(s,6H),
2.08(s,3H), 2.15(s,3H), 5.22(s,2H), 6.71(m,lH),
6.81(m,lH), 7.08(m,lH), 7.22(m,lH), 8.22(br
s,lH), 8.62(m,lH);
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-
6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-
2-methylpropanamide,(compound 137) NMR
l.l(t,3H), 1.65(s,6H), 2.35(q,2H), 5.22(s,2H),
6.86(m,lH), 6.92(m,lH), 7.25(m,2H), 7.3(m,lH),
7.58(m,lH), 7.75(m,lH), 8.5(br s,lH);
N-(3-chlorophenyl)-2-[2,3-dihydro-6-ethyl-4-
oxo-S-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 138) NMR l.l(t,3H),
1.63(s,6H), 2.35(q,2H), 5.22(s,2H), 6.85(m,lH),
6.95(m,2H), 7.1(m,lH), 7.23(m,2H), 7.55(m,lH),
8.4(br s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-
ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-
methylpropanamide,(compound 139) NMR 1.1(t,3H),
1.61(s,6H), 2.36(q,2H), 5.23(s,2H), 6.62(m,lH),
6.9(m,3H), 7.25(m,1H), 8.1(m,2H);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-
dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-
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WO97140041 PCT~P97/01733
- 32 -
oxazin-3-yl]-2-methylpropanamide,(compound 140)
NMR l.l(t,3H), 1.62(s,6H), 2.36(q,2H),
5.25(s,2H), 6.9(m,2H), 7.05(m,lH), 7.25(m,2H),
8.22(br s,lH), 8.62(m,lH);
N-(5-chloro-2-methylphenyl)-2-[2,3-dihydro-
6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 141) NMR
l.l(t,3H), 1.65(s,6H), 2.1(s,3H), 2.36(q,2H),
5.21(s,2H), 6.86-7.0(br m,4H), 7.26(m,lH),
7.93(m,lH), 8.0(br s,lH);
N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-
ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 142) NMR l.l(t,3H),
1.62(s,6H), 2.35(q,2H), 5.2(s,2H), 6.88(m,1H),
6.95(m,2H), 7.26(m,lH), 7.4(m,2H), 8.55(br
s,lH);
N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-
ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 143) NMR l.l(t,3H),
1.62(s,6H), 2.35(q,2H), 5.21(s,2H), 6.44(m,lH),
6.87(m,lH), 6.94(m,lH), 7.03(m,2H), 7.26(m,lH),
8.6(br s,lH);
N-(2,5-difluorophenyl)-2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 53)
NMR 1.6 (s,6H), 2.1 (s,3H), 5.2 (s,2H), 6.6
(m,2H), 6.7 (d,lH), 6.9 (m,lH), 8.1 (m,2H);
N-(3,5-difluorophenyl)-2-~5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 56)
NMR 1.7 (s,6H), 2.1 (s,3H), 5.3 (s,2H), 6.5
(m,lH), 6.7 (d,lH), 6.8 (d,lH), 7.1 (m,2H), 8.5
(s,lH);
N-(2,4-difluorophenyl)-2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 144)
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WO97140041 PCT~P97101733
- 33 -
NMR 1.6 ~s,6H), 2.1 (s,3H), 5.2 (s,2H), 6.6
(d,lH), 6.7 (m,3H), 7.9 (s,lH), 8.1 (m,lH);
N-(5-chloro-2-methylphenyl)-2-[5-(5-chloro-
2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 57)
NMR 1.6 (s,6H), 2.1 (s,3H), 2.1 (s,3H), 5.2
(s,2H~, 6.6 (d,lH), 6.7 (d,lH), 6.9 (m,2H), 7.9
(s,lH), 7.9 (s,lH);
N-(3-chlorophenyl)-2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 54)
NMR 1.7 (s,6H), 2.2 (s,3H), 5.2 (s,2H), 6.7
(d,lH), 6.8 (d,lH), 7.0 (d,lH), 7.2 (m,2H), 7.6
(s,lH), 8.3 (s,lH);
N-(3,5-dichlorophenyl)-2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 5',)
NMR 1.7 (s,6H), 2.14 (s,3H), 5.25 (s,2H), 6.68
(d,lH), 6.8 (d,lH), 7.23 (s,lH), 7.48 (d,2H),
8.48 (s,lH);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[5-
(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-
4H-1,3-oxazin-3-yl]-2-methylpropanamide,
(compound 145) NMR 1.6 (s,6H), 2.1 (s,3H), 5.2
(s,2H), 6.6 (d,lH), 6.7 (d,lH), 7.1 (t,lH), 7.2
(m,lH), 8.1 (s,lH), 8.6 (d,lH);
N-(3-pentafluorosulphanylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 146)
NMR 1.65(s,6H), 2.1(s,3H), 5.3(s,2H), 7.0(m,3H),
7.28-7.95(m,4H), 8.6(s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-5-~3-
methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-
3-yl]-2-methylpropanamide,(compound 20) NMR
1.6(s,6H), 2.0(s,3H), 3.7(s,3H), 5.25(s,2H),
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WO 97t40041 PCT/EP97/01733
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- 6.6(m,1H), 6.7(d,lH), 6.9(m,lH), 7.0(m,lH),
7.2(d,lH), 8.1(m,lH), 8.2(s,lH);
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-
5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 19)
NMR 1.7(s,6H), 2.0(s,3H), 2.1(s,3H), 3.7(s,3H),
5.25(s,2H), 6.75(d,lH), 7.15(d,lH), 7.2-
7.4(m,2H), 7.7(d,lH), 7.8(s,lH), 8.7(s,lH);
N-(2-chloro-3,5-difluorophenyl)-2-~2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 147)
NMR 1.65(s,6H), 2.12(s,3H), 5.3(s,2H),
6.65(m,1H), 6.92(m,1H), 8.1(m,1H), 8.48(s,1H);
N-(2-fluoro-S-trifluoromethylphenyl)-2-[2,3-
dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-
