U.S. patent application number 09/964370 was filed with the patent office on 2002-04-18 for 4-benzoyl isoxazoles derivatives and their use as herbicides.
Invention is credited to Musil, Tibor, Pettit, Simon Neil, Smith, Philip Henry Gaunt.
Application Number | 20020045551 09/964370 |
Document ID | / |
Family ID | 26302184 |
Filed Date | 2002-04-18 |
United States Patent
Application |
20020045551 |
Kind Code |
A1 |
Musil, Tibor ; et
al. |
April 18, 2002 |
4-benzoyl isoxazoles derivatives and their use as herbicides
Abstract
4-Benzoylisoxazole derivatives of formula (I), wherein R 1
represents hydrogen or ester; R.sup.1 represents alkyl, haloalkyl
or optionally substituted cycloalkyl; R.sup.2 represents halogen,
optionally halogenated alkyl, alkenyl or alkynyl; alkyl substituted
by one or more groups --OR.sup.5; nitro, cyano, --CO.sub.2R.sup.5,
--S(O).sub.pR.sup.6, --O(CH.sub.2).sub.mOR.sup.5, --COR.sup.5,
--NR.sup.5R.sup.6, --N(R.sup.8)SO.sub.qR.sup.7,
--CONR.sup.9R.sup.10 or --OR.sup.51; optionally substituted phenyl;
R.sup.3 represents --S(O).sub.qR.sup.7; X represents
--N(R.sup.8)--; n represents zero or an integer from one to four;
R.sup.5, R.sup.51 and R.sup.6 independently represent hydrogen,
optionally halogenated alkyl, alkenyl or alkynyl; optionally
substituted phenyl; or cycloalkyl; R.sup.7 represents alkyl,
alkenyl or alkynyl optionally substituted by halogens; cycloalkyl;
optionally substituted phenyl; or amino; R.sup.8 represents
hydrogen; alkyl, alkenyl or alkynyl optionally substituted by
halogens; cycloalkyl; optionally substituted phenyl; or alkoxy; m
is 1, 2 or 3; p is 0, 1 or 2; and q is zero or two; and their used
as herbicides is described.
Inventors: |
Musil, Tibor; (Ohw, GB)
; Pettit, Simon Neil; (Ohw, GB) ; Smith, Philip
Henry Gaunt; (Ohw, GB) |
Correspondence
Address: |
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
26302184 |
Appl. No.: |
09/964370 |
Filed: |
September 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09964370 |
Sep 28, 2001 |
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08454370 |
Nov 1, 1995 |
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6323155 |
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08454370 |
Nov 1, 1995 |
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PCT/EP93/03537 |
Dec 15, 1993 |
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Current U.S.
Class: |
504/271 ;
548/248 |
Current CPC
Class: |
A01N 51/00 20130101;
C07D 261/08 20130101; A01N 43/80 20130101; C07D 261/18
20130101 |
Class at
Publication: |
504/271 ;
548/248 |
International
Class: |
A01N 043/80; C07D
261/18 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 1992 |
GB |
92 26396.1 |
May 18, 1993 |
GB |
93.10204.4 |
Claims
1. A 4-benzoylisoxazole derivative of formula (I): 20wherein: R
represents the hydrogen atom or a group --CO.sub.2R.sup.4; R.sup.1
represents:--a straight- or branched-chain alkyl group containing
up to six carbon atoms which is optionally substituted by one or
more halogen atoms; or a cycloalkyl group containing from three to
six carbon atoms optionally substituted by one or more R.sup.5
groups or one or more halogen atoms; R.sup.2 represents:--a halogen
atom; a straight- or branched-chain alkyl alkenyl or alkynyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms; a straight- or branched-chain alkyl group
containing up to six carbon atoms which is substituted by one or
more groups --OR.sup.5; a group selected from nitro, cyano,
--CO.sub.2R.sup.5, --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --COR.sup.5, --NR.sup.5R.sup.6,
-N(R.sup.8)SO.sub.qR.sup.7, --CONR.sup.9R.sup.10 and --OR.sup.51;
phenyl optionally substituted by from one to three groups R.sup.21
which may be the same or different; R.sup.3 represents
--S(O).sub.qR.sup.7; X represents a group --N(R.sup.8)--; n
represents zero or an integer from one to four; where n is greater
than one the groups R.sup.2 may be the same or different; R.sup.4
represents a straight- or branched-chain alkyl group containing up
to six carbon atoms optionally substituted by one or more halogen
atoms; R.sup.5, R.sup.51 and R.sup.6, which may be the same or
different, each represents:--the hydrogen atom; a straight- or
branched-chain allyl, alkenyl or alkynyl group containing up to six
carbon atoms optionally substituted by one or more halogen atoms;
phenyl optionally substituted by from one to five groups R.sup.2
which may be the same or different; or a cycloalkyl group
containing from three to six carbon atoms; R.sup.7 represents:--a
straight- or branched-chain alkyl, alkenyl or alkynyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms; a cycloalkyl group containing from three to six
carbon atoms; phenyl or benzyl optionally substituted by from one
to five groups R.sup.21 which may be the same or different; or
--NR.sup.9R.sup.10; R.sup.8 represents: the hydrogen atom; or a
straight- or branched-chain alkyl, alkenyl or alkynyl group
containing up to ten carbon atoms optionally substituted by one or
more halogen atoms; a cycloalkyl group containing from three to six
carbon atoms; phenyl optionally substituted by from one to five
groups which may be the same or different selected from halogen,
nitro, cyano, R.sup.5, S(O).sub.pR.sup.5 and --OR.sup.5; or a group
--OR.sup.11; R.sup.9 represents:--the hydrogen atom; a straight- or
branched-chain alkyl group containing up to six carbon atoms
optionally substituted by one or more halogen atoms; or phenyl
optionally substituted by from one to five groups R.sup.2 which may
be the same or different; R.sup.10 represents a group selected from
R.sup.5 and --OR.sup.11; or R.sup.9 and R.sup.10, together with the
nitrogen to which they are attached, may form a 5 or 6 membered
ring optionally containing an oxygen or nitrogen atom in the ring,
wherein the ring is optionally substituted by one or more alkyl
groups containing up to 3 carbon atoms; R.sup.11 represents a
straight- or branched-chain alkyl group containing up to six carbon
atoms; R.sup.21 represents:--a halogen atom; a straight- or
branched-chain alkyl group containing up to three carbon atoms
optionally substituted by one or more halogen atoms; or a group
selected from nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5; m
represents one, two or three; p represents zero, one or two; and q
represents zero or two; or an agriculturally acceptable salt
thereof
2. A compound according to claim 1 wherein: R represents the
hydrogen atom or a group --CO.sub.2R.sup.4; R.sup.1 represents:--a
straight- or branched-chain alkyl group containing up to six carbon
atoms which is optionally substituted by one or more halogen atoms;
or a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more R.sup.5 groups; R.sup.2
represents:--a straight- or branched-chain alkyl, alkenyl or
alkynyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms; a straight- or
branched-chain alkyl group containing up to six carbon atoms which
is substituted by a group --OR.sup.5; a halogen atom; phenyl
optionally substituted by from one to three groups R.sup.21 which
may be the same or different; a group selected from --COR.sup.5,
nitro, cyano, --CO.sub.2R.sup.5; --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --N(R.sup.8)SO.sub.2R.sup.7,
--CONR.sup.9R.sup.10 and --OR.sup.51; R.sup.3 represents
--S(O).sub.qR.sup.7; X represents a group --N(R.sup.8)--; n
represents zero or an integer from one to four; where n is greater
than one the groups R.sup.2 may be the same or different; R.sup.4
represents a straight- or branched-chain alkyl group containing up
to six carbon atoms optionally substituted by one or more halogen
atoms; R.sup.5 represents:--a straight- or branched-chain alkyl,
alkenyl or alkynyl group containing up to six carbon atoms
optionally substituted by one or more halogen atoms; or a
cycloalkyl group containing from three to six carbon atoms;
R.sup.51 represents:--a straight- or branched-chain alkyl, alkenyl
or alkynyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms; a cycloalkyl group
containing from three to six carbon atoms; or phenyl optionally
substituted by from one to five groups which may be the same or
different elected from a halogen atom, a straight- or
branched-chain alkyl group containing up to three carbon atoms
optionally substituted by one or more halogen atoms; nitro, cyano,
--S(O).sub.pR.sup.5 and --OR.sup.5; R.sup.6 represents:--a
straight- or branched-chain alkyl, alkenyl or alkynyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms; a cycloalkyl group containing from three to six
carbon atoms; or phenyl optionally substituted by from one to five
groups which may be the same or different selected from a halogen
atom, a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more halogen
atoms; nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5; R.sup.7
represents:--a straight- or branched-chain alkyl, alkenyl or
alkynyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms; a cycloalkyl group
containing from three to six carbon atoms; phenyl optionally
substituted by from one to five groups R.sup.21 which may be the
same or different; or --NR.sup.9R.sup.10; R.sup.8 represents: the
hydrogen atom; or a straight- or branched-chain alkyl, alkenyl or
alkynyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms; a cycloalkyl group
containing from three to six carbon atoms; phenyl optionally
substituted by from one to five groups which may be the same or
different selected from a halogen atom, a straight- or
branched-chain alkyl group containing up to three carbon atoms
optionally substituted by one or more halogen atoms; nitro, cyano,
--S(O).sub.pR.sup.5 and --OR.sup.5; or a group --OR.sup.11; R.sup.9
represents hydrogen or a straight- or branched-chain alkyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms; R.sup.10 represents a group selected from
R.sup.5 and --OR.sup.11; or R.sup.9 and R.sup.10, together with the
nitrogen to which they are attached, may form a 5 or 6 membered
ring optionally containing an oxygen or nitrogen atom in the ring,
wherein the ring is optionally substituted by one or more alkyl
groups containing up to 3 carbon atoms; R.sup.11 represents a
straight- or branched-chain alkyl group containing up to six carbon
atoms; R.sup.21 represents:--a halogen atom; a straight- or
branched-chain alkyl group containing up to three carbon atoms
optionally substituted by one or more halogen atoms; or a group
selected from nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5; m
represents one, two or three; p represents zero, one or two; and q
represents two.
3. A compound according to claim 1 wherein: R represents the
hydrogen atom or a group --CO.sub.2R.sup.4; R.sup.1 represents:--a
straight- or branched-chain alkyl group containing up to six carbon
atoms which is optionally substituted by one or more halogen atoms;
or a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more R.sup.5 groups or one or more
halogen atoms; R.sup.2 represents:--a halogen atom; a straight- or
branched-chain alkyl group containing up to six carbon atoms
optionally substituted by one or more halogen atoms; a straight- or
branched-chain alkyl group containing up to six carbon atoms which
is substituted by one or more groups --OR.sup.5; a group selected
from nitro, cyano, --CO.sub.2R.sup.5, --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --COR.sup.5, --NR.sup.5R.sup.6,
--N(R.sup.8)SO.sub.qR.sup.7 and --OR.sup.51; R.sup.3 represents
--S(O)R.sup.7; X represents a group --N(R.sup.8)--n represents zero
or an integer from one to four; where n is greater than one the
groups R.sup.2 may be the same or different; R.sup.4 represents a
straight- or branched-chain alkyl group containing up to six carbon
atoms which is optionally substituted by one or more halogen atoms;
R.sup.5, R.sup.51 and R.sup.6, which may be the same or different,
each represents: the hydrogen atom; a straight- or branched-chain
alkyl group containing up to six carbon atoms which is optionally
substituted by one or more halogen atoms; phenyl optionally
substituted by from one to five groups R.sup.2 which may be the
same or different; R.sup.7 represents: a straight- or
branched-chain alkyl group containing up to six carbon atoms which
is optionally substituted by one or more halogen atoms: phenyl
optionally substituted by from one to five groups R.sup.21 which
may be the same or different; or a group --NR.sup.9R.sup.10;
R.sup.8 represents: the hydrogen atom; a straight- or
branched-chain alkyl, alkenyl or alkynyl group containing up to ten
carbon atoms which is optionally substituted by one or more halogen
atoms; or phenyl optionally substituted from one to five groups
which may be the same or different selected from nitro, halogen,
R.sup.5 and --OR.sup.5; R.sup.9 and R.sup.10, which may be the same
or different, each represents:--the hydrogen atom; a straight- or
branched-chain alkyl group containing up to six carbon atoms
optionally substituted by one or more halogen atoms; or phenyl
optionally substituted by from one to five groups R.sup.2 which may
be the same or different; R.sup.21 represents:--a halogen atom; a
straight- or branched-chain alkyl group containing up to three
carbon atoms optionally substituted by one or more halogen atoms;
or a group selected from nitro, cyano, --S(O).sub.pR.sup.6 and
--OR.sup.5; p represents zero, 1 or 2; q represents zero or 2; and
m represents 1, 2 or 3.
4. A compound according to claim 1, 2 or 3 wherein the 5- and 6-
positions of the benzoyl ring are unsubstituted.
5. A compound according to any one of the preceding claims wherein
the 2-position of the benzoyl ring is substituted.
6. A compound according to any one of claims 1, 2, 4 and 5 wherein:
R.sup.1 represents:--a straight- or branched-chain alkyl group
containing up to six carbon atoms which is optionally substituted
by one or more halogen atoms; or a cycloalkyl group containing from
three to six carbon atoms optionally substituted by one or more
methyl groups; R.sup.2 represents:--a halogen atom; a straight- or
branched-chain alkyl, alkenyl or alkynyl group containing up to six
carbon atoms optionally substituted by one or more halogen atoms; a
straight- or branched-chain alkyl group containing up to six carbon
atoms which is substituted by a group --OR.sup.5; phenyl optionally
substituted by from one to three groups R.sup.21 which may be the
same or different; or a group selected from --COR.sup.5, cyano,
nitro, --CO.sub.2R.sup.5, --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --N(R.sup.8)SO.sub.2R.sup.7 and
--OR.sup.51; n represents zero or an integer from one to three;
where n is greater than one the groups R.sup.2 may be the same or
different; R.sup.5 represents:--a straight- or branched-chain alkyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms; or a cycloalkyl group containing from
three to six carbon atoms; R.sup.51 and R.sup.6, which may be the
same or different, each represents:--a straight- or branched-chain
alkyl or alkenyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms; a straight- or
branched-chain alkynyl group containing from three to six carbon
atoms; a cycloalkyl group containing three to six carbon atoms;
R.sup.7 represents:--a straight- or branched-chain alkyl or alkenyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms; a straight- or branched-chain alkynyl
group containing from three to six carbon atoms; a cycloalkyl group
containing three to six carbon atoms; or phenyl optionally
substituted by from one to three groups R.sup.21 which may be the
same or different; R.sup.8 represents:--the hydrogen atom; or a
straight- or branched-chain alkyl or alkenyl group containing up to
six carbon atoms optionally substituted by one or more halogen
atoms; a straight- or branched-chain alkynyl group containing from
three to six carbon atoms; or a cycloalkyl group containing three
to six carbon atoms; R.sup.21 represents:--a halogen atom; a
straight- or branched-chain alkyl group containing up to three
carbon atoms optionally substituted by one or more halogen atoms;
or a group selected from nitro, cyano, --S(O).sub.pR.sup.5 and
--OR.sup.5; q represents two; m represents two or three; and p
represents zero, one or two.
7. A compound according to-any one of claims 1, 2 and 4 to 6
wherein: R.sup.1 represents:--a straight- or branched-chain alkyl
group containing up to three carbon atoms; or a cycloalkyl group
containing three or four carbon atoms optionally substituted by a
methyl group; R.sup.2 represents:--a chlorine, bromine or fluorine
atom; or a straight- or branched-chain alkyl, alkenyl or alkynyl
group containing up to four carbon atoms optionally substituted by
one or more halogen atoms; a straight- or branched-chain alkyl
group containing up to four carbon atoms which is substituted by a
group --OR.sup.5; or a group selected from --COR.sup.5,
--CO.sub.2R.sup.5, --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --N(R.sup.8)SO.sub.2R.sup.7 and
--OR.sup.51; R.sup.5 and R.sup.6, which may be the same or
different, each represents:--a straight- or branched-chain alkyl
group containing up to four carbon atoms optionally substituted by
one or more chlorine, bromine or fluorine atoms; or a cyclopropyl
group; R.sup.51 and R.sup.7, which may be the same or different,
each represents:--a straight- or branched-chain alkyl or alkenyl
group containing up to four carbon atoms optionally substituted by
one or more chlorine, bromine or fluorine atoms; a straight- or
branched-chain alkynyl group containing three or four carbon atoms;
or a cyclopropyl group; R.sup.8 represents:--the hydrogen atom; a
straight- or branched-chain alkyl or alkenyl group containing up to
four carbon atoms optionally substituted by one or more chlorine,
bromine or fluorine atoms; a straight- or branched-chain alkynyl
group containing three or four carbon atoms; or a cyclopropyl
group; q represents two; m represents two or three; and p
represents zero, one or two.
8. A compound according to any one of claims 1, 2 and 4 to 7
wherein: R.sup.1 represents methyl, ethyl, isopropyl, cyclopropyl
or 1-methylcyclopropyl; R.sup.2 represents:--a bromine, chlorine or
fluorine atom; or a straight- or branched-chain allyl or alkenyl
group containing up to four carbon atoms optionally substituted by
one or more chlorine, bromine or fluorine atoms; a group selected
from --COR.sup.5, --CO.sub.2R.sup.5, --SR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --OR.sup.51 and
--N(R.sup.8)SO.sub.2R.sup.7; or a straight- or branched chain alkyl
group containing up to four carbon atoms which is substituted by
--OR.sup.5; R.sup.5 and R.sup.6, which may be the same or
different, each represents a straight- or branched-chain alkyl
group containing up to three carbon atoms; R.sup.51 represents:--a
straight- or branched-chain alkyl group containing up to four
carbon atoms optionally substituted by one or more chlorine,
bromine or fluorine atoms; a straight- or branched-chain alkenyl or
alkynyl group containing three or four carbon atoms; or a
cyclopropyl group; R.sup.7 represents:--a straight- or
branched-chain allyl group containing up to three carbon atoms
optionally substituted by one or more chlorine, bromine, or
fluorine atoms; or I an allyl group optionally substituted by one
or more chlorine, fluorine or bromine atoms; R.sup.8
represents:--the hydrogen atom; a straight- or branched-chain alkyl
group containing up to three carbon atoms optionally substituted by
one or more chlorine, bromine, or fluorine atoms; or an allyl group
optionally substituted by one or more chlorine, fluorine or bromine
atoms; q represents two; and m represents two or three.