4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 148) NMR 1.65(s,6H),
2.0(s,3H), 3.07(s,3H), 5.02(s,2H), 6.75(d,1H),
7.3(m,2H), 8.3(s,lH), 8.65(d,lH);
N-(5-chloro-2-methylphenyl)-2-~2,3-dihydro-
5-(2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-
yl}-2-methylpropanamide,(compound 10) NMR
1.8(s,6H), 2.1(s,3H), 5.3(s,2H), 6.9-7.05(m,4H),
7.35(m,lH), 7.95(m,lH), 8.1(s,lH);
N-(3,4,5-trifluorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 149) NMR
1.55(s,6H), 2.05(s,3H), 5.2(s,2H), 6.85(m,lH),
7.15(m,2H), 8.6(s,lH);
N-(2-methyl-5-nitrophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 150) NMR
1.7(s,6H), 2.1(s,3H), 2.3(s,3H), 5.35(s,2H),
7.0(m,3H), 7.3~m,lH), 7.4(m,lH), 8.48(s,lH),
8.8(m,1H);
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N-(cyclopropyl)-2-[2,3-dihydro-6-methyl-4-
oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide,~compound lSl) NMR 0.4(q, 2H),
0.65 (q, 2H), 1.5(s,6H), 2.05(s,3H), 2.6(m,lH),
5.15(s,2H), 6.1(s,lH), 6.95(m,lH);
N-(cyclobutyl)-2-[2,3-dihydro-6-methyl-4-
oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide,(compound 11) NMR 1.5(s,6H),
1.65(m,2H), 1.85(m,2H), 2.1(s,3H), 2.3(m,2H),
4.3(m,lH), 5.2(s,2H), 6.2(s,lH), 7.0(m,3H);
N-( 2-chloro-5-fluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide,(compound 152) NMR
1.6(s,6H), 2.1(s,3H), 5.3(s,2H), 6.7(m,1H),
7.0(m,3H), 8.25(m,lH), 8.4(s,lH);
N- (3-chloro-5-trifluoromethylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 153)
NMR 1.65(s,6H), 2.05(s,3H), 5.2(s,2H),
6.9(m,3H), 7.2(m,lH), 7.65(m,2H), 8.7(s,lH);
N- (3,5-difluorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 49) NMR 1.5
(s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.4 (m,lH), 7.0
(m,3H), 7.2 (m,2H), 8.4 (s,lH);
N-(2,4-difluorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 154) NMR 1.6
(s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.8 (m,2H), 7.0
(d,lH), 7.2 (m,2H), 7.9 (s lH), 8.1 (m,lH);
N-( 5-chloro-2-methylphenyl)-2-~2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide,(compound 50) NMR 1.6
(s,6H), 2.0 (s,3H), 2.1 (s,3H), 5.2 (s,2H), 6.9
(m,3H), 7.2 (m,2H), 7.9 (s lH), 7.9 (s lH);
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' - 36 -
~ N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide,(compound 48) NMR
1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 7.0
(m,2H), 7.2 (m,2H), 7.4 (s 2H), 8.4 (s lH);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-
dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanamide,(compound 155)
NMR 1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 7.0
(m,2H), 7.2 (m,3H), 8.2 (s lH), 8.6 (d lH); and
N-(2-chloro-5-fluorophenyl)-2-[2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide,(compound 156) NMR 1.6
(s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.6 (m,lH), 7.0
(d,lH), 7.2 (m,3H), 8.2 (d lH), 8.3 (s lH).
By proceeding in a similar manner but using
a mixture of triphenylphosphine and carbon
tetrachloride in dichloromethane to prepare the
appropriate acid chloride the following
compounds were also prepared:
N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-
4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanamide (compound 8), m.p. 68-69.5~C;
N-(3-trifluoromethylphenyl)-2-~2,3-dihydro-
6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-
yl]-2-methylpropanamide (compound 9), m.p. 55-
59 C; and
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-
methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-
2-methylpropanamide (compound 47), NMR
1.67(s,6H), 2.05(s,3H), 5.29(s,2H), 6.64-
673(m,lH), 6.94-7.03( m,lH), 7.06(dd,lH), 7.25-
7.3(m,2H), 8.12-8.2(m,2H).
REFERENCE EXAMPLE 1
A solution of sodium hydroxide ~1.91 g) in
water (40 ml) was added to a stirred solution of
CA 022~0l02 l998-09-2~
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- ethyl 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-
thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate
(7.37 g) in ethanol at room temperature. The
mixture was then heated at 40~C for 3 hours, and
s evaporated. Ether was added to the residue,
which was acidified with hydrochloric acid (2 M)
and extracted (ethyl acetate). The organic
phase was dried (magnesium sulphate) and
evaporated to give 2-[2,3-dihydro-6-methyl-4-
oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanoic acid (4.0 g) as a pink solid,
m.p. 149-150~C.
By proceeding in a similar manner the
following compounds were prepared:
2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-
4H-1,3-oxazin-3-yl]-2-methylpropanoic acid, m.p.
155-159~C (using a mixture of ethanol and dioxan
as solvent).;
2-~2,3-dihydro-6-methyl-(5-methyl-2-
thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoic acid, NMR 1.48(s,6H), 2.0(s,3H),
2.13(s,3H), 5.13(s,2H), 6.7(m,1H), 6.78(m,1H),
9.45(br s,lH);
2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-
4H-l~3-oxazin-3-yl]-2-methylpropanoic acid, NMR
1.14(t,3H), 1.59(s,6H), 2.38(q,2H), 5.25(s,2H),
6.95(m,lH), 6.99(m,lH), 7.3(m,lH), 9.7(br s,lH);
and
2-~2,3-dihydro-5-(3-methoxy-2-thienyl)-6-
methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoic acid, NMR 1.5(s,6H), l.9(s,3H),
3.7(s,3H), 5.2(s,2H), 6.75(d,lH), 7.2(d,lH),
9.3(s,lH).
REFERENCE EXAMPLE 2
A mixture o~ 2-(tributylstannyl)thiophene
(11.2 g), ethyl 2-[2,3-dihydro-5-iodo-6-methyl-
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WO97/40041 PCT~P97/01733
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4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate
(lO.0 g) and bis(triphenylphosphine)palladium
(II) chloride (1.02 g) was heated in
tetrahydrofuran at 50~C for 48 hours. Eithium
s chloride (6.a3 g) was added and heating
continued at 50~C for a further 3 hours. The
mixture was poured into water and extracted with
ether. The extract was washed ~brine) and
purified by column chromatography eluting with
cyclohexane/ethyl acetate to give ethyl 2-[2,3-
dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-
oxazin-3-yl]-2-methylpropanoate (7.37 g) as a
white solid, m.p. 113~C.
By proceeding in a similar manner were
prepared:
ethyl 2-[2,3-dihydro-6-methyl-5-(5-methyl-2-
thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoate NMR 1.15(t,3H), 1.46(s,6H),
2.03(s,3H), 2.15(s,3H), 4.08(q,2H), 5.15(s,2H),
6.7(m,lH), 6.8(m,lH); and
ethyl 2-[2,3-dihydro-5-(3-methoxy-2-
thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoate NMR 1.6(s,6H), 2.0(s,3H),
3.85(s,3H), 4.2(q,2H), 5.3(s,2H), 6.75(s,lH),
6.8(s,lH), 7.2(s,lH), 7.25(s,lH), 7.3(s,lH),
7.4(s,lH), 7.7(s,lH).
By proceeding in a similar manner but
replacing the bis(triphenylphosphine)palladium
(II) chloride with a mixture of palladium (II)
chloride and triphenylphosphine, and omitting
the lithium chloride, there was prepared:
ethyl 2-[2,3-dihydro-6-methyl-4-oxo-s-(3-
thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate,
m.p. 95-98~C.
REFERENCE EXAMPLE 3
, , .
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WO97/4~41 PCT~P97/01733
- 39 -
A mixture of ethyl 2-[2,3-dihydro-6-methyl-
4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate
(95.7g) and N-iodosuccinimide (115 g) in acetic
acid was stirred at 40~C for 5 hours, and then
left overnight at room temperature. The solvent
was evaporated, ether added to the residue and
the solution washed in turn with brine, sodium
carbonate solution (2 M) and brine, until the
washings were neutral. The solution was dried
(magnesium sulphate), evaporated and the residue
recrystallised from ethanol to give ethyl 2-
[2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-
oxazin-3-yl]-2-methylpropanoate (46 g) as a
yellow solid, m.p. 83-85~C.
REFERENCE EXAMPLE 4
A mixture of 2,2,6-trimethyl-4H-1,3-dioxin-
4-one (20.0 g) and ethyl 2-(N-methyleneamino)-2-
methylpropanoate (24.2 g) was heated under
reflux in toluene with distillation of solvent.
An equal volume of fresh toluene was added to
replace that lost by distillation and the
distillation continued. The solution was cooled
and evaporated to give ethyl 2-[2,3-dihydro-6-
methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoate (39 g), NMR 1.23(t,3H),
1.5(s,6H), 2.0(s,3H~, 4.17(q,2H), 5.18(s,2H),
5.22(s,lH).
RJ5~;K~ r~ ; EXAMPLE S
A stirred suspension of 2-amino-2-
methylpropanoic acid (165 g) in ethanol at 0~C
was saturated with hydrogen chloride gas. The
mixture was heated at reflux for 4 hours and the
solvent was evaporated under reduced pressure to
give ethyl 2-amino-2-methylpropanoate
hydrochloride as a white solid. Sodium carbonate
(100 g) was slowly added to a suspension of the
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solid in water followed by 40% aqueous
formaldehyde solution ~150 g) and the suspension
was stirred for 3 hours. The mixture was
extracted with ether, the organic solution was
washed with water, dried (magnesium sulphate)
and solvent evaporated under reduced pressure to
give ethyl 2-(N-methyleneamino)-2-
methylpropanoate (137.8 g) in equilibrium with
its trimer, 1,3,5-tri(1-ethoxycarbonyl-1-
methylethyl)hexahydro-1,3,5-triazine, as a
colourless oil, ~R (liquid film) 2980(s),
1725(vs), 1250(s), 1140(vs).
REFERENCE EXAMPLE 6
A solution of lithium hexamethyldisilazide
(10.6ml of a lM solution in tetrahydrofuran) was
added during 35 minutes to a stirred solution of
ethyl 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-
thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate
(3.22g) in tetrahydrofuran at below -70~C under
nitrogen. After 6 hours under these conditions
iodomethane (2ml) was added and the solution
stirred for 50 minutes before allowing to warm
to 20~C. Water was added after 60 hours and the
ether extract washed (sodium thiosulphate
solution), dried (magnesium sulphate) and
evaporated to give ethyl 2-[2,3-dihydro-6-ethyl-
4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-
methylpropanoate (4.0g), NMR 1.15(t,3H),
1.21(t,3H), 1.56(s,6H), 2.4~q,2H), 4.15(q,2H),
5.25(s,2H), 6.92(m,1H), 6.98(m,1H). 7.3(m,1H).