9. A compound according to claim 1 wherein R represents hydrogen or
--CO.sub.2Et; R.sup.1 represents cyclopropyl; R.sup.2 represents a
halogen atom or a group selected from nitro, trifluoromethyl,
methyl, trifluoromethoxy, --S(O).sub.pMe and
--N(R.sup.8)SO.sub.2R.sup.7; R.sup.7 represents a straight- or
branched-chain allyl group containing up to three carbon atoms,
phenyl or benzyl; R.sup.8 represents a straight- or branched-chain
alkyl group containing up to four carbon atoms, methoxy or phenyl;
p is zero, one or two; n represents zero, one or two; and q
represents two.
10. A compound according to any one of the preceding claims wherein
a group --XR3 is in the 2- or 4- position of the benzoyl ring.
11. A compound according to any one of the preceding claims
wherein: R.sup.1 represents cyclopropyl; R.sup.2 represents a
halogen atom; R.sup.7 represents methyl; R.sup.8 represents
hydrogen or methyl; and n represents zero or one.
12. The compound according to claim 1 which is:
4-[2-chloro-4-(methylsulph-
onyl)aminobenzoyl]-5-cyclopropylisoxazole;
4-[4-chloro-2-(N-methyl-N-methy-
lphonyl)aminobenzoyl]-5-cyclopropylisoxazole;
5-cyclopropyl-4-[2-(N-methyl-
-N-methylsulphonyl)amino-benzoyl]isoxazole;
4-[4-chloro-2-(N-ethyl-N-methy-
lsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;
5-cyclopropyl-4-[2-(N-met-
hyl-N-methylsulphonyl)amino-4-nitro-benzoyl]isoxazole;
5-cyclopropyl-4-[4-(N-methyl-N-methylsulphonyl)amino-2-nitro-benzoyl]isox-
azole;
5-cyclopropyl-4-[4-methyl-2-(N-methyl-N-methylsulphonyl)amino-benzo-
yl]isoxazole;
4-[4-chloro-2-(N-n-propyl-N-methylsulphonyl)aminobenzoyl]-5--
cyclopropylisoxazole;
5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonyl)amino--
4-methylsulphonylbenzoyl]isoxazole;
5-cyclopropyl-4-[3,4-dichloro-2-(N-met-
hyl-N-methylsulphonyl)-aminobenzoyl]isoxazole;
5-cyclopropyl4-[2-(N-methyl-
-N-methylsulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole;
5-cyclopropyl4-[2-(N-phenyl-N-methylsulphonyl)amino-benzoyl]isoxazole;
4-[4-bromo-2-(N-methyl-4-methylsulphonyl)amino-benzoyl]-5-cyclopropylisox-
azole;
5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-4-methylsulpho-
nylbenzoyl]isoxazole; ethyl
5-cyclopropyl4-[4-chloro-2-(N-methyl-N-methyls-
ulphonylamino)benzoyl]isoxazole-3-carboxylate;
4-[4-chloro-2-(N-methyl-N-e-
thylsulphonylamino)benzoyl]-5-cyclopropyl-isoxazole;
5-cyclopropyl-4-[2,4bis(N-methyl-N-methylsulphonyl)-aminobenzoyl]isoxazol-
e; 5-cyclopropyl
[2-(N-methyl-N-methylsulphonyl)amino4-fluorobenzoyl]isoxa- zole;
-4-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropy-
lisoxazole;
4-[2-chloro-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyco-
propylisoxazole;
4-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluo-
romethoxybenzoyl]-5-cyclopropylisoxazole;
5-cyclopropyl-4-[2-(N-methyl-N-m-
ethylsulphonyl)amino4-trifluoromethoxybenzoyl]isoxazole;
4-[5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopropylisox-
azole;
5-cyclopropyl-4-[2-fluoro4(N-methyl-N-methylsulphonyl)aminobenzoyl]-
isoxazole;
5-cyclopropyl-4-[3,4-difluoro-2-(N-methyl-N-methylsulphonyl)ami-
nobenzoyl]isoxazole;
5-cyclopropyl-4-[4,5-difluoro-2-(N-methyl-N-methylsul-
phonyl)aminobenzoyl]isoxazole;
5-cyclopropyl4-[4-iodo-2-(N-methyl-N-methyl-
sulphonyl)aminobenzoyl]isoxazole;
4-[4-chloro-2-(N-isobutyl-N-methylsulpho-
nyl)aminobenzoyl]-5-cyclopropylisoxazole;
4-[4-chloro-2-(N-methyl-N-n-prop-
ylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;
4-[4-chloro-2-(N-methyl--
N-phenylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazole;
4-[4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoyl]-5-cyclopropylisox-
azole;
4-[4-chloro-2-(N-methyl-N-isopropylsulphonyl)aminobenzoyl]-5-cyclop-
ropylisoxazole;
4-[4-chloro-2-(N-methoxy-N-methylsulphonyl)aminobenzoyl]-5-
-cyclopropylisoxazole; or ethyl
5-cyclopropyl4-[2-(N-methyl-N-methylsulpho-
nyl)amino-4-trifluoromethylbenzoyl]isoxazole-3-carboxylate.
13. A process for the preparation of a compound of formula (I) as
defined in claim 1 which comprises: (a) where R represents hydrogen
excluding compounds of formula (I) in which a group --XR.sup.3 is
in the ortho position and X is --NH--, reacting a compound of
formula (II): 21wherein L is a leaving group and R.sup.1, R.sup.2,
R.sup.3, a and X are as defined in claim 1 provided that when X is
--NH-- the group --XR.sup.3 is not in the ortho position of the
phenyl ring, with hydroxylamine or a salt of hydroxylamine; (b)
where R represents hydrogen, reacting a compound of formula (m):
22wherein R.sup.1 is as defined in claim 1 and Y represents a
carboxy group or a reactive derivative thereof or a cyano group,
with an appropriate organometallic reagent; (c) where R represents
a group --CO.sub.2R.sup.4 excluding compounds of formula (I) in
which a group --XR.sup.3 is in the ortho position and X is --NH--,
reacting a compound of formula (IV) 23wherein R.sup.1,
R.sup.2.sub.1 R.sup.3, X and n are as defined in claim 1 provided
that when X is --NH-- the group --XR.sup.3 is not in the ortho
position of the phenyl ring, and P is a leaving group, with a
compound of formula R.sup.4O.sub.2CC(Z)=NOH wherein R.sup.4 is as
defined in claim 1 and Z is a halogen atom; (d) where R represents
a group --CO.sub.2R.sup.4 excluding compounds of formula (I) in
which a group --XR.sup.3 is in the ortho position and X is --NH--,
reacting a compound of formula (V): 24wherein R.sup.1, R.sup.2,
R.sup.3, X and n are as defined provided that when X is --NH-- the
group --XR.sup.3 is not in the ortho position of the phenyl ring,
with a compound of formula R.sup.4O.sub.2CC(Z)=NOH wherein R.sup.4
is as defined in claim 1 and Z is a halogen atom; (e) where R
represents a group --CO.sub.2R.sup.4 excluding compounds of formula
(I) in which a group --XR.sup.3 is in the ortho position and X is
--NH--, reacting a salt of a compound of formula (VI): 25wherein
R.sup.1, R.sup.2, R.sup.3, X and n are as defined in claim 1
provided that when X is --NH-- the group --XR.sup.3 is not in the
ortho position of the phenyl ring, with a compound of formula
R.sup.4O.sub.2CC(Z)=NOH wherein R.sup.4 is as defined in claim I
and Z is a halogen atom; (f) where X represents --NH--,
deprotecting a compound of formula (VII): 26wherein R, R.sup.1,
R.sup.2 and n are as defined in claim 1 and A represents
--NX.sup.1R.sup.3 wherein R.sup.3 is as defined in claim 1 and XI
represents a protecting group which can be removed under acidic or
neutral reaction conditions (g) where p is one or two and/or q is
the oxidation of the sulphur atom of the corresponding compound of
formula (I) in which p is 0 or 1 and/or q is zero; optionally
followed by the conversion of the compound of formula (I) thus
obtained into an agriculturally acceptable salt.
14. A herbicidal composition which comprises as active ingredient a
herbicidally effective amount of a 4-benzoylisoxazole derivative of
formula (I) as defined in any one of claims 1 to 11 or an
agriculturally acceptable salt-thereof in association with an
agriculturally acceptable diluent or carrier and/or surface active
agent.
15. A herbicidal composition according to claim 14 in the form of
an aqueous suspension concentrate, a wettable powder, a water
soluble or water dispersible powder, a liquid water soluble
concentrate, a liquid emulsifiable suspension concentrate, a
granule or an emulsifiable concentrate.
16. A method for controlling the growth of weeds at a locus which
comprises applying to the locus a herbicidally effective amount of
a 4-benzoylisoxazole derivative of formula (I) as defined in any
one of claims 1 to 11 or an agriculturally acceptable salt
thereof.
17. A method according to claim 16 in which the locus is an area
used, or to be used, for growing of crops and the compound is
applied at an application rate from 0.01 kg to 4.0 kg per
hectare.
18. A compound of formula: 27in which R, R.sup.1, R.sup.2 and n
are-as defined in claim 1 and A represents --NX.sup.1R.sup.3,
wherein R.sup.3 is as defined in claim 1 and X.sup.1 represents a
protecting group which can be removed under acidic or neutral
reaction conditions.
Description
[0001] This invention relates to novel 4-benzoylisoxazole
derivatives, compositions containing them, processes for their
preparation, intermediates in their preparation and their use as
herbicides.
[0002] Herbicidal 4-benzoylisoxazoles are described in European
Patent Publication Number 0418175.
[0003] The present invention provides 4-benzoylisoxazole
derivatives of formula (I): 2
[0004] wherein:
[0005] R represents the hydrogen atom or a group
--CO.sub.2R.sup.4;
[0006] R.sup.1 represents:--
[0007] a straight- or branched- chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms; or
[0008] a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more R.sup.5 groups or one or more
halogen atoms;
[0009] R.sup.2 represents:--
[0010] a halogen atom;
[0011] a straight- or branched- chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0012] a straight- or branched- chain alkyl group containing up to
six carbon atoms which is substituted by one or more groups
--OR.sup.5;
[0013] a group selected from nitro, cyano, --CO.sub.2R.sup.5,
--S(O).sub.pR.sup.6, --O(CH.sub.2).sub.mOR.sup.5, --COR.sup.5,
--NR.sup.5R.sup.6, --N(R.sup.8)SO.sub.qR.sup.7,
--CONR.sup.9R.sup.10 and --OR.sup.51;
[0014] phenyl optionally substituted by from one to three groups
R.sup.21 which may be the same or different;
[0015] R.sup.3 represents S(O).sub.qR.sup.7;
[0016] X represents a group --N(R.sup.8)--;
[0017] n represents zero or an integer from one to four; where n is
greater than one the groups R.sup.2 may be the same or
different;
[0018] R.sup.4 represents a straight- or branched- chain alkyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0019] R.sup.5, R.sup.51 and R.sup.6, which may be the same or
different, each represents:--
[0020] the hydrogen atom;
[0021] a straight- or branched-chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0022] phenyl optionally substituted by from one to five groups
R.sup.2 which may be the same or different; or
[0023] a cycloalkyl group containing from three to six carbon
atoms;
[0024] R.sup.7 represents:--
[0025] a straight- or branched- chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0026] a cycloalkyl group containing from three to six carbon
atoms;
[0027] phenyl or benzyl optionally substituted by from one to five
groups R.sup.21 which may be the same or different;
[0028] or --NR.sup.9R.sup.10;
[0029] R.sup.8 represents:
[0030] the hydrogen atom;
[0031] a straight- or branched- chain alkyl alkenyl or alkynyl
group containing up to ten carbon atoms optionally substituted
by-one or more halogen atoms;
[0032] a cycloalkyl group containing from three to six carbon
atoms;
[0033] phenyl optionally substituted by from one to five groups
which may be the same or different selected from halogen, nitro,
cyano, R.sup.5, S(O).sub.pR.sup.5 and --OR.sup.5; or
[0034] a group --OR.sup.11;
[0035] R.sup.9 represents:--
[0036] the hydrogen atom;
[0037] a straight- or branched- chain alkyl group containing up to
six carbon atoms optionally substituted by one or more halogen
atoms;
[0038] or phenyl optionally substituted by from one to five groups
R.sup.2 which may be the same or different;
[0039] R.sup.10 represents a group selected from R.sup.5 and
--OR.sup.11;
[0040] or R.sup.9 and R.sup.10, together with the nitrogen to which
they are attached, may form a 5 or 6 membered ring optionally
containing an oxygen or nitrogen atom in the ring (e.g.
pyrrolidine, morpholine, pyrrole, piperidine and piperazine),
wherein the ring is optionally substituted by one or more alkyl
groups containing up to 3 carbon atoms;
[0041] R.sup.11 represents a straight- or branched- chain alkyl
group containing up to six carbon atoms;
[0042] R.sup.21 represents:--
[0043] a halogen atom;
[0044] a straight- or branched- chain alkyl group containing up to
three carbon atoms optionally substituted by one or more halogen
atoms;
[0045] or a group selected from nitro, cyano, --S(O).sub.pR.sup.5
and --OR.sup.5;
[0046] m represents one, two or three; and
[0047] p represents zero, one or two.
[0048] q represents zero or two;
[0049] and agriculturally acceptable salts thereof, which possess
valuable herbicidal properties.
[0050] Furthermore in certain cases the groups R, R.sup.1, R.sup.2,
and R.sup.3 may give rise to geometric and/or optical isomers. All
such forms are embraced by the present invention
[0051] 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.
[0052] The compounds of the invention, in some aspects of their
activity, for example in their control of important weeds found in
cereal crops, e.g. Galium aparine and Avena fatua, and in their
selectivity in important cereal crops, e.g. wheat, show advantages
over known compounds.
[0053] It will be understood that in the above definition R.sup.2
does not include substituents containing two or more phenyl rings
linked through a bridging group.
[0054] In one embodiment the invention provides compounds of
formula I above wherein:
[0055] R represents the hydrogen atom or a group
--CO.sub.2R.sup.4;
[0056] R.sup.1 represents:--
[0057] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms; or
[0058] a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more R.sup.5 groups;
[0059] R.sup.2 represents:--
[0060] a straight- or branched-chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0061] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is substituted by a group --OR.sup.5;
[0062] a halogen atom;
[0063] phenyl optionally substituted by from one to three groups
R.sup.21 which may be the same or different;
[0064] a group selected from --COR.sup.5, nitro, cyano,
--CO.sub.2R.sup.5, --S(O) R.sup.6, --O(CH.sub.2).sub.mOR.sup.5,
--N(R.sup.8)SO.sub.2R.sup.7, --CONR.sup.9R.sup.10 and
--OR.sup.51;
[0065] R.sup.3 represents --S(O).sub.qR.sup.7;
[0066] X represents a group --N(R.sup.8)--;
[0067] n represents zero or an integer from one to four; where n is
greater than one the groups R.sup.2 may be the same or
different;
[0068] R.sup.4 represents a straight- or branched- chain alkyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0069] R.sup.5 represents:--
[0070] a straight- or branched- chain alkyl alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms; or
[0071] a cycloalkyl group containing from three to six carbon
atoms;
[0072] R.sup.51 represents:--
[0073] a straight- or branched- chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0074] a cycloalkyl group containing from three to six carbon
atoms;
[0075] or phenyl optionally substituted by from one to five groups
which may be the same or different selected from a halogen atom, a
straight- or branched- chain alkyl group containing up to three
carbon atoms optionally substituted by one or more halogen atoms;
nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5;
[0076] R.sup.6 represents:--
[0077] a straight- or branched- chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0078] a cycloalkyl group containing from three to six carbon
atoms;
[0079] or phenyl optionally substituted by from one to five groups
which may be the same or different selected from a halogen atom, a
straight- or branched-chain alkyl group containing up to three
carbon atoms optionally substituted by one or more halogen atoms;
nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5;
[0080] R.sup.7 represents:--
[0081] a straight- or branched-chain alkyl alkenyl or alkynyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms;
[0082] a cycloalkyl group containing from three to six carbon
atoms;
[0083] phenyl optionally substituted by from one to five groups
R.sup.21 which may be the same or different;
[0084] or --NR.sup.9R.sup.10;
[0085] R.sup.8 represents:
[0086] the hydrogen atom; or
[0087] a straight- or branched-chain alkyl alkenyl or alkynyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms;
[0088] a cycloalkyl group containing from three to six carbon
atoms;
[0089] phenyl optionally substituted by from one to five groups
which may be the same or different selected from a halogen atom, a
straight- or branched-chain alkyl group containing up to three
carbon atoms optionally substituted by one or more halogen atoms;
nitro, cyano, --S(O).sub.pR.sup.5 and --OR.sup.5;
[0090] or a group --OR.sup.11;
[0091] R.sup.9 represents hydrogen or a straight- or branched-chain
alkyl group containing up to six carbon atoms optionally
substituted by one or more halogen atoms;
[0092] R.sup.10 represents a group selected from R.sup.5 and
--OR.sup.11;
[0093] or R.sup.9 and R.sup.10, together with the nitrogen to which
they are attached, may form a S or 6 membered ring optionally
containing an oxygen or nitrogen atom in the ring (e.g.
pyrrolidine, morpholine, pyrrole, piperidine and piperazine),
wherein the ring is optionally substituted by one or more alkyl
groups containing up to 3 carbon atoms;
[0094] R.sup.11 represents a straight- or branched-chain alkyl
group containing up to six carbon atoms;
[0095] R.sup.21 represents:--
[0096] a halogen atom;
[0097] a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more halogen
atoms; or
[0098] a group selected from nitro, cyano, --S(O).sub.pR5 and
--OR.sup.5;
[0099] m represents one, two or three; p represents zero, one or
two;
[0100] and q represents two.