REFERENCE EXAMPLE 7
A mixture of tert-butyl 2-[5-(5-chloro-2-
thienyl)-2,3-dihydro-6-methyl-4-oxo-5-4H-1,3-
oxazin-3-yl]-2-methylpropanoate (1.24g) and
trifluoroacetic acid was stirred at 50~C for 23
hours and stood at 20~C for 4 days. Additional
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trifluoroacetic acid was added. After 2.5 hours
at 60~C the mixture was evaporated to give 2-~5-
(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-
4H-1,3-oxazin-3-yl]-2-methylpropanoic acid
(1.2g), NMR 1.5(s,6H), 2.1(s,3H), 5.2(s,2H),
6.6(d,lH), 6.7(d,lH).
REFERENCE E~AMPLE 8
A mixture of tert-butyl 2-[2,3-dihydro-5-iodo-
6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-
methylpropanoate (7.31g), 5-chlorothienylboronic
acid (3.42g),
tetrakis(triphenylphosphine~palladium(0) (2.2g)
and sodium bicarbonate (1.61g) was stirred and
heated at reflux under nitrogen in
dimethoxyethane for 18 hours. The cooled mixture
was diluted (2M hydrochloric acid), extracted
(ether) and the extarct dried (magnesium
sulphate), evaporated and purified by column
chromatography on silica gel eluting with ethyl
acetate/isohexane to give tert-butyl 2-[5-(5-
chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-
1,3-oxazin-3-yl]-2-methylpropanoate (2.77g), NMR
1.3(s,9H), 1.5(s,6H), 2.1(s,3H), 5.1(s,2H),
6.6(d,lH), 6.7(d,lH).
R~KJSr~l_lS EXAMP~ 9
A solution of tert-butyl 2-(N-methyleneamino)-
2-methylpropanoate (3.53g) and 5-iodo-2,2,6-
trimethyl-1,3-dioxin-4-one (4.9g) was heated at
reflux in toluene with distillation of toluene
during 1 hour using a Dean and Stark apparatus.
The evaporated solution was dissolved in
dichloromethane, washed (sodium thiosulphate and
with 2M hydrochloric acid), dried (magnesium
sulphate) and evaporated to give tert-butyl 2-
[2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-
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oxazin-3-yl]-2-methylpropanoate (7.0g), NMR
1.35(s,9H), 1.42(s,6H), 2.22(s,3H), 5.1(s,2H).
REFERENCE EXANPLE 10
n-Butyl lithium (33.5ml of a 2.5M solution in
hexane) was added at -10~C to a stirred solution
of 3-methoxythiophene (9.5g) in ether. After l
hour the mixture was cooled to -70~C and stirred
overnight. Tributyl tin chloride (26.lml) was
added at -70~C and the mixture allowed to warm
to 20~C. Water and ethyl acetate were added and
the organic phase washed (brine), dried
(magnesium sulphate) and evaporated.
Distillation gave 2-tributylstannyl-3-
methoxythiophene (22.6g), b.p.115-122~C at 0.3mm
Hg.
According to a further feature of the present
invention, there are provided compositions
suitable for herbicidal use comprising one or
more of the 1,3-oxazin-4-one derivative of
formula (I) or an agriculturally acceptable salt
thereof, in association with, and preferably
homogeneously dispersed in, one or more
compatible agriculturally- acceptable diluents
or carriers and/or surface active agents Li.e.
diluents or carriers and/or surface active
agents of the type generally accepted in the art
as being suitable for use in herbicidal
compositions and which are compatible with
compounds of formula (I)]. The term
llhomogeneously dispersed" is used to include
compositions in which the compounds of formula
(I) are dissolved in other components. The term
llherbicidal compositions" is used in a broad
sense to include not only compositions which are
ready for use as herbicides but also
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concentrates which must be diluted before use.
Preferably, the compositions contain from 0.05
to 90% by weight of one or more compounds of
formula (I).
The herbicidal compositions may contain both a
diluent or carrier and surface-active (e.g.
wetting, dispersing, or emulsifying) agent.
Surface-active agents which may be present in
herbicidal compositions of the present invention
may be of the ionic or non-ionic types, for
example sulphoricinoleates, quaternary ~on;um
derivatives, products based on condensates of
ethylene oxide with alkyl and polyaryl phenols,
e.g. nonyl- or octyl-phenols, or carboxylic acid
esters of anhydrosorbitols which have been
rendered soluble by etherification of the free
hydroxy groups by con~ensation with ethylene
oxide, alkali and alkaline earth metal salts of
sulphuric acid esters and sulphonic acids such
as dinonyl- and dioctyl-sodium
sulphonosuccinates and alkali and alkaline earth
metal salts of high molecular weight sulphonic
acid derivatives such as sodium and calcium
lignosulphonates and sodium and calcium
alkylbenzene sulphonates.
Suitably, the herbicidal compositions
according to the present invention may comprise
up to 10% by weight, e.g. from 0.05% to 10% by
weight, of surface-active agent but, if desired,
herbicidal compositions according to the present
invention may comprise higher proportions of
surface-active agent, for example up to 15~ by
weight in liquid emulsifiable suspension
concentrates and up to 25~ by weight in liquid
water soluble concentrates.
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Examples of suitable solid diluents or
carriers are aluminium silicate, microfine
silicon dioxide, talc, chalk, calcined magnesia,
kieselguhr, tricalcium phosphate, powdered cork,
adsorbent carbon black and clays such as kaolin
and bentonite. The solid compositions (which may
take the form of dusts, granules or wettable
powders) are preferably prepared by grinding the
compounds of formula ~I) with solid diluents or
by impregnating the solid diluents or carriers
with solutions of the compounds of formula (I)
in volatile solvents, evaporating the solvents
and, if necessary, grinding the products so as
to obtain powders. Granular formulations may be
prepared by absorbing the compounds of formula
(I) (dissolved in suitable solvents, which may,
if desired, be volatile) onto the solid diluents
or carriers in granular form and, if desired,
evaporating the solvents, or by granulating
compositions in powder form obtained as
described above. Solid herbicidal compositions,
particularly wettable powders and granules, may
contain wetting or dispersing agents (for
example of the types described above), which may
also, when solid, serve as diluents or carriers.
~iquid compositions according to the invention
may take the form of aqueous, organic or
aqueous-organic solutions, suspensions and
emulsions which may incorporate a surface-active
agent. Suitable liquid diluents for
incorporation in the liquid compositions include
water, glycols, glycol ethers,
tetrahydrofurfuryl alcohol, acetophenone,
cyclohexanone, isophorone, N-alkyl pyrrolidones,
toluene, xylene, mineral, animal and vegetable
oils, esterified vegetable oils and light
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aromatic and naphthenic fractions of petroleum
~ (and mixtures of these diluents). Surface-active
agents, which may be present in the liquid
compositions, may be ionic or non-ionic (for
example of the types described above) and may,
when liquid, also serve as diluents or carriers.
Powders, dispersible granules and liquid
compositions in the form of concentrates may be
diluted with water or other suitable diluents,
for example mineral or vegetable oils,
particularly in the case of liquid concentrates
in which the diluent or carrier is an oil, to
give compositions ready for use.
When desired, liquid compositions of the
compound of formula (I) may be used in the form
of self-emulsifying concentrates containing the
active substances dissolved in the emulsifying
agents or in solvents containing emulsifying
agents compatible with the active substances,
the simple addition of such concentrates to
water producing compositions ready for use.
Liquid concentrates in which the diluent or
carrier is an oil may be used without further
dilution using the electrostatic spray
technique.
Herbicidal compositions according to the
present invention may also contain, if desired,
conventional adjuvants such as adhesives,
protective colloids, thickeners, penetrating
agents, spreading agents, stabilisers,
se~uestering agents, anti-caking agents,
colouring agents and corrosion inhibitors. These
adjuvants may also serve as carriers or
diluents.
Unless otherwise specified, the following
percentages are by weight. Preferred herbicidal
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compositions according to the present invention
are:
aqueous suspension concentrates which
comprise from 10 to 70% of one or more compounds
of formula (I), from 2 to 10% of surface-active
agent, from 0.1 to 5% of thickener and from 15
to 87.9% of water;
wettable powders which comprise from 10 to
90% of one or more compounds of formula (I),
from 2 to 10% of surface-active agent and from 8
to 88% of solid diluent or carrier;
water dispersible granules which comprise
from 1 to 75%, e.g. 50 to 75% of one or more
compounds of formula (I), from 2 to 10% of
surface-active agent and from 1 to 20%, e.g. 5
to 15%, of water soluble binder;
liquid emulsifiable suspension concentrates
which comprise from 10 to 70% of one or more
compounds of formula (I) from 5 to 15% of
surface-active agent, from 0.1 to 5% of
thickener and from 10 to 84.9% of organic
solvent;
granules which comprise from 1 to 90%, e.g.
2 to 10% of one or more compounds of formula (I)
from 0.5 to 7%, e.g. 0.5 to 2%, of surface-
active agent and from 3 to 98.5%, e.g. 88 to
97.5% of granular carrier and
emulsifiable concentrates which comprise
0.05 to 90%, and preferably from 1 to 60% of one
or more compounds of formula (I), from 0.01 to
10%, and preferably from 1 to 10%, of surface-
active agent and from 9.99 to 99.94%, and
preferably from 39 to 98.99~, of organic
solvent.
Herbicidal compositions according to the
present invention may also comprise the
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compounds of formula (I) in association with,
and preferably homogeneously dispersed in, one
or more other pesticidally active compounds and,
if desired, one or more compatible pesticidally
acceptable diluents or carriers, surface-active
agents and conventional adjuvants as
hereinbefore described.
Examples of other pesticidally active
compounds which may be included in, or used in
conjunction with, the herbicidal compositions of
the present invention include herbicides, for
example to increase the range of weed species
controlled for example alachlor [2-chloro-2,6~-
diethyl-N-(methoxy-methyl)-acetanilide],
atrazine [2-chloro-4-ethylamino-6-
isopropylamino-l,3,5-triazine], bromoxynil [3,5-
dibromo-4-hydroxybenzonitrile], chlortoluron
[N~-(3-chloro-4-methylphenyl)-N,N-dimethylurea],
cyanazine [2-chloro-4-(l-cyano-l-
methylethylamino)-6-ethylamino-l,3,5-triazine],
2,4-D [2,4-dichlorophenoxy-acetic acid], dicamba
[3,6-dichloro-2-methoxybenzoic acid],
difenzoquat [l,2- dimethyl-3,5-diphenyl-
pyrazolium salts], flampropmethyl [methyl N-2-
(N- benzoyl-3-chloro-4-fluoroanilino)-
propionate], fluometuron [N'-(3-trifluoro-
methylphenyl)-N,N-dimethylurea], isoproturon
[N'-(4-isopropylphenyl)-N,N-dimethylurea],
diclofop { (RS)-2-[4-2,4-
dichlorophenoxy)phPnoxy]propionic acid},
fenoxaprop and fenoxaprop-P { 2-[4-(6-chloro-
l,3-benzoxazol-2-yloxy)phenoxy]propionic acid},
diflufenican{N-(2,4-difluorophenyl)-2-[3-
(trifluoromethyl)phenoxy]-
3-pyridinecarboxamide}, tralkoxydim {2-[l-
(ethoxyimino)propyl]-3-hydroxy-5-
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mesitylcyclohex-2-enone}, clodinafop {2-[4-(5-
chloro-3-fluoro-2-pyridyloxy)phenoxy]propionic
acid~, sulcotrione [2-(2-chloro-4-
methylsulphonylbenzoyl)cyclohexane-l,3-dione],
flurtamone {5-methylamino-2-phenyl-4-[3-
(trifluoromethyl)phenyl]-3(2H)-furanone},
aclonifen (2-chloro-6-nitro-3-phenoxyaniline),
and sulfonylureas (e.g. nicosulfuron);
insecticides, e.g. synthetic pyrethroids, e.g.