[0101] In a further embodiment the invention provides compounds of
formula I above wherein:
[0102] R represents the hydrogen atom or a group
--CO.sub.2R.sup.4;
[0103] R.sup.1 represents:--
[0104] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms; or
[0105] a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more R.sup.5 groups or one or more
halogen atoms;
[0106] R.sup.2 represents:--
[0107] a halogen atom;
[0108] a straight- or branched-chain alkyl group containing up to
six carbon atoms optionally substituted by one or more halogen
atoms;
[0109] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is substituted by one or more groups
--OR.sup.5;
[0110] a group selected from nitro, cyano, --CO.sub.2R.sup.5,
--S(O).sub.pR.sup.6, --O(CH.sub.2).sub.mOR.sup.5, --COR.sup.5,
--NR.sup.5R.sup.6, --N(R.sup.8)SO.sub.qR.sup.7 and --OR.sup.51;
[0111] R.sup.3 represents --S(O).sub.qR.sup.7;
[0112] X represents a group --N(R.sup.8)--;
[0113] n represents zero or an integer from one to four; where n is
greater than one the groups R.sup.2 may be the same or
different;
[0114] R.sup.4 represents a straight- or branched-chain alkyl group
containing up to six carbon atoms which is optionally substituted
by one or more halogen atoms;
[0115] R.sup.5, R.sup.51 and R.sup.6, which may be the same or
different, each represents:
[0116] the hydrogen atom;
[0117] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms;
[0118] phenyl optionally substituted by from one to five groups
R.sup.2 which may be the same or different;
[0119] R.sup.7 represents:
[0120] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms;
[0121] phenyl optionally substituted by from one to five groups
R.sup.21 which may be the same or different; or
[0122] a group --NR.sup.9R.sup.10;
[0123] R.sup.8 represents:
[0124] the hydrogen atom;
[0125] a straight- or branched-chain alkyl, alkenyl or alkynyl
group containing up to ten carbon atoms which is optionally
substituted by one or more halogen atoms; or
[0126] phenyl optionally substituted from one to five groups which
may be the same or different selected from nitro, halogen, R.sup.5
and --OR.sup.5;
[0127] R.sup.9 and R.sup.10, which may be the same or different,
each represents:--
[0128] the hydrogen atom;
[0129] a straight- or branched-chain alkyl group containing up to
six carbon atoms optionally substituted by one or more halogen
atoms;
[0130] or phenyl optionally substituted by from one to five groups
R.sup.2 which may be the same or different;
[0131] R.sup.21 represents:--
[0132] a halogen atom;
[0133] a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more halogen
atoms;
[0134] or a group selected from nitro, cyano, --S(O).sub.pR.sup.6
and --OR.sup.5;
[0135] p represents zero, 1 or 2;
[0136] q represents zero or 2; and
[0137] m represents 1, 2 or 3.
[0138] Preferably the 5- and 6-positions of the benzoyl ring are
unsubstituted.
[0139] Preferably the 2-position of the benzoyl ring is
substituted.
[0140] A preferred class of compounds of formula (I) are those
wherein:
[0141] R.sup.1 represents:--
[0142] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is optionally substituted by one or more
halogen atoms; or
[0143] a cycloalkyl group containing from three to six carbon atoms
optionally substituted by one or more methyl groups;
[0144] R.sup.2 represents:--
[0145] a halogen atom;
[0146] a straight- or branched-chain alkyl, alkenyl or alkynyl
group containing up to six carbon atoms optionally substituted by
one or more halogen atoms;
[0147] a straight- or branched-chain alkyl group containing up to
six carbon atoms which is substituted by a group --OR.sup.5;
[0148] phenyl optionally substituted by from one to three groups
R.sup.21 which may be the same or different;
[0149] or a group selected from --COR.sup.5, cyano, nitro,
--CO.sub.2R.sup.5, --S(O).sub.pR.sup.6,
--O(CH.sub.2).sub.mOR.sup.5, --N(R.sup.8)SO.sub.2R.sup.7 and
--OR.sup.51;
[0150] n represents zero or an integer from one to three; where a
is greater than one the groups R.sup.2 may be the same or
different;
[0151] R.sup.5 represents:--
[0152] a straight- or branched-chain alkyl group containing up to
six carbon atoms optionally substituted by one or more halogen
atoms;
[0153] or a cycloalkyl group containing from three to six carbon
atoms;
[0154] R.sup.51 and R.sup.6, which may be the same or different,
each represents:--
[0155] a straight- or branched-chain alkyl or alkenyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms;
[0156] a straight- or branched-chain alkynyl group containing from
three to six carbon atoms;
[0157] a cycloalkyl group containing three to six carbon atoms;
[0158] R.sup.7 represents:--
[0159] a straight- or branched-chain alkyl or alkenyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms;
[0160] a straight- or branched-chain alkynyl group containing from
three to six carbon atoms;
[0161] a cycloalkyl group containing three to six carbon atoms;
or
[0162] phenyl optionally substituted by from one to three groups
R.sup.21 which may be the same or different;
[0163] R.sup.8 represents:--
[0164] the hydrogen atom; or
[0165] a straight- or branched-chain alkyl or alkenyl group
containing up to six carbon atoms optionally substituted by one or
more halogen atoms;
[0166] a straight- or branched-chain alkynyl group containing from
three to six carbon atoms;
[0167] or a cycloalkyl group containing three to six carbon
atoms;
[0168] R.sup.21 represents:--
[0169] a halogen atom;
[0170] a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more halogen
atoms; or
[0171] a group selected from nitro, cyano, --S(O).sub.pR.sup.5 and
--OR.sup.5;
[0172] q represents two;
[0173] m represents two or three; and
[0174] p represents zero, one or two.
[0175] A further preferred class of compounds of formula (I) are
those wherein:--
[0176] R.sup.1 represents:--
[0177] a straight- or branched-chain alkyl group containing up to
three carbon atoms; or
[0178] a cycloalkyl group containing three or four carbon atoms
optionally substituted by a methyl group;
[0179] R.sup.2 represents:--
[0180] a chlorine, bromine or fluorine atom; or
[0181] a straight- or branched-chain alkyl alkenyl or alkynyl group
containing up to four carbon atoms optionally substituted by one or
more halogen atoms;
[0182] a straight- or branched-chain alkyl group containing up to
four carbon atoms which is substituted by a group --OR.sup.5,
or
[0183] a group selected from --COR.sup.5, --CO.sub.2R.sup.5,
--S(O).sub.pR.sup.6, --O(CH.sub.2).sub.mOR.sup.5,
--N(R.sup.8)SO.sub.2R.s- up.7 and --OR.sup.51;
[0184] R.sup.5 and R.sup.6, which may be the same or different,
each represents:--
[0185] a straight- or branched-chain alkyl group containing up to
four carbon atoms optionally substituted by one or more chlorine,
bromine or fluorine atoms; or
[0186] a cyclopropyl group;
[0187] R.sup.51 and R.sup.7, which may be the same or different,
each represents:--
[0188] a straight- or branched-chain alkyl or alkenyl group
containing up to four carbon atoms optionally substituted by one or
more chlorine, bromine or fluorine atoms;
[0189] a straight- or branched-chain alkynyl group containing three
or four carbon atoms; or
[0190] a cyclopropyl group;
[0191] R.sup.8 represents:--
[0192] the hydrogen atom;
[0193] a straight- or branched-chain alkyl or alkenyl group
containing up to four carbon atoms optionally substituted by one or
more chlorine, bromine or fluorine atoms;
[0194] a straight- or branched-chain alkynyl group containing three
or four carbon atoms; or
[0195] a cyclopropyl group;
[0196] q represents two;
[0197] m represents two or three; and
[0198] p represents zero, one or two.
[0199] A further preferred class of compound are those
wherein:--
[0200] R.sup.1 represents:--
[0201] a methyl, ethyl, isopropyl, cyclopropyl or
1-methylcyclopropyl group;
[0202] R.sup.2 represents:--
[0203] a bromine, chlorine or fluorine atom; or
[0204] a straight- or branched-chain alkyl or alkenyl group
containing up to four carbon atoms optionally substituted by one or
more chlorine, bromine or fluorine atoms;
[0205] a group selected from --COR.sup.5, --CO.sub.2R.sup.5,
--SR.sup.6, --O(CH.sub.2).sub.mOR.sup.5, --OR.sup.51 and
--N(R.sup.8)SO.sub.2R.sup.7; or
[0206] a straight- or branched chain alkyl group containing up to
four carbon atoms which is substituted by --OR.sup.5;
[0207] R.sup.5 and R.sup.6, which may be the same or different,
each represents a straight- or branched-chain alkyl group
containing up to three carbon atoms;
[0208] R.sup.51 represents:--
[0209] a straight- or branched-chain alkyl group containing up to
four carbon atoms optionally substituted by one or more chlorine,
bromine or fluorine atoms;
[0210] a straight- or branched-chain alkenyl or alkynyl group
containing three or four carbon atoms; or
[0211] a cyclopropyl group;
[0212] R.sup.7 represents:--
[0213] a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more chlorine,
bromine, or fluorine atoms; or
[0214] an allyl group optionally substituted by one or more
chlorine, fluorine or bromine atoms;
[0215] R.sup.8 represents:--
[0216] the hydrogen atom;
[0217] a straight- or branched-chain alkyl group containing up to
three carbon atoms optionally substituted by one or more chlorine,
bromine, or fluorine atoms; or
[0218] an allyl group optionally substituted by one or more
chlorine, fluorine or bromine atoms;
[0219] q represents two; and
[0220] m represents two or three.
[0221] A further preferred class of compounds of formula (I) are
those wherein:
[0222] R.sup.1 represents cyclopropyl;
[0223] R.sup.2 represents:
[0224] a halogen atom;
[0225] R.sup.7 represents methyl;
[0226] R.sup.8 represents hydrogen or methyl; and
[0227] n represents zero or one.
[0228] A further preferred class of compounds of formula (I) are
those wherein a group --XR.sup.3 is in the 2- or 4-position of the
benzoyl ring.
[0229] A further preferred class of compounds of formula (I) are
those wherein:
[0230] R represents hydrogen or --CO.sub.2Et;
[0231] R.sup.1 represents cyclopropyl;
[0232] R.sup.2 represents a halogen atom or a group selected from
nitro, trifluoromethyl, methyl, trifluoromethoxy, --S(O).sub.pMe
and --N(R.sup.8)SO.sub.2R.sup.7;
[0233] R.sup.7 represents a straight- or branched-chain alkyl group
containing up to three carbon atoms, phenyl or benzyl;
[0234] R.sup.8 represents a straight- or branched-chain alkyl group
containing up to four carbon atoms, methoxy or phenyl;
[0235] p is zero, one or preferably two;
[0236] n represents zero, one or two; and
[0237] q represents two.
[0238] Particularly important compounds of formula (I) include the
following:
[0239] 1.
4-[2-chloro4-(methylsulphonyl)aminobenzoyl]-5-cyclopropylisoxazo-
le;
[0240] 2.
4-[4-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclop-
ropylisoxazole;
[0241] 3.
5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-benzoyl]isox-
azole;
[0242] 4.
4-[4-chloro-2-(N-ethyl-N-methylsulphonyl)aminobenzoyl]-5-cyclopr-
opylisoxazole;
[0243] 5.
5-cyclopropyl4-[2-(N-methyl-N-methylsulphonyl)amino-4-nitro-benz-
oylisoxazole;
[0244] 6. 5-cyclopropyl 4-[4-(N-methyl-N-methylsulphonyl)amino-2
nitro-benzoyl]isoxazole;
[0245] 7.
5-cyclopropyl4-[4-methyl-2-(N-methyl-N-methylsulphonyl)amino-ben-
zoyl]isoxazole;
[0246] 8.
4-[4-chloro-2-(N-n-propyl-N-methylsulphonyl)amninobenzoyl]-5-cyc-
lopropylisoxazole;
[0247] 9. 5-cyclopropyl-4-[2-(N-ethyl-N-methylsulphonyl)amino4
methylsulphonylbenzoyl]isoxazole;
[0248] 10.
5-cyclopropyl-4-[3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-am-
inobenzoyl]isoxazole;
[0249] 11.
5-cyclopropyl4q[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoro-
methylbenzoyl]isoxazole;
[0250] 12. 5S-cyclopropyl4
2-(N-phenyl-N-methylsulphonyl)amino-benzoyl]iso- xazole;
[0251] 13.
[4-(4-bromo-2-(N-methyl-N-methylsulphonyl)amino-benzoyl]-5-cycl-
opropylisoxazole;
[0252] 14.
5-cyclopropyl4-([2-(N-methyl-N-methylsulphonyl)amino-4-methylsu-
lphonylbenzoyl]isoxazole;
[0253] 15. ethyl
5-cyclopropyl-4-[4-chloro-2-(N-methyl-N-methylsulphonylam-
ino)benzoyl]isoxazole-3-carboxylate;
[0254] 16.
4-[4chloro-2-(N-methyl-N-ethylsulphonylamino)benzoyl]-5-cyclopr-
opyl-isoxazole;
[0255] 17.
5-cyclopropyl-4-[2,4-bis(N-methyl-N-methylsulphonyl)-aminobenzo-
yl]isoxazole;
[0256] 18.
5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino4-fluoroben-
zoyl]isoxazole;
[0257] 19.
4-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclop-
ropylisoxazole;
[0258] 20.
4-[2-chloro4-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclop-
ropylisoxazole;
[0259] 21.
4-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluorometh-
oxybenzoyl]-5-cyclopropylisoxazole;
[0260] 22. 5-cyclopropyl([2-(N-methyl-N-methylsulphonyl)amino4
trifluoromethoxybenzoyl]isoxazole;
[0261] 23.
4-[5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoyl]-5-cyclo-
propylisoxazole;
[0262] 24.
5-cyclopropyl4-[2-fluoro-4-(N-methyl-N-methylsulphonyl)aminoben-
zoyl]isoxazole;
[0263] 25.
5-cyclopropyl4-[3,4-difluoro-2-(N-methyl-N-methylsulphonyl)amin-
obenzoyl]isoxazole;
[0264] 26.
5-cyclopropyl4-[4,5-difluoro-2-(N-methyl-N-methylsulphonyl)amin-
obenzoyl]isoxazole;
[0265] 27. 5-cyclopropyl4
[4-iodo-2-(N-methyl-N-methylsulphonyl)aminobenzo- yl]isoxazole;
[0266] 28.
4-[4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminobenzoyl]-5-cyc-
lopropylisoxazole;
[0267] 29.
4-[4-chloro-2-(N-methyl-N-n-propylsulphonyl)aminobenzoyl]-5-cyc-
lopropylisoxazole;
[0268] 30.
4-([4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoyl]-5-cycl-
opropylisoxazole;
[0269] 31.
4-[4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoyl]-5-cyclo-
propylisoxazole;
[0270] 32.
4-[4-chloro-2-(N-methyl-N-isopropylsulphonyl)aminobenzoyl]-5-cy-
clopropylisoxazole;
[0271] 33.
4-[4-chloro-2-(N-methoxy-N-methylsulphonyl)aminobenzoyl]-5-cycl-
opropylisoxazole;
[0272] 34. ethyl
5-cyclopropyl-4-[2-(N-methyl-N-methylsulphonyl)amino-4-tr-
ifluoromethylbenzoyl]isoxazole-3-carboxylate.
[0273] The numbers 1 to 34 are assigned to these compounds for
reference and identification hereinafter.
[0274] Compounds of formula (I) may be prepared by the application
or adaptation of known methods (i.e. methods heretofore used or
described in the literature), for example as hereinafter
described.
[0275] In the following description where symbols appearing in
formulae are not specifically defined, it is to be understood that
they are "as hereinbefore defined" in accordance with the first
definition of each symbol in the specification.
[0276] 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.
[0277] According to a feature of the present invention compounds of
formula (I) in which R represents hydrogen excluding those wherein
a group --XR.sup.3 is in the ortho position and X is --NH-- may be
prepared by the reaction of a compound of formula (II): 3
[0278] wherein L is a leaving group and R.sup.1, R.sup.2, R.sup.3,
n and X are as hereinbefore defined provided that when X is --NH--
the group --XR.sup.3 is not in the ortho position of the phenyl
ring, with hydroxylamine or a salt of hydroxylamine. Hydroxylamine
hydrochloride is generally preferred. Generally L is alkoxy, for
example ethoxy, or N,N-dialkylamino, for example dimethylamino. The
reaction is generally carried out in an organic solvent such as
ethanol or acetonitrile or a mixture of a water-miscible organic
solvent and water, preferably in a ratio of organic solvent: water
of from 1:99 to 99:1, optionally in the presence of a base or acid
acceptor such as triethylamine or sodium acetate at a temperature
from room temperature to the boiling point of the solvent.
[0279] According to a further feature of the present invention
compounds of formula (I) in which R represents hydrogen may be
prepared by the reaction of a compound of formula (III): 4
[0280] wherein R.sup.1 is as hereinbefore defined and Y represents
a carboxy group or a reactive derivative thereof (such as a
carboxylic acid chloride or carboxylic ester), or a cyano group,
with an appropriate organometallic reagent such as a Grignard
reagent or an organolithium reagent. The reaction is generally
carried out in an inert solvent such as ether or tetrahydrofuran at
a temperature from 0.degree. C. to the reflux temperature of the
mixture.
[0281] According to a further feature of the present invention
compounds of formula (I) wherein R represents a group
--CO.sub.2R.sup.4 excluding those wherein a group --XR.sup.3 is in
the ortho position-and X is --NH-- may be prepared by the reaction
of a compound of formula (IV) 5
[0282] wherein R.sup.1, R.sup.2, R.sup.3, X and n are as
hereinbefore defined provided that when X is --NH-- the group
--XR.sup.3 is not in the ortho position of the phenyl ring, and P
is a leaving group such as N,N-diallylamino, with a compound of
formula R.sup.4O.sub.2CC(Z)=NOH wherein R.sup.4 is as hereinbefore
defined and Z is a halogen atom. Generally Z is chlorine or
bromine. The reaction is generally performed in an inert solvent
such as toluene or dichloromethane either in the presence of a base
such as triethylamnine or a catalyst such as a 4 Angstrom molecular
sieve or fluoride ion.
[0283] According to a further feature of the present invention
compounds of formula I in which R represents a group
--CO.sub.2R.sup.4 excluding those wherein a group --XR.sup.3 is in
the ortho position and X is --NH-- may be prepared by the reaction
of a compound of formula (V): 6
[0284] wherein R.sup.1, R.sup.2, R.sup.3, X and n are as
hereinbefore defined provided that when X is --NH-- the group
--XR.sup.3 is not in the ortho position of the phenyl ring, with a
compound of formula R.sup.4O.sub.2CC(Z)=NOH wherein Z and R.sup.4
are as hereinbefore defined. The reaction is generally performed in
an inert solvent such as toluene or dichloromethane optionally in
the presence of a base such as triethylamine or a catalyst such as
a 4 Angstrom molecular sieve or fluoride ion. The reaction can be
carried out at a temperature between room temperature and the
reflux temperature of the mixture.
[0285] According to a further feature of the present invention
compounds of formula (I) wherein R represents --CO.sub.2R.sup.4
excluding those wherein a group --XR.sup.3 is in the ortho position
of the phenyl ring and X is --NH-- may be prepared by the reaction
of a salt of compounds of formula (VI): 7
[0286] wherein R.sup.1, R.sup.2, R.sup.3, X and n are as
hereinbefore defined provided that when X is --NH-- the group
--XR.sup.3 is not in the ortho position of the phenyl ring, with a
compound of formula R.sup.4O.sub.2CC(Z)=NOH wherein R.sup.4 and Z
are as hereinbefore defined. Preferred salts include sodium or
magnesium salts. The reaction may be performed in an inert solvent
such as dichloromethane or acetonitrile at a temperature between
room temperature and the reflux temperature of the mixture. The
salt of a compound of formula (VI) is generally prepared in situ by
treating the compound of formula (VI) with a base. Examples of
suitable bases include alkaline earth metal alkoxides such as
magnesium methoxide.
[0287] According to a further feature of the present invention
compounds of formula (I) in which X represents --NH-- may be
prepared by the deprotection of a compound of formula (VII): 8
[0288] wherein R, R.sup.1, R.sup.2 and n are as hereinbefore
defined and A represents --NX.sup.1R.sup.3 wherein R.sup.3 is as
hereinbefore defined and X.sup.1 represents a protecting group
which can be removed under acidic or neutral reaction conditions.
The protecting group may be for example a benzyl group (which may
be removed by hydrogenolysis) or a t-butyloxycarbonyl group
(t-BOC). Suitable methods of protection and deprotection are
described in the literature (for example in "Protective Groups in
Organic Synthesis", by T. W. Greene and P. G. M. Wuts). The
intermediates of formula (VII) are novel and as such constitute a
further feature of the present invention.
[0289] Intermediates in the preparation of compounds of formula (I)
may be prepared by the application or adaptation of known
methods.
[0290] Compounds of formula (II) may be prepared by the reaction of
compounds of formula (VI) with either a trialkyl orthoformate such
as triethyl orthoformate or a dimethylformamide diallyl acetal such
as dimethylformamide dimethyl acetal.
[0291] The reaction with a trialkyl orthoformate can be carried out
in the presence of acetic anhydride at the reflux temperature of
the mixture and the reaction with dialkylformamide dialkyl acetal
is carried out optionally in the presence of an inert solvent at a
temperature from room temperature to the reflux temperature of the
mixture.
[0292] Compounds of formula (IV) may be prepared by the reaction of
a compound of formula (VIII) with a benzoyl chloride of formula
(IX): 9
[0293] The reaction is generally carried out in the presence of an
organic base such as triethylamine in an inert solvent such as
toluene or dichloromethane at a temperature between -20.degree. C.
and room temperature.
[0294] Compounds of formula (V) may be prepared by the metallation
of the appropriate acetylene of formula (X):
R.sup.1.ident.CH (X)
[0295] followed by reaction of the metal salt thus obtained with a
benzoyl chloride of formula (IX). The metallation is generally
performed using n-butyl lithium in an inert solvent such as ether
or tetrahydrofuran at a temperature from -78.degree. C. to
0.degree. C. The subsequent reaction with the benzoyl chloride is
carried out in the 15 same solvent at a temperature between
-78.degree. C. and room temperature.
[0296] Compounds of formula (VI) may be prepared by the reaction of
an acid chloride of formula (IX) with the metal salt of a compound
of formula (XI): 10
[0297] wherein R.sup.1 is as hereinbefore defined, to give a
compound of formula (XII): 11
[0298] wherein R.sup.1, R.sup.2 R.sup.3, X and n are as
hereinbefore defined, which is subsequently decarboxylated to give
a compound of formula (VI). Generally the reaction to produce the
compound of formula (XII) is performed in a solvent such as a lower
alcohol, preferably methanol, in the presence of a metal,
preferably magnesium. The reaction may also be performed using a
pre-prepared metal salt of a compound of formula (XI). The
decarboxylation is Generally performed by refluxing the compound of
formula (XII) in the presence of a catalyst, such as
paratoluenesulphonic acid or trifluoroacetic acid, in an inert
solvent e.g. toluene or 1,2-dichloroethane.
[0299] Compounds of formula (VII) may be prepared by the processes
hereinbefore described for preparing compounds of formula (I) in
which R, R.sup.1, R.sup.2 and n are as hereinbefore defined and the
group --XR.sup.3 is replaced by the group A.
[0300] Acid chlorides of formula (IX) may be prepared by the
reaction of a benzoic acid of formula (XIII): 12
[0301] with a chlorinating agent, for example thionyl chloride at
the reflux temperature of the mixture. In some cases the benzoyl
chlorides may also be prepared by reaction of the benzoic acid with
oxalyl chloride in a solvent such as 1,2-dichloroethane at from
ambient to reflux temperature.
[0302] A number of the benzoic acids of formula (XII) are novel and
as such constitute a further feature of the present invention.
Compounds of formula (XIII) in which R.sup.2 represents a chlorine,
bromine or iodine atom or a group selected from nitro,
trifluoromethyl, methyl, trifluoromethoxy, --SMe, --SOMe,
SO.sub.2Me and --N(R.sup.8)SO.sub.2R.sup- .7; R.sup.7 represents a
straight- or branched-chain alkyl group containing up to three
carbon atoms, phenyl or benzyl; R.sup.8 represents a straight- or
branched-chain alkyl group containing up to four carbon atoms,
methoxy or phenyl; and q represents two, are especially
preferred.
[0303] Compounds of formula (XIII) in which R.sup.3 represents
--SO.sub.2R.sup.7 may be prepared by the hydrolysis of the
corresponding ester of formula (XIV): 13
[0304] wherein R.sup.1a is an alkyl group and X is --NR.sup.8--.
The reaction is generally carried out in the presence of a base
(e.g. sodium S hydroxide or lithium hydroxide) in a solvent such as
an aqueous alcohol (e.g. ethanol) at a temperature from room
temperature to reflux.
[0305] Esters of formula (XIV) in which R.sup.8 is not hydrogen may
be prepared by the reaction of the corresponding compound of
formula (XIV) in which R.sup.8 is hydrogen with a compound of
formula R.sup.8-L.sup.1, wherein R.sup.8 is as hereinbefore defined
excluding hydrogen and L.sup.1 is a leaving group in the presence
of a base. The reaction is particularly useful for producing esters
of formula (XIV) in which R.sup.8 is alkyl. Generally L.sup.1 is
halogen (preferably iodine) or --OH and the base is potassium
carbonate. The reaction is performed at a temperature from room
temperature to reflux in an inert solvent, preferably acetone.
[0306] Esters of formula (XIV) in which R.sup.8 is the same as
R.sup.1amay also be prepared from compounds of formula (XIII) in
which R.sup.3 is --SO.sub.2R.sup.7 and R.sup.8 is hydrogen by
reaction with a compound of formula R.sup.1a-L.sup.1, as described
in the above reaction. Where L is OH optionally a mixture of
thionyl chloride with R.sup.1aOH may be used.
[0307] Esters of formula (XIV) in which R.sup.8 is the hydrogen
atom may also be prepared by the reaction of a compound of formula
(XI) in which R.sup.8 is hydrogen with a compound of formula
R.sup.1a-OH. The reaction is performed in the presence of a strong
acid (preferably concentrated sulphuric acid) optionally using the
alcohol of formula R.sup.1a-OH as solvent, at a temperature from
ambient to reflux.
[0308] Compounds of formula (XIII) in which R.sup.3 represents
--SO.sub.2R.sup.7 and X is --NH-- may also be prepared by the
hydrolysis of a compound of formula (XV): 14
[0309] wherein Z.sup.1 is hydrogen or --SO.sub.2R.sup.7, R.sup.1b
is alkyl or hydrogen and at least one of R.sup.1b and Z.sup.1 is
not hydrogen, using a base. Preferably sodium hydroxide or lithium
hydroxide is used and the reaction is conveniently performed in a
solvent such as aqueous ethanol at a temperature from room
temperature to reflux.
[0310] Compounds of formula (XV) in which Z.sup.1 is hydrogen and
R.sup.1b is alkyl may be prepared by the hydrolysis of the
corresponding compound of formula (XV) in which Z.sup.1 is
--SO.sub.2R.sup.7 by the same procedure described above for the
preparation of a compound of formula (XIII) from a compound of
formula (XV) wherein the reaction is performed for a shorter period
(to prevent hydrolysis of the ester group --CO.sub.2R.sup.1b).
[0311] Compounds of formula (XV) in which Z.sup.1 is hydrogen may
be prepared by the sulphonation of an aniline of formula (XVI):
15
[0312] using a compound of formula R.sup.7SO.sub.2Cl in the
presence of a base. Preferably the base used is triethylamine and
the reaction is performed in an inert solvent (e.g. dichloromethane
or acetonitrile) at a temperature from 0.degree. C. to reflux.
Compounds of formula (XV) in which Z.sup.1 is --SO.sub.2R.sup.7 may
also be prepared by this method, using an excess of compound of
formula R.sup.7SO.sub.2Cl.
[0313] Compounds of formula (XIII) in which the group --XR.sup.3 is
ortho to the acid group and R.sup.3 is --SO.sub.2R.sup.7 may be
prepared by the reaction of a compound of formula (XVII): 16
[0314] wherein X.sup.2 is chlorine or preferably bromine or iodine,
with a compound of formula R.sup.8NHSO.sub.2R.sup.7 in the presence
of a strong base. Generally the reaction is performed in the
presence of a catalyst e.g. copper (I) chloride or preferably
copper (I) bromide or iodide, in an inert solvent such as dioxan or
toluene. The preferred strong base is sodium hydride and the
reaction is conveniently performed at a temperature from 50.degree.
C. to reflux.
[0315] Compounds of formula (XIII) in which the group XR.sub.3 is
ortho to the acid group, R.sup.3 is --SO.sub.2R.sup.7 and n is zero
may be prepared by the reaction of a salt of formula (XVIII):
17
[0316] with a compound of formula R.sup.8NHSO.sub.2R.sup.7 in the
presence of a strong base (e.g. sodium hydride) and a catalyst
(e.g. copper acetate). The reaction is typically performed in an
inert solvent, preferably dimethoxyethane according to the methods
described by R. A, Scherrer and H. R. Beatty (J. Org. Chem., Vol.
45, p2127, 1980).
[0317] Intermediates of formula (III), (V), (VIII), (X), (XI),
(XIV), (XV), (XVI), (XVII) and (XVIII) are known or may be prepared
by the application or adaptation of known methods.
[0318] Those skilled in the art will appreciate that some compounds
of formula (I) may be prepared by the interconversion of other
compounds of formula (I) and such interconversions constitute yet
more features of the present invention. Examples of such
interconversions are hereafter described.
[0319] According to a further feature of the present invention
compounds in which p is one or two and/or q is two may be prepared
by the oxidation of the sulphur atom of the corresponding compounds
in which p is 0 or I and/or q is zero. The oxidation of the sulphur
atom is generally carried out using for example
3-chloroperoxybenzoic acid in an inert solvent such as
dichloromethane at a temperature from 40.degree. C. to room
temperature.
[0320] The following examples illustrate the preparation of 10
compounds of formula (I) and the following reference examples
illustrate the preparation of intermediates of the invention. In
the present specification b.p. means boiling point; m.p. means
melting point; cPr represents cyclopropyl.
EXAMPLE 1
[0321] Hydroxylamine hydrochloride (053 g) was added to a stirred
solution of
1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropyl-2-ethoxymeth-
ylenepropane-1,3-dione (2.8 g) in ethanol. Sodium acetate (0.63 g)
was then added portionwise over a period of ten minutes. The
mixture was then stirred at room temperature for 0.5 hours. Further
quantities of hydroxylamine hydrochloride (0.2 g) and sodium
acetate (0.24 g) were added and stirring was continued for 0.5
hours. Water was added, the mixture was extracted with
dichloromethane and the combined organic extracts were washed with
water, dried and the solvent evaporated. The crude product was
purified by column chromatography to yield
4-[2-chloro-4-(methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole
(compound 1) as a white solid, 1.66 g, map.
122.8.degree.-124.5.degree. C.
[0322] By proceeding in a similar manner, the following compounds
of formula I were prepared:--
1 Cpd. Name m.p./NMR 2
4-[4-chloro-2-(N-methyl-N-methylsulphonyl)amino- 128.3-
benzoyl]-5-cyclopropylisoxazole 130.8.degree. C. 3
5-cyclopropyl-4-[2-(N-methyl-N-methyl- 110.8-
sulphonyl)aminobenzoyl]isoxazole 113.8.degree. C. 11
5-cyclopropyl-4-[2-(N-methyl-N-methyl- (a)
sulphonyl)amino-4-trifluoromethylbenzoyl]isoxazole 21
4-[3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4- (b)
trifluoromethoxy]benzoyl-5-cyclopropylisoxazole 22
5-cyclopropyl-4-[2-(N-methyl-N-methyl- (c)
sulphonyl)amino-4-trifluoromethoxy]benzoylisoxazole 23
4-[5-chloro-2-(N-methyl-N-methylsulphonyl)amino]- 111-
benzoyl-5-cyclopropylisoxazole 113.degree. C. (a) NMR (CDCl.sub.3):
1.2-1.5(m, 4H), 2.65(m, 1H), 2.95(s, 3H), 3.3(s, 3H), 7.6(dd, 1H),
7.75(m, 2H), 8.2(s, 1H). (b) NMR (CDCl.sub.3): 1.15(m, 2H), 1.25(m,
2H), 2.6(m, 1H), 2.9(s, 3H), 3.3(s, 3H), 7.35(m, 2H), 8.15(s, 1H).
(c) NMR (CDCl.sub.3): 1.15(m, 2H), 1.25(m, 2H), 2.6(m, 1H), 2.9(s,
3H), 3.2(s, 3H), 7.2(m, 2H), 7.5(d, 1H), 8.1(s, 1H).
EXAMPLE 2
[0323] Hydroxylamine hydrochloride (0.76 g) was added to a mixture
of
1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dim-
ethylaminomethylenepropan-1,3-dione (3.83 g) in ethanol. The
mixture was stirred for 1 hour and evaporated to dryness. The
residue was dissolved in dichloromethane and washed with water,
dried (magnesium sulphate) and filtered. The filtrate was
evaporated to dryness and the residue was purified by
chromatography eluted with a mixture of cyclohexane,
dichloromethane and ethyl acetate. The product was triturated with
a mixture of ether and hexane and filtered to give
4-[4-chloro-2-(N-ethyl-N-
-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (compound 4,
0.81 g) as a white solid, m.p. 114.degree.-115.8.degree. C.
[0324] By proceeding in a similar manner the following compounds of
formula (I) were prepared from the appropriately substituted
starting materials.
2 m.p.(.degree. C.) Cpd R R.sup.1 X-R.sup.3 (R.sup.2).sub.n NMR 5 H
cPr 2-N(Me)SO.sub.2Me 4-NO.sub.2 113-115 6 H cPr 4-N(Me)SO.sub.2Me
2-NO.sub.2 116-117 7 H cPr 2-N(Me)SO.sub.2Me 4-Me 120-122 8 H cPr
2-N(nPr)SO.sub.2Me 4-Cl 127-128 9 H cPr 2-N(Et)SO.sub.2Me
4-SO.sub.2Me 171-172 10 H cPr 2-N(Me)SO.sub.2Me 3,4-Cl.sub.2
153-154 12 H cPr 2-N(Ph)SO.sub.2Me -- 114-115 13 H cPr
2-N(Me)SO.sub.2Me 4-Br 128-130 14 H cPr 2-N(Me)SO.sub.2Me
4-SO.sub.2Me 130-132 16 H cPr 2-N(Me)SO.sub.2Et 4-Cl 77.5-78.5 17 H
cPr 2-N(Me)SO.sub.2Me 4-N(Me)SO.sub.2Me 74-76 18 H cPr
2-N(Me)SO.sub.2Me 4-F 154-155 19 H cPr 4-N(Me)SO.sub.2Me 2-Br 84-85
20 H cPr 4-N(Me)SO.sub.2Me 2-Cl 92.4-94.2 24 H cPr
4-N(Me)SO.sub.2Me [2-F 103-104 25 H cPr 2-N(Me)SO.sub.2Me 3,4-diF
134-136 26 H cPr 2-N(Me)SO.sub.2Me 4,5-diF 140-143 27 H cPr
2-N(Me)SO.sub.2Me 41 128-129 28 H cPr 2-N(iBu)SO.sub.2Me 4-Cl
118-118.5 29 H cPr 2-N(Me)SO.sub.2nPr 4-Cl 112-113 30 H cPr
2-N(Me)SO.sub.2Ph 4-Cl (a) 31 H cPr 2-N--(Me)SO.sub.2Bz 4-Cl (b) 32
H cPr 2-N(Me)SO.sub.2iPr 4-Cl 130-132 33 H cPr 2-N(OMe)SO.sub.2Me
4-Cl 85-87 Note that Ph represents phenyl; Bz represents benzyl.
(a) NMR (CDCl.sub.3) 1.15(m, 2H), 1.3(m, 2H), 2.65(m, 1H), 3.15(s,
3H), 6.8(d, 1H), 7.48(m, 7H), 8.1(s, 1H). (b) NMR (CDCl.sub.3)
1.15(m, 2H), 1.3(m, 2H), 2.6(m, 1H), 3.1(s, 3H), 4.25(s, 2H),
6.9(d, 1H), 7.3(m, 7H), 8.15(s, 1H).