permethrin and cypermethrin,
and fungicides, e.g. carbamates, e.g. methyl
N-(l-butyl-carbamoyl- benzimidazol-2-
yl)carbamate, and triazoles e.g. l-(4-chloro-
phenoxy)-3,3- dimethyl-l-(l,2,4-triazol-l-yl)-
butan-2-one.
Pesticidally active compounds and other
biologically active materials which may be
included in, or used in conjunction with, the
herbicidal compositions of the present
invention, for example those hereinbefore
mentioned, and which are acids, may, if desired,
be utilised in the form of conventional
derivatives, for example alkali metal and amine
salts and esters.
According to a further feature of the present
invention there is provided an article of
manufacture comprising at least one of the l,3-
oxazin-4-one derivative of formula (I) or, as is
preferred, a herbicidal composition as
hereinbefore described, and preferably a
herbicidal concentrate which must be diluted
before use, comprising at least one of the l,3-
oxazin-4-one derivative of formula ~I) within a
container for the aforesaid derivative or
derivatives of formula (I), or a said herbicidal
composition, and instructions physically
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associated with the aforesaid container setting
out the manner in which the aforesaid derivative
or derivatives of formula (I) or herbicidal
composition contained therein is to be used to
control the growth of weeds. The containers will
normally be of the types conventionally used for
the storage of chemical substances which are
solid at normal ambient temperatures and
herbicidal compositions particularly in the form
of concentrates, for example cans and drums of
metal, which may be internally lacquered, and
plastics materials, bottles or glass and
plastics materials and, when the contents of the
container is a solid, for example granular,
herbicidal compositions, ~oxes, for example of
cardboard, plastics materials and metal, or
sacks. The containers will normally be of
sufficient capacity to contain amounts of the N-
substituted pyrazole derivative or herbicidal
compositions sufficient to treat at least one
acre of ground to control the growth of weeds
therein but will not exceed a size which is
convenient for conventional methods of handling.
The instructions will be physically associated
with the container, for example by being printed
directly thereon or on a label or tag affixed
thereto. The directions will normally indicate
that the contents of the container, after
dilution if necessary, are to be applied to
control the growth of weeds at rates of
application between 0.5 g and 5000 g of active
material per hectare in the manner and for the
purposes hereinbefore described.
The following Examples illustrate herbicidal
compositions according to the present invention.
The following trademarks appear in these
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Examples:- Arylan CA, Synperonic, Solvesso,
Arylan SX8S, Arkopon T, Sopropon T36, Tixosil
38, Soprophor FL, Ethylan BCP, Attagel,
Rhodorsil.
Exam~le C1:
An emulsifiable concentrate is formed from:
Active ingredient (Compound 1) 20% w/v
N-Methylpyrrolidone (NMP) 25% w/v
Calcium dodecylbenzenesulphonate
(CaDDBS) (Arylan CA) 4% w/v
Nonylphenol ethylene oxide propylene oxide
condensate (NPEOPO)(Synperonic NPE 1800)
6% w/v
Aromatic solvent (Solvesso) to 100 volumes
by stirring NMP, active ingredient (Compound
1), CaDDBS, NPEOPO and 90% Aromatic solvent
until a clear solution is formed, and adjusting
to volume with Aromatic solvent.
ExamPle C2
A wettable powder is formed from:
Active ingredient (Compound 1) 50% w/w
Sodium dodecylbenzenesulphonate
(Arylan SX85) 3% w/w
Sodium methyl oleoyl taurate
(Arkopon T) 5% w/w
Sodium polycarboxylate
(Sopropon T36) l~ w/w
Microfine silicon dioxide
(Tixosil 38) 3% w/w
China clay 38% w/w
by blending the above ingredients together
and grinding the mixture in an air jet mill.
Exam~le C3
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A suspension concentrate is formed from:
Active ingredient (Compound 1~ 50~ w/v
Antifreeze (Propylene glycol) 5% w/v
Ethoxylated tristyrylphenol
phosphate(Soprophor FL) 0.5% w/v
Nonyl phenol 9 mole ethoxylate
(Ethylan BCP) 0.5% w/v
Sodium polycarboxylate
(Sopropon T36) 0.2% w/v
Attaclay (Attagel) 1.5% w/v
Antifoam ~Rhodorsil AF426R) 0.003% w/v
Water to 100 volumes
by stirring the above ingredients together
and milling in a bead mill.~5
Exam~le C4
A water dispersible granule is formed from:
Active ingredient (Compound 1) 50% w/w
Sodium dodecylbenzenesulphonate
(Arylan SX 85) 3% w/w
Sodium methyl oleoyl taurate
(Arkopon T) 5% w/w
Sodium polycarboxylate
(Sopropon T36) 1% w/w
Binder ~Sodium lignosulphonate) 8% w/w
China clay 30~ w/w
Microfine silicon dioxide
(Tixosil 38) 3% w/w
by blending the above ingredients together,
grinding the mixture in an air jet mill and
granulating by addition of water in a suitable
granulation plant (e.g. Fluid bed drier) and
drying. Optionally the active ingredient may be
ground either on its own or admixed with some or
all of the other ingredients.