EXAMPLE 3
[0325]
1-[4-Chloro-2-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropy-
lpropan-1,3-dione (3.8 g) and magnesium turnings (0.3 g) were
stirred at room temperature in anhydrous methanol. Reaction was
initiated by adding carbon tetrachloride (3 ml) and the resulting
solution was stirred at room temperature for a further 0.5 hours
and evaporated to dryness. Toluene was added and the solution was
re-evaporated to give a brown solid which was suspended with
stirring in dry acetonitrile. The suspension was heated to
65.degree. C. and a solution of ethyl chloroximidoacetate (2.6 g)
in dry acetonitrile was added dropwise over one hour. The resulting
suspension was stirred at 65.degree. C. for a further 2 hours, then
cooled to about 40.degree. C. Dilute hydrochloric acid (2N) was
added with stirring, the resulting layers were separated and the
aqueous layer was extracted with ethyl acetate. The organic phases
were combined, washed with brine, dried (sodium sulphate) and
evaporated to give an orange oil which was crystallised from
diethyl ether to yield ethyl
4-[4chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoy-
l]-5-cyclopropylisoxazole-3-carboxylate (compound 15, 2.8 g) as a
beige solid, m.p. 134.degree.-135.6.degree. C.
[0326] By proceeding in a similar manner ethyl
5-cyclopropyl4-[2-(N-methyl-
-N-methylsulphonyl)amino-4-trifluoromethyl]benzoylisoxazole-3-carboxylate,
compound 34 was prepared, m.p. 98.degree.-99.5.degree. C.
REFERENCE EXAMPLE 1
[0327] A solution of
3-cyclopropyl-1-[2-(N-methyl-N-methylsulphonyl)amino4-
trifruoromethylphenyl]propan-1,3-dione (4.21 g) and
triethylorthoformate (3.44 g) in acetic anhydride was stirred at
reflux temperature for 35 hours and then at room temperature
overnight. Excess solvents were removed by evaporation and
remaining traces of solvent were removed by azeotropic evaporation
with toluene to yield 3-cyclopropyl-2-ethoxymethyl-
ene-1-[2-(N-methyl-N-methylsulphonyl)amino
trifluoromethylphenyl]propan-1,- 3-dione as a brown oil (4.9
g).
[0328] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials.
3 18 R.sup.1 -X-R.sup.3 (R.sup.2).sub.n cPr 4-NHSO.sub.2Me 2-Cl cPr
4-N(Me)SO.sub.2Me 4-Cl cPr 2-N(Me)SO.sub.2Me 3-Cl-4-OCF.sub.3 cPr
2-N(Me)SO.sub.2Me 4-OCF.sub.3 cPr 2-N(Me)SO.sub.2Me 5-Cl cPr
2-N(Me)SO.sub.2Me --
REFERENCE EXAMPLE 2
[0329] A mixture of
1-[4-chloro-2-(N-ethyl-N-methyl-sulphonylamino)phenyl]-
-3-cyclopropylpropan-1,3-dione (3.5 g) and dimethylformamide
dimethyl acetal (15ml) in dichloromethane was stirred at room
temperature overnight and heated at reflux for 3 days. After
cooling the mixture was evaporated to dryness to give
1-[4-chloro-2-(N-ethyl-N-methylsulphonylami-
nophenyl]-3-cyclopropyl-2-dimethylaminomethylenepropan-1,3-dione
(3.83 g) as an orange gum which was not purified further.
[0330] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials.
4 19 R.sup.1 X-R.sup.3 (R.sup.2).sub.n cPr 2-N(Me)SO.sub.2Me
4-NO.sub.2 cPr 4-N(Me)SO.sub.2Me 2-Cl cPr 4-N(Me)SO.sub.2Me
2-NO.sub.2 cPr 2-N(Me)SO.sub.2Me 4-Me cPr 2-N(nPr)SO.sub.2Me 4-Cl
cPr 2-N(Et)SO.sub.2Me 4-SO.sub.2Me cPr 2-N(Me)SO.sub.2Me
3,4-Cl.sub.2 cPr 2-N(Ph)SO.sub.2Me cPr 2-N(Me)SO.sub.2Me
4-SO.sub.2Me cPr 2-N(Me)SO.sub.2Me 4-Br cPr 2-N(Me)SO.sub.2Et 4-Cl
cPr 2-N(Me)SO.sub.2Me 4-N(Me)SO.sub.2Me cPr 2-N(Me)SO.sub.2Me 4-F
cPr 4-N(Me)SO.sub.2Me 2-Br cPr 4-N(Me)SO.sub.2Me 2-Cl cPr
4-N(Me)SO.sub.2Me 2-F cPr 2-N(Me)SO.sub.2Me 3,4-F.sub.2 cPr
2-N(Me)SO.sub.2Me 4,5-F.sub.2 cPr 2-N(Me)SO.sub.2Me 4-I cPr
2-N(isobutyl)SO.sub.2Me 4-Cl cPr 2-N(Me)SO.sub.2nPr 4-Cl cPr
2-N(Me)SO.sub.2Ph 4-Cl cPr 2-N(Me)SO.sub.2Bz 4-Cl cPr
2-N(Me)SO.sub.2iPr 4-Cl cPr 2-N(OMe)SO.sub.2Me 4-Cl
REFERENCE EXAMPLE 3
[0331] A suspension of magnesium (0.47 g) in methanol was warmed
gently to initiate reaction and then heated at reflux until all of
the magnesium had dissolved. It was cooled slightly and t-butyl
3-cyclopropyl-3-oxoprop- ionate (239 g) was added. The mixture was
stirred and heated at reflux for 25 minutes then evaporated to
dryness. It was dissolved in toluene and re-evaporated to dryness.
The residue was again dissolved in toluene and
2-chloro-4-(methylsulphonylamino)benzoyl chloride (32 g) was added.
The mixture was stirred at room temperature overnight Hydrochloric
acid (2M) was added and the mixture was stirred. The layers were
separated and the organic layer was dried (magnesium sulphate) and
filtered. The filtrate was evaporated to give t-butyl
2-[2-chloro-4-(methylsulphonylamino)benzoy-
l]-3-cyclopropyl-3-oxopropionate (3.7 g) as a white solid, m.p.
137.degree.-140.degree. C.
[0332] t-Butyl
2-[2-chloro-4-(methylsulphonylamino)benzoyl]-3-cyclopropyl--
3-oxopropionate (2 g) was dissolved in toluene and
p-toluenesulphonic acid (0.2 g) was added. The mixture was stirred
and heated at reflux for 0.5 hours. It was cooled, washed with
water, dried (magnesium sulphate) and filtered. The filtrate was
evaporated to dryness to give
1-[2-chloro-4-(methylsulphonylamino)phenyl]-3-cyclopropylpropan-1,3-dione
(1.48 g) as a white solid, m.p. 119.9.degree.-121.6.degree. C.
[0333] By proceeding in a similar manner the following compounds of
formula (VI) above were prepared from the appropriately substituted
starting materials without isolation of the intermediate ester.
5 m.p. (.degree. C.) or R X-R.sup.3 (R.sup.2).sub.n NMR cPr
2-N(Me)SO.sub.2Me 4-Cl 93.3-96.5 cPr 2-N(Me)SO.sub.2Me 4-NO.sub.2
-- cPr 2-N(Et)SO.sub.2Me 4-Cl a cPr 4-N(Me)SO.sub.2Me 2-Cl -- cPr
4-N(Me)SO.sub.2Me 2-NO.sub.2 -- cPr 2-N(Me)SO.sub.2Me 4-Me b cPr
2-N(nPr)SO.sub.2Me 4-Cl c cPr 2-N(Et)SO.sub.2Me 4-SO.sub.2Me d cPr
2-N(Me)SO.sub.2Me 3,4-Cl.sub.2 -- cPr 2-N(Ph)SO.sub.2Me e cPr
2-N(Me)SO.sub.2Me 4-CF.sub.3 -- cPr 2-N(Me)SO.sub.2Me
4-N(Me)SO.sub.2Me f cPr 2-N(Me)SO.sub.2Et 4-F g cPr
4-N(Me)SO.sub.2Me 2-Cl -- cPr 2-N(Me)SO.sub.2Me 4-SO.sub.2Me h cPr
2-N(Me)SO.sub.2Me 3-Cl-4-OCF.sub.3 i cPr 2-N(Me)SO.sub.2Me
4-OCF.sub.3 j cPr 2-N(Me)SO.sub.2Me 5-Cl k cPr 2-N(Me)SO.sub.2Me
4,5-F.sub.2 104-105 cPr 2-N(Me)SO.sub.2Me 4-I 131.5-134 cPr
2-N(Me)SO.sub.2Me -- 110-113 Note: a NMR(CDCl.sub.3) 0.9-1.4(m, 7H)
1.7-1.9(m, 1H) 3.0(s, 3H) 3.65(q, 2H) 6.1(s, 1H) 7.4(m, 2H) 7.55(d,
1H) 16.0-16.3(bs, 1H). b NMR(CDCl.sub.3) 0.9-1.1(m, 2H)
1.15-1.25(m, 2H) 1.7-1.85(m, 1H) 2.35(s, 3H) 2.95(s, 3H) 3.25(s,
3H) 6.1(s, 1H) 7.15(d, 1H) 7.2(s, 1H) 7.5(d, 1H) 16.1-16.3(bs, 1H).
c NMR(CDCl.sub.3) 0.9(t, 3H) 1.05(m, 2H) 1.25(m, 2H) 1.45-11.65(m,
4H) 1.78(m, 1H) 3.03(s, 3H) 6.15(s, 1H) 7.38-7.48(m, 2H) 7.57(dd,
1H) 16.12(0.5H, bs). d NMR(CDCl.sub.3) 1.0-1.3(m, 7H) 1.79(m, 1H)
3.00(s, 3H) 3.06(s, 3H) 6.15(s, 1H) 7.78(d, 1H) 7.98(m, 2H). e
NMR(CDCl.sub.3) 0.88(m, 2H) 1.06(m, 2H) 1.58(m, 1H) 3.0(s, 3H)
5.82(s, 1H) 7.0-7.6(m, 9H). f NMR(CDCl.sub.3) 1.05(m, 2H) 1,23(m,
2H) 1.78(m, 1H) 2.9(s, 3H) 2.98(s, 3H) 3.28(s, 3H) 3.33(s, 3H)
6.15(s, 1H) 7.43(dd, 1H) 7.5(d, 1H) 7.66(d, 1H). g NMR(CDCl.sub.3)
1.0(m, 2H) 1.18(m, 2H) 1,72(m, 1H) 2,96(s, 3H) 3.2(s, 3H) 6.07(s,
1H) 7.0-7.2(m, 2H) 16.1(bs, 0.5H). h NMR(CDCl.sub.3) 1.0(m, 2H)
1.18(m, 2H) 1.72(m, 1H) 2.9(s, 3H) 3.05(s, 3H) 3.24(s, 3H) 6.07(s,
2H) 7.71(d, 1H) 7.9(m, 1H) 7.97(d, 1H). i NMR(CDCl.sub.3) 0.9(m,
2H) 1.1(m, 2H) 1.65(m, 1H) 2.9(s, 3H) 3.25(s, 3H) 6.0(s, 1H)
7.35(m, 1H) 7.45(d, 1H) 16.0(brs, 1H). j NMR(CDCl.sub.3) 1.0(m, 2H)
1.2(m, 1H) 1.7(m, 1H) 3.0(s, 3H) 3.25(s, 3H) 6.05(s, 1H) 7.,25(m,
2H) 7.6(d, 1H) 16.0(s, 1H). k NMR(CDCl.sub.3) 0.9(m, 2H) 1.1(m, 2H)
1.65(m, 1H) 2.9(s, 3H) 3.2(s, 3H) 6.0(s, 1H) 7.35(m, 2H) 7.5(d, 1H)
16.0(brs, 1H).
REFERENCE EXAMPLE 4
[0334] For the following diketones of formula (VI) an alternative
decarboxylation method was used, the corresponding t-butyl
2-aroyl-3-cyclopropyl-3-oxopropionate being prepared as described
above. t-Butyl
2-[4chloro-2-(N-ethylsulphonyl-N-methyl)aminobenzoyl]-3-cycloprop-
yl-3-oxopropionate was dissolved in 1,2-dichloroethane. The
solution was stirred and trifluoroacetic acid (1.5 equivalent) was
added. The mixture was stirred at room temperature for 3 hours then
evaporated to dryness. The residue was purified by column
chromatography (ethyl acetate /cyclohexane/dichloromethane) to
yield 1-[4-chloro-2-(N-ethylsulphonyl-N--
methyl)aminophenyl]-3-cyclopropylpropan-1,3-dione (6.79 g) as a red
oil, NMR (CDCl3) 1.05 (m,2H), 1.2(m,2H), 1.41(t,3H), 1.77(m,1H),
3.16(q,2H), 328(s,3H), 6.1(s,1H), 7.4(dd,1H), 7.47(d,1H),
7.65(d,1H), 16.05(bs,0.5H).
[0335] By proceeding in a similar manner the following compounds of
formula (VI) above were prepared from the appropriately substituted
starting materials:
[0336]
1-[4-bromo-2-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropyl-
propan-1,3-dione, m.p. 120.degree.-122.degree. C.;
[0337]
1-[2-bromo-4-(N-methyl-N-methylsulphonyl)aminophenyl]-3-cyclopropyl-
propan-1,3-dione, NMR (CDCl3) 1.03(m,2H), 1.23(m,2H), 1.77(m,1H),
2.9(s,3H), 3.37(s,3H), 6.08(s,1H) 7.45(dd,1H), 7.58(d,.sub.1H),
7.67(d,1H), 15.87(bs,0.5H);
[0338]
1-cyclopropyl-3-([2-fluoro4-(N-methyl-N-methylsulphonyl)-aminopheny-
l]-propan-1,3-dione as a yellow solid (using toluene as the solvent
in place of 1,2-dichloroethane);
[0339]
1-cyclopropyl-3-[2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromet-
hylphenyl]propan-1,3-dione as a brown gum (using dichloromethane as
the solvent in place of 1,2-dichloroethane);
1-[4-chloro-2-(N-methyl-N-propyl-
sulphonyl)aminophenyl]-3-cyclopropylpropan-1,3-dione.
[0340] Benzoyl chlorides were prepared by heating the appropriately
substituted benzoic acids with thionyl chloride. The excess thionyl
chloride was removed by evaporation the benzoyl chlorides thus
obtained were used without further purification. In some cases the
benzoyl chlorides were prepared by reaction of the benzoic acid
with oxalyl chloride in 1,2-dichloroethane at ambient temperature.
Evaporation of the solvents in vacuo gave the corresponding benzoyl
chlorides.
REFERENCE EXAMPLE 5
[0341] 2N Sodium hydroxide solution (20 ml) was added to a stirred
solution of methyl
4-chloro-2-(N-methyl-N-methylsulphonylamino)-benzoate (2.75 g) in
methanol. The mixture was stirred at reflux for 05 hours. After
cooling, the mixture was acidified with 2N hydrochloric acid and
extracted with ethyl acetate. The organic extracts were combined,
dried and evaporated to yield
4chloro-2-(N-methyl-N-methylsulphonylamino)benzoi- c acid as a
white solid (2.45 g), m.p. 161.degree.-164.degree. C.
[0342] By proceeding in a similar manner, the following compounds
were prepared:--
[0343] 2-(N-methyl-N-methylsulphonylamino) 4nitrobenzoic acid NMR
(DMSO-d.sub.6) 3.1(s,3H) 3.3(s,3H) 7.95(d,1H) 8.3(d,1H) 8.4(s,1H)
13.3-13.8(bs,1H);
[0344] 4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoic acid m.p.
148.degree.-151.degree. C.;
[0345] 2-chloro4-(N-methyl-N-methylsulphonylamino)benzoic acid m.p.
152.degree.-153.degree. C.;
[0346] 4-(N-methyl-N-methylsulphonylamino)-2-nitrobenzoic acid m.p.
177.degree.-178.6.degree. C.;
[0347] 4-methyl-2-(N-methyl-N-methylsulphonylamiino)benzoic acid
m.p. 185.degree.-187.degree. C.;
[0348] 4-chloro-2-(N-methylsulphonyl-N-propyl)aminobenzoic acid,
m.p. 133.degree.-135.degree. C.;
[0349] 3,4-dichloro-2-(N-methyl-N-methylsulphonyl)aminobenzoic
acid, m.p. 118.degree.-119.4.degree. C.;
[0350]
2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethyl-benzoic acid,
m.p. 157.degree.-160.degree. C.;
[0351] 4-bromo-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid,
m.p. 181.degree.-182.degree. C.;
[0352] 4-chloro-2-(N-ethylsulphonyl-N-methyl)aminobenzoic acid,
m.p. 132.degree.-134.degree. C.;
[0353] 2-bromo4(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.
153.5.degree.-155.5.degree. C.;
[0354] 2,4-bis(N-methyl-N-methylsulphonyl)aminobenzoic acid, NMR
(CDCl.sub.3); 2.8 (s,3H), 2.9(s,3H), 3.23(s,3H), 3.3(s,3H),
7.4(dd,1H), 7.48(d,1H), 8.03(d,1H);
[0355] 4fluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, NMR
(CDCl.sub.3); 3.06(s,3H), 3.28(s,3H), 7.1-73(m,2H), 8.1(m1H);
[0356] 2-fluoro4-(N-methyl-N-methylsulphonyl)aminobenzoic acid,
m.p. 189.degree.-191.degree. C.;
[0357] 3,4-difluoro-2-(N-methyl-N-methylsulphonyl)aminobenzoic
acid, m.p. 159.5.degree.-161.degree. C.;
[0358]
3-chloro-2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenz-
oic acid, NMR(CDCl.sub.3) 3.0(s,3H), 33(s,3H), 6.7 (brs,1H),
7.4(m,1H), 8.0(d,1H);
[0359] 2-(N-methyl-N-methylsulphonyl)amino4-trifluoromethoxybenzoic
acid, m.p. 138.5.degree.-141.degree. C.;
[0360] 5-chloro-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid.
NMR(DMSOd.sub.6) 3.0(s,3H), 3.2(s,3H), 7.6(d,1H), 7.65(m,1H),
7.75(m,1H);
[0361] 4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminobenzoic acid,
m.p. 158.degree.-159.degree. C.,
[0362] 4-chloro-2-(N-methyl-N-propylsulphonyl)aminobenzoic acid,
m.p. 143.5.degree.-144.5.degree. C.;
[0363] 4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoic acid,
m.p. 180.degree.-181.degree. C.;
[0364] 4-chloro-2-(N-benzylsulphonyl-N-methyl)aminobenzoic acid,
m.p. 180.degree.-185.degree. C.
[0365] 2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.
146.degree.-149.degree. C.
REFERENCE EXAMPLE 6
[0366] Potassium carbonate (125 g) was added to a stirred solution
of methyl 4chloro-2-(N-methylsulphonylamino)benzoate (7.5 g) in
acetone. The mixture was stirred for 15 minutes and methyl iodide
(8.0 g) was added. The resultant mixture was stirred at room
temperature for 1 hour and left to stand overnight. The mixture was
evaporated to dryness and the residue was dissolved in ethyl
acetate and washed with sodium hydroxide solution (2M) and water,
dried (anhydrous magnesium sulphate) and filtered. The filtrate was
evaporated to dryness to give methyl 4-chloro-2-(N-methyl-N--
methylsulphonylamino)benzoate (4.9 g) as a white solid, m-p.
73.degree.-75.degree. C.
[0367] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0368] methyl 2-chloro4(N-methyl-N-methylsulphonylamino)-benzoate,
NMR (DMSO-d.sub.6) 3.05(s,3H) 3.35(s,3H) 3.85(s,3H) 7.5(d,1H)
7.6(s,1H) 7.85(d,1H);
[0369] methyl 2-(N-methyl-N-methylsulphonylamino)-4 nitrobenzoate,
NMR (DMSO-d.sub.6) 3.05(s,3H) 3.25(s,3H) 3.8(s,3H) 8.0(d,1H)
83(d,1H) 8.4(s,1H);
[0370] ethyl 4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoate,
NMR (CDCl.sub.3) 1.1(t,3H) 1.35(t,3H) 2.9(s,3H) 3.65(q,2H)
4.3(q,2H) 7.3(d,1H) 7.35(s,1H) 7.8(d,1H);
[0371] methyl
3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate, NMR
(CDCl.sub.3); 2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H),
7.71(d,1H);
[0372] methyl
2-(N-methyl-N-methylsulphonyl)amino-4-trifluoromethoxybenzoa- te,
NMR (CDCl.sub.3) 2.95(s,3 H), 3.3(s,3H), 3.95(s,3H), 7.25(m,2H),
8.0(d,1H);
[0373] methyl
5-chloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate, m.p.
91.degree.-93.degree. C.;
[0374] methyl
4-chloro-2-(N-isobutyl-N-methylsulphonyl)-aminobenzoate, m.p.
89.degree.-90.degree. C., employing isobutyl iodide instead of
methyl iodide;
[0375] methyl 4-chloro-2-(N-methyl-N-propylsulphonyl)-aminobenzoate
as an orange oil;
[0376] methyl 2-(N-methyl-N-methylsulphonyl)-aminobenzoate, m.p.
60.degree.-62.degree. C.
REFERENCE EXAMPLE 7
[0377] Methyl iodide (22.0 ml) was added to a stirred suspension of
4-methyl-2-(N-methylsulphonylamino)benzoic acid (8.0 g) and
anhydrous potassium carbonate (24.2 g) in acetone and the mixture
was stirred and heated at reflux overnight. The mixture was cooled
and filtered and the filtrate was evaporated to dryness. The
residue was dissolved in dichloromethane and washed with aqueous
sodium bicarbonate solution, water, dried (magnesium sulphate) and
filtered. The filtrate was evaporated to dryness to give methyl
4-methyl-2-(N-methyl-N-methylsulphou- ylamino)benzoate (8.36 g) as
a cream solid, m.p. 100.degree.-103.degree. C.
[0378] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0379] methyl 4-(N-methyl-N-methylsulphonylamino)-2-nitrobenzoate,
NMR (CDCl.sub.3) 2.95(s,3H) 3.4(s,3H) 3.9(s,3H) 7.7(d,1H)
7.75(d,1H) 7.85(s,1H); propyl
4-chloro-2-(N-methylsulphonyl-N-propylamino)-benzoate m.p.
81.degree.-83.degree. C.;
[0380] ethyl
2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonyl-benzoate m.p.
108.6.degree.-109.4.degree. C.;
[0381] methyl
2-(N-methyl-N-methylsulphonyl)amino4-trifluoromethylbenzoate- , NMR
(CDCl.sub.3) 2.93(s,3H). 3.3(s,3H), 3.9(s,3H), 7.65(m,2H), 8.0(dd,
1H);
[0382] methyl 4-bromo-2-(N-methyl-N-methylsulphonnyl)-aminobenzoate
NMR (CDCl.sub.3) 2.95(s,3H), 3.23(s,1H), 3.83(s,3H), 7.5(dd,1H),
7.58(d,1H), 7.75(d,1H);
[0383] methyl
4-chloro-2-(N-ethylsulphonyl-N-methyl)amino-benzoate;
[0384] methyl 2-bromo-4-(N-methyl-N-methylsulphonyl)aminobenzoate,
NMR (CDCl.sub.3); 2.9(s,3H), 3.38(s,3H), 3.93(s.3H), 7.46(dd, 1H),
7.68(d, 1H), 7.87(d, 1H);
[0385] methyl 2,4-bis(N-methyl-N-methylsulphonyl)aminobenzoate NMR
(CDCl.sub.3); 2.9(s,3H), 2.96(s,3H), 3.23(s,3H), 3.79(s,3H),
3.87(s,3H), 7.42(dd,1H), 7.48(d,1H), 7.95(d,1H);
[0386] methyl 4-fluoro-2-(N-methyl-N-methylsulphonyl)amino-benzoate
NMR (CDCl.sub.3); 2.97(s,3H), 3.23(s,3H), 3.87(s,3H),
7.06-7.24(m,2H), 7.96(m,1H);
[0387] methyl 2-(N-methyl[-N-methylsulphonyl)amino
4-methylsulphonylbenzoa- te NMR (acetone-d.sub.6); 3.02 (s,3H),
3.22(s,3H), 3.35(s,3H), 3.9(s,3 H), 8.06(m,2H), 8.17(m,1H);
[0388] methyl 2-fluoro-4( N-methyl-N-methylsulphonyl)-aminobenzoate
as an orange oil, NMR (CDCl.sub.3) 2.89(s,3H), 3.34(s,3H),
3.91(s,3H), 7.1(m,2H), 7.93(t,1H);
[0389] methyl
3,4-difluoro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate as an
orange solid, NMR (CDCl.sub.3) 3.01(s,3H), 3.3(s,3H), 3.91(s,3H),
7.24(q,1H), 7.73(m,1H);
[0390] methyl 4-chloro-2-(
N-methyl-N-phenylsulphonyl)-aminobenzoate as a white solid, m.p.
100.degree.-107.degree. C.;
[0391] methyl
4-chloro-2-(.i-methyl-N-benzylsulphonyl-N-methyl)aminobenzoa- te as
a cream solid, m.p. 89.degree.-91.degree. C.
REFERENCE EXAMPLE 8
[0392] A solution of methanesulphonyl chloride (6.3 g) in
dichloromethane was added to a stirred, cooled (0.degree.-5.degree.
C.) solution of methyl 2-amino-4-chlorobenzoate (9.5 g) in
dichloromethane. Triethylamine (7.1 g) was then added and the
mixture was stirred at 0.degree.-5.degree. C. for 10 minutes and
then at room temperature for 0.5 hours.
[0393] The mixture was diluted with 2N hydrochloric acid. The
organic phase was separated, washed with water, dried and
evaporated. The crude product was purified by column chromatography
to yield methyl 4-chloro-2-(N-methylsulphonylamino)benzoate as a
white solid. (3.6 g) m.p. 125.5.degree.-128.1.degree. C.
[0394] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0395] methyl
2-(N-methyl-N-methylsulphonyl)amino-4-(N,N-bis-methylsulphon-
ylamino)benzoate as an orange gum, NMR (CDCl.sub.3) 2.57(s,3 H),
3.)(s,3 H), 3.4(s,6H), 3.94(s,3H), 7.4(m,1H), 7.5(m,1H), 7.97(d,
1H):
[0396] methyl 2-(N-methylsulphonylamino)benzoate, m.p.
88.degree.-90.degree. C.
REFERENCE EXAMPLE 9
[0397] Concentrated sulphuric acid (20 ml) was added to a
suspension of 2-chloro4-(N-methylsulphonylamino)benzoic acid (10.3
g) in methanol and the mixture was stirred and heated at reflux for
22 hours. It was cooled, evaporated to dryness and diluted with
water, extracted with ethyl acetate, washed with aqueous sodium
bicarbonate solution, water, dried (magnesium sulphate) and
filtered. The filtrate was evaporated to dryness to give methyl
2-chloro4-(N-methylsulphonylamino)benzoate(10.0 g) as an off-white
solid, NMR (DMSO-d.sub.6) 3.15(s,3H) 3.85(s,3H) 7.2(d.1H) 7.3(s,1H)
7.85(d, 1H) 10.5(s, 1H),
[0398] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0399] methyl 2-(N-methylsulphonylamino)4-nitrobenzoate, NMR
(CDCl.sub.3): 3.15 (s,3H) 4.0(s,3H) 7.9(d,1H) 8.25(d,1H) 8.5(s,1H)
10.65(s,1H);
[0400] methyl
3,4-dichloro-2-(N-methyl-N-methylsulphonyl)-aminobenzoate, NMR
(CDCl.sub.3); 2.95(s,3H), 3.28(s,3H), 3.89(s,3H), 7.5(d,1H),
7.71(d,1H);
[0401] methyl
2-chloro-4-(N-methyl-N-methylsulphonyl)amino-benzoate, NMR (DMSO
d.sub.6) 3.0(s,3H), 3.35(s,3H), 3.82(s,3H), 7.5(dd, 1H),
7.63(d,1H), 7.87(d,1H),
[0402] methyl 2-amino-4-trifluoromethylbenzoate m.p.
60.degree.-62.degree. C.;
[0403] methyl 2-amino4-methylbenzoate m.p. 41.degree.-43.degree.
C.;
[0404] methyl 4-bromo-2-nitrobenzoate m.p. 41.degree.-43.degree.
C.;
[0405] methyl 2-bromo-4-nitrobenzoate m.p. 83.degree.-85.degree.
C.;
[0406] methyl 2-amino-3,4-dichlorobenzoate, NMR (CDCl.sub.3):
3.9(s,3H), 6.4(bs,2H), 6.7-7.7(m,2H);
[0407] methyl 2-amino-3,4-difluorobenzoate.
REFERENCE EXAMPLE 10
[0408] A mixture of .sup.2-chloro-4-(N-methylsulphonylamino)benzoic
acid and 2-chloro-4-[N,N-bis(methylsulphonyl)amino]benzoic acid
(3.6 g) in aqueous sodium hydroxide (2M) and methanol was stirred
and heated at reflux for 0.5 hours. It was cooled and the methanol
- was removed by evaporation. The aqueous residue was acidified and
the product was filtered off to give
2-chloro-4-(N-methylsulphonylamino)benzoic acid (3.4 g) as a white
solid, m.p. 256.degree.-258.degree. C.
[0409] By proceeding in a similar manner the following compounds 10
were prepared from the appropriately substituted starting
materials: 2-(N-methylsulphonylamino)4-nitrobenzoic acid, NMR
(DMSO-d.sub.6) 3.3(s,3H) 7.9(d,1H) 8.2(d,1H) 8.35(s,1H)
10.5-11.1(bs,1H);
[0410] N-(methylsulphonyl)aniline, starting from
[N,N-(bis)methylsulphonyl- ]aniline.
REFERENCE EXAMPLE 11
[0411] An aqueous solution of sodium hydroxide (11.0 g) was added
to a solution of a mixture of methyl
4-methyl-2-(N,N-bis(methylsulphonyl)amino- ]benzoate and methyl
4-methyl-2-(N-methylsulphonylamino)benzoate (23.26 g) in methanol
and the resulting suspension was heated at reflux for 1 hour. It
was cooled and the methanol was removed by evaporation. The aqueous
solution was acidified and the resultant solid was filtered off to
give 4-methyl-2-(N-methylsulphonylamino)benzoic acid (16.42 g) as a
cream solid, m.p. 202.degree.-205.degree. C.
[0412] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0413] 4-(N-methylsulphonylamino)-2-nitrobenzoic acid, NMR
(DMSO-d.sub.6) 3.2(s,3H) 7.5(d,1H) 7.6(s,1H) 7.9(d,1H) 10.8(s,1H)
13.3-14.1(bs,1H);
[0414] 4-bromo-2-(N-methylsulphonyl)aminobenzoic acid m.p.
178.degree.-186.degree. C.;
[0415] 4-chloro-2-(N-ethylsulphonyl)aminobenzoic acid m.p.
177.degree.-179.degree. C.;
[0416] 2-bromo-4-(N-methylsulphonyl)aminobenzoic acid
m.p.-244.degree.-245.degree. C.;
[0417] 4-fluoro-2-( N-methylsulphonyl)aminobenzoic acid NMR
(DMSO-d.sub.6) 3.33(s,3H), 7.0(m,1H), 7.36(dd, H), 8.08(m.1H),
10.92(brs,0.5H);
[0418] 2-chloro-4-( N-methylsulphonyl)aminobenzoic acid NMR
(DMSO-d.sub.6) 3.1(s,.3H), 7.24(dd,1H), 7.29(d,1H), 7.85(d.1H),
10.38(brs,1H), 13.08(bs,1H),
REFERENCE EXAMPLE 12
[0419] Methanesulphonyl chloride (5.72 g) was added to a stirred,
cooled (0.degree. C.) mixture of 4-amino-2-chlorobenzoic acid (6.9
g) and triethylamine (13.1 g) in acetonitrile. The mixture was then
stirred at room temperature for 3.5 hours. Triethylamine (4 g) was
added and the mixture was cooled to 0.degree. C. and further
methanesulphonyl chloride (3.8 g) was added. The mixture was then
stirred at room temperature for one hour. The mnixture was filtered
and the filtrate evaporated. The residue was dissolved in 2N sodium
hydroxide solution and washed with diethyl ether. The aqueous
solution was acidified to pH 2-3 with 2N hydrochloric acid and then
extracted with ethyl acetate. The organic extracts were evaporated.
The residue was triturated with diethyl ether to yield a mixture of
2-chloro4-(N-methylsulphonylamino)benzoic acid and
2-chloro-4-[N,N-bis(methylsulphonyl)amino]benzoic acid.
REFERENCE EXAMPLE 13
[0420] Methanesulphonyl chloride (12.2 ml) was added to a stirred,
cooled solution of methyl 2-amino-4-methylbenzoate (10.3 g) and
triethylamine (19.5 ml) in dichloromethane while maintaining the
temperature below 0.degree. C. The mixture was stirred at room
temperature for 4 hours. Hydrochloric acid (2M) was added and the
layers were separated. The organic layer was washed with water,
dried (magnesium sulphate) and filtered. The filtrate was
evaporated to dryness to give a mixture of methyl
4-methyl-2-[N,N-bis(methylsulphonyl)amino]benzoate and methyl
4-methyl-2-(N-methylsulphonylamino)benzoate (18.26 g) as a yellow
solid which was not further purified.
[0421] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0422] 4-[N,N-bis-(methylsulphonyl)amino]-2-nitrobenzoic acid;
[0423] methyl
2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonyl-benzoate- ;
[0424] N,N-bis(methylsulphonyl)aniline, m.p.
172.degree.-177.6.degree. C.,
[0425] methyl
2-[N,N-bis(methylsulphonyl)]amino-4-trifluoromethyl-benzoate m.p.
159.degree.-163.degree. C.;
[0426] methyl 4-bromo-2-[N,N-bis( methylsulphonyl)]aminobenzoate,
m.p. 221.degree.-225.degree. C.;
[0427] methyl 4-chloro-2-( N-ethylsulphonyl)amino]benzoate and
[0428] methyl
4-chloro-2-]N,N-bis(ethylsulphonyl)amino]benzoate:
[0429] methyl 2-bromo4-[N,N-bis(methylsulphonyl)amino]benzoate
and
[0430] methyl 2-bromo4-(N-methylsulphonyl)aminobenzoate;
[0431] methyl 2-(methyl-N-methylsulphonyl)amino-4-N,N-bis
(methylsulphonyl)aminobenzoate, NMR(CDCl.sub.3), 2.97(s,3H),
3.32(s,3H), 3.38(s,6H), 3.92(s,3H), 7.43(dd,1H), 7.52(d,1H),
7.98(d,1H);
[0432] methyl 4-fluoro-2-[N,N-bis(methylsulphonyl)amino]benzoate
NMR (CDCl.sub.3); 3.5(s,6H), 3.95(s,3H), 7.16(dd.1H) 7.27(m,1H),
8.06(m, 1H);
[0433] methyl 2-chloro4-[N,N-bis(methylsulphonyl)amino]benzoate NMR
(CDCl.sub.3): 3.43(s,6H), 3.92(s,3H), 7.3;(dd,1H), 7.47(d,1H),
7.9(d,1H);
[0434] methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonyl
benzoate m.p. 207.4.degree.-211.2.degree. C.;
[0435] methyl-2-(N,N-bis(methylsulphonyl)amino]-4-nitrobenzoate as
a yellow solid. NMR (CDCl.sub.3) 3.5(s,6H), 4.0(s,3H), 8.18(d.1H),
8.26(m,1H), 8.39(m,1H);
[0436] methyl 2-fluoro-4-[N,N-bis(methylsulphonyl)amino]benzoate as
a white solid. NMR (CDCl.sub.3) 3.42(s,6H), 3.95(s,3H), 7,21(m.2H),
8.04(t,1H);
[0437] methyl 3.4-difluoro-2-[N,N-bis(
methylsulphonyl)amino]-benzoate as a solid, NMR (CDCl.sub.3)
3.42(s,6H), 3.S7(s,3H), 7.3(q.1H), 7.79(m,1H):
[0438] methyl
2-[N,N-bis(methylsulphonyl)amino]-4-trifluoromethylbenzoate as an
orange oil;
[0439] methyl 2-(N-methylsulphonyl)amino-4-trifluoromethoxybenzoate
and methyl
2-[N,N-bis(methylsulphonyl)-amino]-4-trifluoromethoxybenzoate;
[0440] methyl 5-chloro-2-(N-methylsulphonyl)aminobenzoate and
methyl 5-chloro-2-[N,N-bis(methylsulphonyl)amino]benzoate, m.p.
136.degree.-138.degree. C.;
[0441] methyl 4-chloro-2-[N,N-bis(propylsulphonyl)amino]benzoate as
a brown oil;
[0442] methyl 4-chloro-2-[N,N-bis-(phenylsulphonyl)amino]benzoate
as a cream solid, m.p. 156.5.degree.-158.degree. C.;
[0443] methyl 2-[N,N-bis-(benzylsulphonyl)amino]-4-chlorobenzoate
as a brown solid.