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Similar compositions may be prepared by
replacing compound 1 in each of Examples C1 to
C4 above with other compounds of formula (I).
According to a feature of the present
invention, there is provided a method for
controlling the growth of weeds (i.e. undesired
vegetation) at a locus which comprises applying
to the locus a herbicidally effective amount of
at least one l,3-oxazin-4-one derivative of
formula (I) or an agriculturally acceptable salt
thereof. For this purpose, the 1,3-oxazin-4-one
derivatives are normally used in the form of
herbicidal compositions (i.e. in association
with compatible diluents or carriers and/or
surface active agents suitable for use in
herbicidal compositions), for example as
hereinafter described.
The compounds of formula (I) show herbicidal
activity against dicotyledonous (i.e. broad-
leafed) and monocotyledonous (e.g. grass) weeds
by pre- and/or post-emergence application.
By the term "pre-emergence application" -is
meant application to the soil in which the weed
seeds or seedlings are present before emergence
of the weeds above the surface of the soil. By
the term "post-emergence application" is meant
application to the aerial or exposed portions of
the weeds which have emerged above the surface
of the soil. For example, the compounds of
formula (I~ may be used to control the growth
of:
broad-leafed weeds, for example, Abutilon
theophrasti, Amaranthus retroflexus, Bidens
pilosa, Chenopodium album, Galium aparine,
Ipomoea sPP . e.g. Ipomoea purpurea, Sesbania
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exaltata, Sinapis arvensis, Solanum niqrum and
Xanthium strumarium, and
grass weeds, for example Alopecurus
mYosuroides, Avena fatua, Diqitaria sanquinalis,
s Echinochloa crus-qalli, Eleusine indica and
Setaria spp, e.g. Setaria faberii or Setaria
viridis, and
sedges, for example, C~perus esculentus.
The compound of formula (I) are particularly
preferred as pre-emergence herbicides and for
their control of grass species, in particular
Echinochloa crus-qalli.
The amounts of compounds of formula (I)
applied vary with the nature of the weeds, the
compositions used, the time of application, the
climatic and edaphic conditions and (when used
to control the growth of weeds in crop-growing
areas) the nature of the crops. When applied to
a crop-growing area, the rate of application
should be sufficient to control the growth of
weeds without causing substantial permanent
damage to the crop. In general, taking these
factors into account, application rates between
l g and lO00 g of active material per hectare
give good results. However, it is to be
understood that higher or lower application
rates may be used, depending upon the particular
problem of weed control encountered.
The compounds of formula (I) may be used to
control selectively the growth of weeds, for
example to control the growth of those species
hereinbefore mentioned, by pre- or post-
emergence application in a directional or non-
directional fashion, e.g. by directional or non-
directional spraying, to a locus of weed
infestation which is an area used, or to be
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used, for growing crops, for example cereals,
e.g. wheat, barley, oats, maize and rice, soya
beans, field and dwarf beans, peas, lucerne,
cotton, peanuts, flax, onions, carrots, cabbage,
oilseed rape, sunflower, sugar beet, and
permanent or sown grassland before or after
sowing of the crop or before or after emergence
of the crop. For the selective control of weeds
at a locus of weed infestation which is an area
used, or to be used, for growing of crops, e.g.
the crops hereinbefore mentioned, application
rates between lO g and 500 g, and preferably
between 25 g and 250 g, of active material per
hectare are particularly suitable.
The compounds of the invention are
especially useful for controlling small seeded
grass species, such as Alo~ecurus mYosuroides,
Poa annua, and Apera spica-venti.
The compounds of formula (I) may also be
used to control the growth of weeds, especially
those indicated above, by pre- or post-emergence
application in established orchards and other
tree-growing areas, for example forests, woods
and parks, and plantations, e.g. sugar cane, oil
palm and rubber plantations. For this purpose
they may be applied in a directional or non-
directional fashion (e.g. by directional or non-
directional spraying) to the weeds or to the
soil in which they are expected to appear,
before or after planting of the trees or
plantations at application rates between 50 g
and 5000 g, and preferably between 50 g and 2000
g, most preferably between lO0 g and lO00 g of
active material per hectare.
The compounds of formula (I) may also be
used to control the growth of weeds, especially
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those indicated above, at loci which are not
crop-growing areas but in which the control of
weeds is nevertheless desirable.
Examples of such non-crop-growing areas
include airfields, industrial sites, railways,
roadside verges, the verges of rivers,
irrigation and other waterways, scrublands and
fallow or uncultivated land, in particular where
it is desired to control the growth of weeds in
order to reduce fire risks. When used for such
purposes in which a total herbicidal effect is
frequently desired, the active compounds are
normally applied at dosage rates higher than
those used in crop-growing areas as hereinbefore
described. The precise dosage will depend upon
the nature of the vegetation treated and the
effect sought.
Pre- or post-emergence application, and
preferably pre-emergence application, in a
directional or non-directional fashion (e.g. by
directional or non-directional spraying) at
application rates between 50 g and 5000 g, and
preferably between 50 g and 2000 g, most
preferably between lO0 g and lO00 g of active
material per hectare are particularly suitable
for this purpose.
When used to control the growth of weeds by
pre-emergence application, the compounds of
formula (I) may be incorporated into the soil in
which the weeds are expected to emerge. It will
be appreciated that when the compounds of
formula I are used to control the growth of
weeds by post-emergence application, i.e. by
application to the aerial or exposed portions of
emerged weeds, the compounds of formula I will
also normally come into contact with the soil
CA 022~0102 l998-09-2~
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-
and may also then exercise a pre-emergence
control on later-germinating weeds in the soil.