REFERENCE EXAMPLE 14
[0444] A mixture of ethyl
2-(N-ethyl-N-methylsulphonylamino)-4-methylsulph- onylbenzoate
(11.4 g) and lithium hydroxide monohydrate (1.37 g) in aqueous
ethanol (50%) was stirred at room temperature for 19 hours. The
mixture was then acidified with conc. hydrochloric acid and
extracted with ethyl acetate. The combined organic extracts were
dried (magnesium sulphate), filtered and evaporated to yield
2-(N-ethyl-N-methylsulphonyl-- amino)-4-methylsulphonylbenzoic acid
as a brown solid (9.48 g), NMR (acetone-d.sub.6); 1.15(t,3H),
2.98(s,3H), 3.22(s,3H), 3.85(q,2H), 8.0-8.25(m.3H),
[0445] By proceeding in a similar manner
2-(N-methyl-N-methylsulphonyl)ami- no4-methylsulphonylbenzoic acid
was prepared, m.p. 199.degree.-200.degree. C.
REFERENCE EXAMPLE 15
[0446] A suspension of methyl
2-[N,N-bis(methylsulphonyl)amino]-4-methylsu- lphonylbenzoate (22.9
g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol
(50) was stirred at room temperature for 18 hours. The resulting
solution was acidified with concentrated hydrochloric acid and
extracted with ethyl acetate. The combined organic extracts were
dried (magnesium sulphate), filtered and evaporated to yield
2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige
solid. NMR (acetone d.sub.6): 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H),
8.23(d,1H),
[0447] By proceeding in a similar manner the following compounds
were prepared from the appropriately substituted starting
materials:
[0448] 2-(N-methylsulphonyl)amino-4-trifluoromethylbenzoic acid as
an orange oil;
[0449]
2-(N-methyl-N-methylsulphonyl)amino4-(N-methylsulphonylamino)benzoi-
c acid as an orange solid;
[0450] 2-(N-methylsulphonyl)amino4-methylsulphonylbenzoic acid.
[0451] The following compounds were prepared using sodium hydroxide
in place of lithium hydroxide:
[0452] 2-(N-methylsulphonyl)amino-4-nitrobenzoic acid as an orange
solid;
[0453] 2-fluoro4-(N-methylsulphonyl)aminobenzoic acid as a brown
solid, NMR (DMSO) 3.26(s,3H), 7.04(m,2H), 7.85(t,1H), 10.5(s,1H),
13.0(s,1H);
[0454] 3,4-difluoro-2-(N-methylsulphonyl)aminobenzoic acid as a
brown solid;
[0455] 4-chloro-2-(N-propylsulphonyl)aminobenzoic acid, m.p.
159.degree.-160.degree. C.;
[0456] 4-chloro-2-(N-phenylsulphonyl)aminobenzoic acid, m.p.
186.5.degree.-189.degree. C.;
[0457] 4-chloro-2-(N-benzylsulphonyl)aminobenzoic acid, m.p.
181.degree.-185.degree. C.
REFERENCE EXAMPLE 16
[0458] Concentrated hydrochloric acid (90 ml) was added to a
stirred suspension of methyl 2-nitro 4methylsulphonyl benzoate (25.
g) in methanol at -50.degree. C. (ice/salt bath). The cooling bath
was then removed and iron dust (17.5 g) was added portionwise over
a period of 20 minutes. The resulting exotherm was controlled using
a cooling bath so that the temperature did not exceed 50.degree. C.
After 15 minutes of cooling, the bath was removed and the reaction
mixture was allowed to reach room temperature. Stirring was
continued for a further 3 hours. The mixture was poured onto ice
and then neutralised with sodium carbonate. Dichloromethane was
added and the suspension was filtered. The filtrate was extracted
with further dichloromethane and the combined organic extracts were
dried (magnesium sulphate), filtered and evaporated to yield a
crude product which was purified by recrystallisation from ethyl
acetate/hexane to give methyl 2-amino-4-methylsulphonyl benzoate
(4.5 g) as yellow needles, m.p. 98.3.degree.-98.5.degree. C.
[0459] By proceeding in a similar manner, the following compounds
were prepared from the appropriately substituted starting
material:
[0460] methyl 2-amino-4-bromobenzoate NMR (CDCl.sub.3) 3.8(s,3H),
5.72(bs,2H), 6.7(dd,1H), 6.79(d,1H), 7.65(d,1H);
[0461] methyl 4-amino-2-bromobenzoate m.p. 93.degree.-95.degree.
C.
REFERENCE EXAMPLE 17
[0462] A mixture of methyl 2-amino-3,4-dichlorobenzoate (2.2 g) and
methanesulphonyl chloride (2.86 g) was stirred at 100.degree. C.
for 4 hours. A further quantity of methanesulphonyl chloride (2.86
g) was added and the mixture was stirred at 100.degree. C.
overnight. The mixture was poured into water then extracted with
ethyl acetate. The combined organic extracts were washed with
water, dried (magnesium sulphate) and evaporated to yield a brown
oil which was crystallised from cyclohexane/ethyl acetate to yield
methyl 3,4-dichloro-2-(methylsulphonyl- amino)benzoate as light
brown crystals (1.4 g), m-p. 100.degree.-102.degree. C.
REFERENCE EXAMPLE 18
[0463] A solution of N-(methylsulphonyl)aniline (455 g) in
dimethoxyethane was added under an inert atmosphere to a stirred
suspension of sodium hydride (80% oil dispersion, 0.8 g) in
dimethoxyethane at room temperature. The resulting white emulsion
was stirred at 37.degree. C. for 30 minutes.
Diphenyliodonium-2-carboxylate monohydrate (10 g) and cupric
acetate (0.3 g) were then added and the suspension was stirred at
reflux for 24 hours. The mixture was cooled to room temperature and
water was added. The mixture was made alkaline by addition of 2M
NaOH solution then filtered through `HYFLO` silica. The filtrate
was acidified with concentrated hydrochloric acid and then
extracted with ethyl acetate. The combined organic extracts were
dried (magnesium sulphate) and evaporated to yield
2-(N-methylsulphonyl-N-phenyl)aminobenzoic acid.
REFERENCE EXAMPLE 19
[0464] A suspension of 4-bromo-2-nitrotoluene (50 g) in water was
heated to 97.degree. C. Potassium permanganate (240 g) was then
added over a period of 4.5 hours. The resulting suspension was
heated at reflux overnight. The mixture was filtered whilst hot
(through `HYFLO` silica). The filter cake was washed through with
boiling water. The cooled filtrates were washed with diethyl ether
then acidified to pH 1 with concentrated hydrochloric acid. The
resulting-suspension was cooled in ice water and then filtered. The
solid was dried to yield 4-bromo-2-nitrobenzoic acid (10.83 g) as a
cream solid, m.p. 164.degree.-167.degree. C.
REFERENCE EXAMPLE 20
[0465] A suspension of methyl
2-(N-methyl-N-methylsulphonyl-amino)4-nitrob- enzoate (2.88 g),
iron powder (5 g) and calcium chloride (0.5 g) in ethanol was
stirred at reflux for 2 hours. The suspension was filtered whilst
hot. The filter cake was thoroughly washed with boiling ethanol.
The combined filtrates were cooled to room temperature then
evaporated to dryness to yield
methyl,4-amino-2-(N-methyl-N-methylsulphonyl)-aminobenzo- ate (3 g)
as a light brown solid, NMR (CDCl.sub.3); 3.0 (s,3H), 3.21(s,3H),
3.8(s,3H), 3.6-4.15(bs,2H), 6.6(dd,1H), 6.7(d,1H), 7.83(d,1H),
REFERENCE EXAMPLE 21
[0466] Sodium hydride (60% oil dispersion, 1.0 g) was stirred in
dry toluene under an inert atmosphere and methanesulphonamide (0.8
g) was added. After heating at reflux for 1 hour and cooling,
2-bromo-3-chloro-4-trifluoromethoxybenzoic acid (2.69 g) was added.
After the effervescence had subsided, copper (I) bromide (0.72 g)
was added and the mixture heated at reflux for 8 hours. Two further
additions of copper (I) bromide (total 1.42 g) were made, with
reflux maintained for a further 12 hours. After cooling, a solution
of potassium bisulphate was added and the mixture-extracted (ethyl
acetate), dried (magnesium sulphate) and evaporated to dryness to
give 3-chloro-2-(N-methylsulphonyl- )-amino-trifluoromethoxybenzoic
acid as a white solid (4.14 g). This was used without further
purification in the next stage according the following
procedure.
[0467] This product (1.7 g) was heated at reflux for 10 hours with
stirring with methyl iodide (3.68 ml) and anhydrous potassium
carbonate (4.14 g) in acetone. Additional methyl iodide (26 ml) was
added with heating at reflux for 12 hours. The solvent was
evaporated in vacuo and the residue partitioned between water and
dichloromethane. The organic layer was dried (magnesium sulphate)
and evaporated to give methyl
3-chloro-2-(N-methyl-N-methylsulphonyl)4-trifluoromethoxybenzoate
(1.73 g) as an oil, NMR (CDCl.sub.3) 2.95(s,3H), 3.25(s,3H),
3.90(s,3H), 7.35(m,1H), 7.80(d, 1H),
REFERENCE EXAMPLE 22
[0468] A solution of 3-chloro1trifluoromethoxybenzoic acid (4.15 g)
in dry tetrahydrofuran was treated with n-butyl lithium (15.1 ml of
2.5M solution in hexanes) at 78.degree. C. under an inert
atmosphere. After stirring overnight at this temperature, a
solution of 1,2-dibromotetrachloroethane (8.39 g) in
tetrahydrofuran was added. After 30 minutes, the solution was
allowed to slowly warm to is . 15ambient temperature, then treated
with 2M hydrochloric acid. The mixture was extracted with ether,
the ethereal solution itself extracted with sodium bicarbonate
solution and the latter acidified with dilute hydrochloric acid.
This solution was extracted with ether and evaporated in vacuo to
give 2-bromo-3-chloro4-trifluoromethoxybenzoic acid (55 g) as a
brown solid, NMR (CDCl.sub.3) 73(m,1H), 7.8(d,1H).
REFERENCE EXAMPLE 23
[0469] A solution of n-butyl lithium (4.4 ml of 25M solution in
hexanes) in dry diisopropyl ether was treated at -78.degree. C.
under an inert atmosphere with
3-chloro4-trifluoromethoxy-bromobenzene (2.96 g) in diisopropyl
ether. After 10 minutes, excess carbon dioxide (in the form of
pellets) was added and the mixture left to slowly warm to ambient
temperature. Ice-water was added and the organic layer run off. The
aqueous layer was acidified with dilute hydrochloric acid,
extracted (ether), dried (magnesium sulphate) and evaporated to
dryness to give 3-chloro-4-trifluoromethoxybenzoic acid (1.51 g) as
a white solid, m.p. 110.5.degree.-111.5.degree. C.
REFERENCE EXAMPLE 24
[0470] A solution of 3-chloro4-trifluoromethoxyaniline (5.1 g) in
acetic acid (31 ml) was stirred and treated with sodium nitrite
(2.16 g) in concentrated sulphuric acid (14 ml) at below 18.degree.
C. After an additional 1 hour at 10.degree. C., the solution was
added to a mixture of copper (I) bromide (7.7 g) and hydrobromic
acid (24.5 ml) in water at 40.degree.-50.degree. C. The reaction
was completed by heating at 50.degree. C. for 2 hours, water was
added and the mixture filtered. The filtrate was extracted with
ether, washed with sodium bicarbonate, dried (magnesium sulphate)
and evaporated to give 3-chloro4-trifluoromethoxy-br- omobenzene
(6.05 g) as a brown oil, NMR (CDCl.sub.3) 7.10(m,1H), 7.35(m,1H),
7.35(d,1H),
[0471] By proceeding in a similar manner
2-nitro4-trifluoromethoxy-bromobe- nzene was prepared, NMR
(CDCl.sub.3) 7.35(m,1H), 7.75(m,1H), 7.8(d,1H),
REFERENCE EXAMPLE 25
[0472] A solution of anhydrous tin (II) chloride (17.14 g) in
concentrated hydrochloric acid was added to a solution of
3-chloro-4-trifluoromethoxy-- nitrobenzene (5.2 g) in ethanol with
cooling to maintain a temperature below 30.degree. C. After an
additional 2 hours at ambient temperature and 05 hour at 50.degree.
C., the mixture was poured onto water, basified with sodium
hydroxide solution and extracted with ether. The extracts were
washed with water, dried (magnesium sulphate) and evaporated in
vacuo to give an oil (6.2 g), which was purified by chromatography
eluting with dichloromethane to give
3-chloro-4-trifluoromethoxyaniline (4.1 g), m.p.
32.degree.-33.degree. C. as a yellow solid.
REFERENCE EXAMPLE 26
[0473] A stirred mixture of 2-trifluoromethoxy-5-nitroaniline (8.61
g) and concentrated hydrochloric acid in water was stirred at
0.degree. C. and treated with sodium nitrite (2.93 g) in water
(7ml). After 1 hour at 0.degree. C. the solution was added to a
stirred solution of copper (I) chloride (4.4 g) in water and
concentrated hydrochloric acid keeping below 20.degree. C. After
stirring overnight the mixture was diluted with water, extracted
with ether and the extracts dried (magnesium sulphate) and
evaporated to give an oil (8.7 g). This was purified by
chromatography eluting with hexane/ethyl acetate (98:2) to give
3-chloro4-trifluoromethoxy-nitrobenzene (5.2 g) as a yellow liquid,
NMR (CDCl.sub.3) 7.50(m,1H), 8.20(m,1H), 8.4(d,1H),
REFERENCE EXAMPLE 27
[0474] A mixture of potassium hydroxide (4.71 g) and
5-nitro-2-trifluoromethoxyacetanilide (20 g) in ethanol and water
was heated at reflux for 3.5 hours, poured onto ice and the
resulting solid filtered off and dried. Purification by
chromatography, eluting with hexane/ethyl acetate gave
2-trifluoromethoxy-5-nitroaniline (9.8 g) as a yellow solid, m.p.
90.degree.-91.degree. C.
REFERENCE EXAMPLE 28
[0475] 2-Trifluoromethoxyacetanilide (31.6 g) was added to stirred
concentrated sulphuric acid at -10.degree. C. A mixture of
concentrated nitric acid and concentrated sulphuric acid was added
maintaining at -5.degree. C. to -10.degree. C. The mixture was
stirred at 0.degree. C. for four hours and poured onto excess ice.
The filtered solid was dissolved in dichloromethane, washed with
water, dried (magnesium sulphate) and evaporated to yield a
residue. This was purified by chromatography eluting with
hexane/ethyl acetate to give 5-nitro-2-trifluoromethoxyacetanilide
(21.57 g), m.p. 129.degree.-130.degree. C.
REFERENCE EXAMPLE 29
[0476] Acetyl chloride (66 ml) was added to a stirred solution of
2-trifluoromethoxyaniline (150 g) and triethylamine in dry
dichloromethane (maintaining a temperature below 20.degree. C.).
After 3 hours additional stirring at 20.degree. C. the mixture was
washed with dilute hydrochloric acid, sodium carbonate solution and
water, dried (magnesium sulphate) and evaporated to dryness. The
residue was recrystallised from toluene to furnish
2-trifluoromethoxyacetanilide (113.4 g), m.p.
64.degree.-66.5.degree. C.
REFERENCE EXAMPLE 30
[0477] 6,7-Difluoroisatin (22.2 g) was added to a solution of
sodium hydroxide (2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was
added at 40.degree. C. or less over 20 minutes. After 1 hour the
mixture was heated to 65.degree. C. for 0.5 hours, cooled, poured
onto water and acidified with concentrated hydrochloric acid. The
resulting solid was filtered, washed with water and recrystallised
from ethyl acetate/cyclohexane to give 2-amino-3,4-difluorobenzoic
acid (I 1.3 g) as an orange solid, m.p. 207.degree.-208.degree.
C.
REFERENCE EXAMPLE 31
[0478] 2,3-Difluoro-.alpha.-isonitrosoacetanilide (36.8 g) was
added during 1 hour to a stirred solution of concentrated sulphuric
acid and water at 65.degree.-75.degree. C. After an additional 20
minutes-at 80.degree. C., the cooled mixture was poured onto excess
ice-water. Extraction with ethyl acetate was followed by water
washing, drying (magnesium sulphate) and evaporation to dryness to
give a brown solid. Trituration with boiling cyclohexane gave after
cooling, 6,7-difluoroisatin (22.2 g), m.p.
164.5.degree.-167.degree. C. as a brown solid.
REFERENCE EXAMPLE 32
[0479] Chloral hydrate (38.9 g) was added to a stirred solution of
sodium sulphate (219 g) in water. A solution of 2,3-difluoroaniline
(25 g) in a mixture of concentrated hydrochloric acid (19.4 ml) and
water (117 ml) was added. A solution of hydroxylamine hydrochloride
(41.35 g) in water was then added over 35 minutes and the mixture
stirred for 1 hour at 95.degree.-100.degree. C. After cooling the
solid was filtered, washed with water, then with petroleum ether
and dried in a desiccator to furnish
2,3-difluoro-.alpha.-isonitrosoacetanilide (36.8 g), m.p.
124.5.degree.-125.degree. C.
REFERENCE EXAMPLE 33
[0480] A solution of sodium hydroxide (2.38 g) in water was added
to a mixture of methyl
2-(N-methylsulphonyl)amino-4-trifluoromethoxybenzoate and methyl
2-[N,N-bis( methylsulphonyl)amino] trifluoromethoxybenzoate (8.26
g) in methanol at 15.degree.-20.degree. C. After an additional 15
minutes the solid was filtered, dissolved in ethyl acetate, dried
(magnesium sulphate) and evaporated in vacuo to give methyl
2-(N-methylsulphonyl)amino4-trifluoromethoxybenzoate as a brown
solid (4.15 g) after trituration with hexane, NMR (CDCl.sub.3)
3.0(s,3H), 3.9(s,3H), 6.9(m,1H), 7.55(m,1H), 8.05(d,1H), 10.5(brs,
1H),
[0481] By proceeding in a similar manner methyl
5-chloro-2-(N-methylsulpho- nyl)aminobenzoate was prepared m.p.
117.degree.-120.degree. C.