Where especially prolonged weed control is
required, the application of the compounds of
formula (I) may be repeated if required.
The compounds of the invention have been
used in herbicidal applications according to the
following procedures.
METHOD OF USE OF HERBICIDA~ CONPO~lNDS:
TEST M~:THOD A
a) General
Appropriate quantities of the compounds used
to treat the plants were dissolved in acetone to
give solutions equivalent to application rates
of up to lOOOg test compound per hectare (g/ha).
These solutions were applied from a standard
laboratory herbicide sprayer delivering the
equivalent of 290 litres of spray fluid per
hectare.
b) Weed control : Pre-emerqence
The seeds were sown in 70 mm square, 75 mm
deep plastic pots in non-sterile soil . The
quantities of seed per pot were as follows:-
Weed sPecies A~prox number of seeds/pot
1) Broad-leafed weeds
Abutilon theophrasti 10
Amaranthus retroflexus 20
Galium aparine 10
Ipomoea purpurea 10
Sinapis arvensis 15
Xanthium strumarium 2
2) Grass weeds
Alopecurus myosuroides 15
Avena fatua 10
Echinochloa crus-galli 15
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Setaria viridis 20
3) Sedqes
Cyperus esculentus 3
Crop
l) Broad-leafed
Cotton 3
Soya 3
2) Grass
Maize 2
Rice 6
Wheat 6
The compounds of the invention were applied
to the soil surface, containing the seeds, as
described in (a~. A single pot of each crop and
each weed was allocated to each treatment, with
unsprayed controls and controls sprayed with
acetone alone.
After treatment the pots were placed on
capillary matting kept in a glass house, and
watered overhead. Visual assessment of crop
damage was made 20-24 days after spraying. The
results were expressed as the percentage
reduction in growth or damage to the crop or
weeds, in comparison with the plants in the
control pots.
c) Weed control : Post-emerqence
The weeds and crops were sown directly into
John Innes potting compost in 75 mm deep, 70 mm
square pots except for Amaranthus which was
pricked out at the seedling stage and
transferred to the pots one week before
spraying. The plants were then grown in the
greenhouse until ready for spraying with the
compounds used to treat the plants. The number
of plants per pot were as follows :-
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1) Broad leafed weeds
Weed sPecies Number of Plants
per pot Growth staqe
Abutilon theophrasti 3 1-2 leaves
Amaranthus retroflexus 4 1-2 leaves
Galium aparine 3 lSt whorl
Ipomoea purpurea 3 1-2 leaves
Sinapis arvensis 4 2 leaves
Xanthium strumarium 1 2-3 leaves
2) Grass weeds
Weed sPeciesNumber of plants
per Pot Growth staqe
Alopecurus myosuroides 8-12 1-2 leaves
Avena fatua 12-18 1-2 leaves
Echinochloa crus-galli 4 2-3 leaves
Setaria viridis 15-25 1-2 leaves.
3) Sedqes
Weed sPeciesNumber of plants
per Pot Growth staqe
Cyperus esculentus 3 3 leaves.
1) Broad leafed
CroPs Number of plants
Per pot Growth staqe
Cotton 2 1 leaf
Soya 2 2 leaves.
2) Grass
Crops Number of Plants
per Pot Growth staqe
Maize 2 2-3 leaves
Rice 4 2-3 leaves
Wheat 5 2-3 leaves.
The compounds used to treat the plants were
applied to the plants as described in (a). A
single pot of each crop and weed species was
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allocated to each treatment, with unsprayed
controls and controls sprayed with acetone
alone.
After treatment the pots were placed on
capillary matting in a glass house, and watered
overhead once after 24 hours and then by
controlled sub-irrigation. Visual assessment of
crop damage and weed control was made 20-24 days
after spraying. The results were expressed as
the percentage reduction in growth or damage to
the crop or weeds, in comparison with the plants
in the control pots.
TEST METHOD B
PaddY ~ost-emerqence a~lication in
qreenhouse
Paddy field soil was filled in 170 cm2
plastic pots, a suitable amount of water and
chemical fertilisers were added thereto and
kneaded to convert it to a state of a paddy.
Paddy rice plants (variety; Koshihikari),
that had been grown in advance in a greenhouse
to a stage of two leaves, were transplanted to
each pot (two seedlings per pot). Then in each
pot there were sown predetermined amounts of
seeds of Echinochloa oryzicola, Monochoria
vaqinalis, Lindernia procumbens and Scir~us
juncoides respectively, and water was added to a
depth of 3 cm.
After having grown the plants in a
greenhouse until Echinochloa oryzicola reached a
stage of 1.5 leaves, solutions were prepared in
100% acetone using compounds described in the
Examples so that they contained active
ingredients in an amount equivalent to 75, 300
and 1200 g/ha. The solutions were applied by
dropping with a pipette.
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After 21 days from the application with the
chemicals, herbicidal effects on each weed and
phytotoxicity on paddy rice plants were visually
assessed, and the results expressed as the
percentage reduction in growth or damage to the
crop or weeds in comparison with the plants in
the control pots.
When applied pre- or post-emergence in Test
Method A at lOOOg/ha or less compounds 1 to 8,
10, 11, 19, 20, 40-42, 48-50, 53, 54, 56 and
136-156 gave at least 90~ reduction in growth of
one or more of the weed species.
When applied pre- or post-emergence in Test
Method A at 250g/ha or less compound 57 gave at
least 80% reduction in growth of one or more of
the weed species.
At levels of application toxic to the weeds
these compounds were selective in at least one
of the crop species.
When applied at 1200g/ha or less, in Test
Method B, compounds 1-4, 6-ll, 19, 20, 40-42,
47-50, 53-57, 136-140, 143-156 of the invention
gave at least 90% reduction in growth of one or
more of the weed species listed above.