REFERENCE EXAMPLE 34
[0482] Methyl 2-nitro4-trifluoromethoxybenzoate (10 g) and 5%
palladium on activated carbon (0.5 g) in methanol was hydrogenated
for 20 hours at ambient temperature. The mixture was filtered and
the filtrate evaporated to give methyl
2-amino4-trifluoromethoxybenzoate (8.35 g) as a brown oil, NMR
(CDCl.sub.3) 3.9(s,3H), 5.9(brs,2H), 6.55(m,2H), 7.9(d,1H),
REFERENCE EXAMPLE 35
[0483] 2-Nitro4-trifluoromethoxybenzoic acid (4.7 g) was heated
under reflux conditions for 2 hours with oxalyl chloride (1.95 ml)
and 1,2-dichloroethane (25 ml) containing N,N-dimethylformamide (2
drops). The solvents were evaporated to dryness, the residue
dissolved in dry dichloromethane and added to a solution of
triethylamine (2.08 g) in dry methanol. After 2 days, the solvent
was evaporated and the residue partitioned between dichloromethane
and sodium bicarbonate solution. The organic phase was dried
(magnesium sulphate), evaporated and the residue purified by
chromatography eluting with dichloromethane/hexane to give methyl
2-nitrotrifluoromethoxybenzoate (4.9 g) as a yellow liquid, NMR
(CDCl.sub.3) 3.9(s,3H), 7.5(m,1H), 7.75(brs, 1H), 7.85(d,1H),
REFERENCE EXAMPLE 36
[0484] A mixture of 2-nitro4-trifluoromethoxybenzonitrile (8.7 g)
and a 55% sulphuric acid solution (46 ml) was heated under reflux
conditions for 2 hours, the mixture poured onto ice and extracted
with ether. The ether extracts were washed with water and
back-extracted with sodium hydroxide solution. Re-acidification of
this aqueous extract and subsequent extraction with ether gave a
solution which was dried (magnesium sulphate) and evaporated to
yield 2-nitro 4-trifluoromethoxybenzoic acid (8.5 g) as a cream
solid. NMR (d.sub.6 DMSO) 3.3(brs,1H), 7.8(m,1H), 8.05(d,1H),
8.15(m,1H),
REFERENCE EXAMPLE 37
[0485] A solution of 2-nitro-4-trifluoromethoxy-bromobenzene (2.0
g) in N,N-dimethylformamide (2 ml) was treated with copper (I)
cyanide (0.62 g) and the mixture heated at 150.degree. C. for 1
hour. Toluene (10 ml) was added and the mixture was maintained at
reflux for 1 hour. The mixture was filtered and the filtrate
evaporated to give a dark oil which was purified by chromatography
eluting with ethyl acetate/hexane (1:9) to give
2-nitro4-trifluoromethoxybenzonitrile (1.1 g) as a yellow liquid,
NMR (CDCl.sub.3) 7.65(m,1H), 8.0(d,1H), 8.15(m,1H),
REFERENCE EXAMPLE 38
[0486] Sodium hydride (4.6 g) in dry dioxan was stirred whilst
adding N-methylmethanesulphonamide (6.4 g). When the effervescence
had subsided, 2-chloro4,5-difluorobenzoic acid (10.0 g) was added
portionwise, followed by copper (I) chloride (1.7 g) and the
mixture heated under reflux conditions overnight. After evaporation
to dryness, hydrochloric acid (2N, 100 ml) was added and the ire
extracted with dichloromethane. The extract was dried (magnesium
sulphate) and evaporated to dryness. The residue was dissolved in
acetone, filtered and the filtrate evaporated and triturated with
ether to give 4,5-difluoro-2-(N-methyl-N-methylsulpho-
nyl)aminobenzoic acid, m.p.159.degree.-160.5.degree. C.
[0487] By proceeding in a similar manner the following compounds
were prepared:
[0488] 4-iodo-2-(N-methyl-N-methylsulphonyl)aminobenzoic acid, m.p.
174.degree.-175.degree. C. from 2-chloro-4-iodobenzoic acid;
[0489] 4-chloro-2-(N-methylsulphonylamino)benzoic acid, m.p.
188.degree.-192.degree. C. from 2-bromo4-chlorobenzoic acid,
employing copper (I) bromide and methanesulphonamide and 3
equivalents of sodium hydride;
[0490] 4-chloro-2-( N-methyl-N-isopropylsulphonyl)aminobenzoic
acid, m.p. 178.degree.-180.degree. C., from 2-bromo 4-chlorobenzoic
acid with copper (I) bromide and
N-methyl-isopropylsulphonamide;
[0491] 4-chloro-2-(N -methoxy-N-methylsulphonyl)aminobenzoic acid,
m.p. 159.degree.-160.degree. C., from 2-bromo4-chlorobenzoic acid
employing copper (I) bromide and N-methoxy-methanesulphonamide.
REFERENCE EXAMPLE 39
[0492] Thionyl chloride (21 ml) was added to methanol at 10.degree.
C. and the solution stirred for 0.5 hours before being added to
4-chloro-2-(methylsulphonylamino)benzoic acid (11.1 g). The mixture
was heated under reflux conditions for 2 days after which time a
further addition of thionyl chloride (6ml) was made and reflux
resumed for a further 2 days. The solvent was evaporated to
dryness, water added and the mixture extracted with ethyl acetate.
The extract was washed with sodium hydroxide solution (2N) then
with water, dried (magnesium sulphate) and evaporated to dryness to
give methyl 4-chloro-2-(methylsulphonylamino)benzoate (3.85 g) as a
cream solid, NMR (CDCl.sub.3) 3.25(s,3H), 3.9(s,3H), 73(dd,1H),
7.6(m,1H), 7.95(d,1H), 10.2(brs,1H),
REFERENCE EXAMPLE 40
[0493] A solution of the magnesium salt of t-butyl 3-cyclopropyl
3-oxopropanoate (1.85 g) in dry toluene was treated with a solution
of 4-chloro-2-(N-methyl-N-phenylsulphonyl)aminobenzoyl chloride
(3.19 g) in toluene (10 ml). After stirring overnight at ambient
temperature, trifluoroacetic acid (1.6 ml) was added and the
mixture stirred for 2 hours. The solution was washed (water), dried
(magnesium sulphate), evaporated to dryness and the residue
purified by chromatography eluting with dichloromethane. This gave
1-[4-chloro-2-(N-methyl-N-phenylsulphonyl-
)-amino]phenyl-3-cyclopropylpropan-1,3-dione (1.6 g) as an orange
oil, NMR (CDCl.sub.3) 1.0(m,2H), 1.25(m,2H), 2.15(m,1H), 3.1(s,3H),
5.25(s,2H), 6.4(dd,1H), 7.15-7.7(m,7H) (keto form).
[0494] By proceeding in a similar manner the following compounds
were prepared:
[0495]
1-[4-chloro-2-(N-benzylsulphonyl-N-methyl)amino]phenyl-3-cyclopropy-
lpropan-1,3-dione as an orange gum, NMR (CDCl.sub.3) 1.0(m,2H),
1.2(m,2H), 1.8(m,1H), 3.2(s,3H), 4.4(s,2H), 4.4(s,2H), 6.15(s,1H),
6.85(dd,1H), 7.45(m,7H), 16.0(brs,1H), enol form.
[0496]
1[4-chloro-2-(N-methyl-N-isopropylsulphonyl)amino]phenyl-3-cyclopro-
pylpropan-1,3-dione as an orange oil;
[0497] 1
-[4-chloro-2-(N-methoxy-N-methylsulphonyl)amino]phenyl-3-cyclopro-
pylpropan-1,3-dione, m.p. 84.degree.-88.degree. C.;
[0498]
1-[4-chloro-2-(N-isobutyl-N-methylsulphonyl)aminophenyl]-3-cyclopro-
pylpropan-1,3-dione, NMR (CDCl.sub.3) 0.9(broad m,6H), 1.05(m,2H),
1.25(m,2H), 1.8(m,1H), 2.1(broad m,1H), 3.05(s,3H), 3.38(broad
m,2H), 6.1(s,1H), 7.32(m,2H), 16.1(brs,1H), enol form;
[0499]
1-cyclopropyl-3-[3,4difluoro-2-(N-methyl-N-methylsulphonyl)amino]ph-
enylpropan-1,3-dione as an orange oil.
REFERENCE EXAMPLE 41
[0500] Magnesium (3.0 g) was stirred in methanol, carbon
tetrachloride (0.5ml) added and the mixture warmed at 50.degree. C.
until the metal had dissolved (1.5 hours). Tert-butyl
3-cyclopropyl-3-oxopropanoate (20.0 g) was then added dropwise and
the mixture heated under reflux conditions for 1 hour. The solvent
was evaporated and re-evaporated after addition of toluene to give
tert-butyl 3-cyclopropyl-3-oxopropanoate magnesium salt (29.9 g) as
a white solid, m.p.>300.degree. C., IR max (C=O) 1520, 1540;
(C-O) 1350 cm.
[0501] 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 isoxazole
derivative of formula (I). For this purpose, the isoxazole
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.
[0502] The compounds of formula (I) show herbicidal activity
against dicotyledonous (i.e. broad-leafed) and monocotyledonous
(i.e. 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:
[0503] broad-leafed weeds, for example, Abutilon theophrasti,
Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Galium
aparine, Ipomoea spp. e.g. Ipomoea purpurea, Sesbania exaltata,
Sinapis arvensis, Solanum nigrum and Xanthium strumarium, and
[0504] grass weeds, for example Alopecurus myosuroides, Avena
fatua, Digitaria sanguinalis, Echinochloa crus-galli, Sorghum
bicolor, Eleusine indica and Setaria spp, e.g. Setaria faberii or
Setaria viridis, and
[0505] sedges, for example, Cyperus esculentus.
[0506] 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 0.01 kg and 5 kg 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.
[0507] 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 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 0.01 kg and 4.0
kg, and preferably between 0.01 kg and 2.0 kg, of active material
per hectare are particularly suitable.
[0508] 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 0.25 kg and 5.0 kg, and preferably
between 0.5 kg and 4.0 kg of active material per hectare.
[0509] The compounds of formula (I) may also be used to control the
growth of weeds, especially those indicated above, at loci which
are not crop-growing areas but in which the control of weeds is
nevertheless desirable.
[0510] 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.
[0511] 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 1.0 kg and 20.0 kg, and preferably
between 5.0 and 10.0 kg, of active material per hectare are
particularly suitable for this purpose.
[0512] 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 (1) will also normally come into contact with
the soil and may also then exercise a pre-emergence control on
later-germinating weeds in the soil.
[0513] Where especially prolonged weed control is required, the
application of the compounds of formula (I) may be repeated if
required.
[0514] According to a further feature of the present invention,
there are provided compositions suitable for herbicidal use
comprising one or more of the isoxazole derivatives of formula (I),
in association with, and preferably homogeneously dispersed in, one
or more compatible agriculturally-acceptable diluents or carriers
and/or surface active agents [i.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 "homogeneously
dispersed" is used to include compositions in which the compounds
of formula (I) are dissolved in other components. The term
"herbicidal compositions" is used in a broad sense to include not
only compositions which are ready for use as herbicides but also
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).
[0515] 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 ammonium derivatives, products based on condensates of
ethylene oxide with allyl 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 condensation 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.
[0516] 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.
[0517] Examples of suitable solid diluents or carriers are
aluminium silicate, talc, calcined magnesia, kieselguhr, tricalcium
phosphate, powdered cork, absorbent 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.
[0518] Liquid 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, tetrahydrofurfuryl alcohol,
acetophenone, cyclohexanone, isophorone, toluene, xylene, mineral,
animal and vegetable oils and light 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.
[0519] 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.
[0520] 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 water to such
concentrates producing compositions ready for use.
[0521] Liquid concentrates in which the diluent or carrier is an
oil may be used without further dilution using the electrostatic
spray technique.
[0522] Herbicidal compositions according to the present invention
may also contain, if desired, conventional adjuvants such as
adhesives, protective colloids, thickeners, penetrating agents,
stabilisers, sequestering agents, anti-caking agents, colouring
agents and corrosion inhibitors. These adjuvants may also serve as
carriers or diluents.
[0523] Unless otherwise specified, the following percentages are by
weight. Preferred herbicidal compositions according to the present
invention are
[0524] 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;
[0525] 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;
[0526] water soluble or water dispersible powders which comprise
from 10 to 90% of one or more compounds of formula,(I), from 2 to
40% of sodium carbonate and from 0 to 88%G of solid diluent;
[0527] liquid water soluble concentrates which comprise from 5 to
50%, e.g. 10 to 30%, of one or more compounds of formula (I), from
5 to 25% of surface-active agent and from 25 to 90%, e.g. 45 to
85%, of water miscible solvent, e.g. dimethylformamide, or a
mixture of water-miscible solvent and water;
[0528] 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;
[0529] 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
[0530] 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.
[0531] Herbicidal compositions according to the present invention
may also comprise the 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-1,3,5-triazine], bromoxynil
[3,5-dibromo-4-hydroxybenzonitrile], chlortoluron
[N'-(3-chloro-4-methylp- henyl)-N,N-dimethylurea], cyanazine
[2-chloro-4-(1-cyano-1-
methylethylamino)-6-ethylamino-1,3,5-triazine], 2,4-D
[2,4-dichlorophenoxy-acetic acid], dicamba
[3,6-dichloro-2-methoxybenzoic acid], difenzoquat [1,2-
dimethyl-3,5-diphenyl-pyrazolium salts], flampropmethyl [methyl
N-2-(N- benzoyl-3-chloro4-fluoroanilino)-propionat- e], fluometuron
[N'-(3-trifluoro-methylphenyl)-N,N-dimethylurea], isoproturon
[N'-(4-isopropylphenyl)-N,N-dimethylurea], insecticides, e.g.
synthetic pyrethroids, e.g. permethrin and cypermethrin, and
fungicides, e.g. carbamates, e.g. methyl
N-(1-butyl-carbamoyl-benzimidazol-2-yl)carba- mate, and triazoles
e.g. 1-(4-chloro-phenoxy)-3,3-dimethyl-1-(1,2,4-triazo-
l-1-yl)-butan-2-one.
[0532] 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 utilized in the form of conventional derivatives, for example
alkali metal and amine salts and esters.
[0533] According to a further feature of the present invention
there is provided an article of manufacture comprising at least one
of the isoxazole derivatives 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 isoxazole derivatives of formula (I) within a
container for the aforesaid derivative or derivatives of formula
(I), or a said herbicidal composition, and instructions physically
associated with the aforesaid container setting out the manner in
which the aforesaid derivative or derivatives of formula (1) 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, boxes, for example of cardboard,
plastics materials and metal, or sacks. The containers will
normally be of sufficient capacity to contain amounts of the
isoxazole 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 0.01 kg and 20 kg of active material
per hectare in the manner and for the purposes hereinbefore
described.
[0534] The following Examples illustrate herbicidal compositions
according to the present invention:
EXAMPLE C1
[0535] A soluble concentrate is formed from:
6 Active ingredient (compound 1) 20% w/v Potassium hydroxide
solution 33% w/v 10% v/v Tetrahydrofurfuryl alcohol (THFA) 10% v/v
Water to 100 volumes.
[0536] by stirring THFA, active ingredient (compound 1 +L) and 90%
volume of water and slowly adding the potassium hydroxide solution
until a steady pH 7-8 is obtained then making up to volume with
water.
[0537] Similar soluble concentrates may be prepared as described
above by replacing the isoxazole (compound 1) with other compounds
of formula (I).
EXAMPLE C2
[0538] A wettable powder is formed from:
7 Active ingredient (compound 1) 50% w/w Sodium dodecylbenzene
sulphonate 3% w/w Sodium lignosulphate 5% w/w Sodium formaldehyde
alkylnaphthalene sulphonate 2% w/w Microfine silicon dioxide 3% w/w
and China clay 37% w/w
[0539] by blending the above ingredients together and grinding the
mixture in an air jet mill.
[0540] Similar wettable powders may be prepared as described above
by replacing the isoxazole (compound 1) with other compounds of
formula (I).
EXAMPLE C3
[0541] A water soluble powder is formed from:
8 Active ingredient (compound 1) 50% w/w Sodium
dodecylbenzenesulphonate 1% w/w Microfine silicon dioxide 2% w/w
Sodium bicarbonate 47% w/w
[0542] by mixing the above ingredients and grinding the above
mixture in a hammer mill.
[0543] Similar water soluble powders may be prepared as described
above by replacing the isoxazole (compound 1) with other compounds
of formula (I).
[0544] The compounds of the invention have been used in herbicidal
applications according to the following procedures.
[0545] METHOD OF USE OF HERBICIDAL COMPOUNDS:
[0546] a) General
[0547] Appropriate quantities of the compounds used to treat the
plants were dissolved in acetone to give solutions equivalent to
application rates of up to 4000 g test compound per hectare (g/ha).
These solutions were applied from a standard laboratory herbicide
sprayer delivering the equivalent of 290 liters of spray fluid per
hectare.
[0548] b) Weed control: Pre-emergence
[0549] 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:--
9 Approx number of seeds/pot Weed species 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 Setaria viridis 20 3) Sedges Cyperus esculentus 3
Crop 1) Broad-leafed Cotton 3 Soya 3 2) Grass Maize 2 Rice 6 Wheat
6
[0550] 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.
[0551] 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.
[0552] c) Weed control: Post-emergence
[0553] 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:--
10 Number of plants per pot Growth stage 1) Broad leafed weeds Weed
species Abutilon theophrasti 3 1-2 leaves Amaranthus retroflexus 4
1-2 leaves Galium aparine 3 1.sup.st whorl Ipomoea purpurea 3 1-2
leaves Sinapis arvensis 4 2 leaves Xanthium strumarium 1 2-3 leaves
2) Grass weeds Weed species 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) Sedges Weed species Cyperus
esculentus 3 3 leaves. 1) Broad leafed Crops Cotton 2 1 leaf Soya 2
2 leaves. 2) Grass Crops Maize 2 2-3 leaves Rice 4 2-3 leaves Wheat
5 2-3 leaves.
[0554] 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 allocated to each treatment, with unsprayed controls
and controls sprayed with acetone alone.
[0555] 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.
[0556] The compounds of the invention, used at 4 kg/ha or less,
have shown an excellent level of herbicidal activity together with
crop tolerance on the weeds used in the foregoing experiments.
[0557] When applied pre- or post-emergence at 1000 g/ha compounds 1
to 34 gave at least 90% reduction in growth of one or more of the
weed species.
* * * * *