U.S. patent application number 13/060219 was filed with the patent office on 2011-11-03 for insecticidal compounds.
This patent application is currently assigned to SYNGENTA CROP PROTECTION LLC. Invention is credited to Vladimir Bobosik, Jerome Yves Cassayre, Anne Jacqueline Dalencon, Myriem El Qacemi, Christopher Richard Ayles Godfrey, Pierre Joseph Marcel Jung, Jagadish Pabba, Thomas Pitterna, Peter Renold, Werner Zambach.
Application Number | 20110269804 13/060219 |
Document ID | / |
Family ID | 41078008 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269804 |
Kind Code |
A1 |
Cassayre; Jerome Yves ; et
al. |
November 3, 2011 |
INSECTICIDAL COMPOUNDS
Abstract
A compound of formula (I): ##STR00001## where A, B, C, G, m, n,
o, p, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are as defined in
claim 1; or a salt or N-oxide thereof. Furthermore, the present
invention relates to processes and intermediates for preparing
compounds of formula (I), to insecticidal, acaricidal, nematicidal
and molluscicidal compositions comprising the compounds of formula
(I) and to methods of using the compounds of formula (I) to control
insect, acarine, nematode and mollusc pests.
Inventors: |
Cassayre; Jerome Yves;
(Stein, CH) ; Renold; Peter; (Stein, CH) ;
Pitterna; Thomas; (Stein, CH) ; Bobosik;
Vladimir; (Bratislava, SK) ; El Qacemi; Myriem;
(Stein, CH) ; Dalencon; Anne Jacqueline;
(Berkshire, GB) ; Zambach; Werner; (Stein, CH)
; Godfrey; Christopher Richard Ayles; (Stein, CH)
; Jung; Pierre Joseph Marcel; (Stein, CH) ; Pabba;
Jagadish; (Goa, IN) |
Assignee: |
SYNGENTA CROP PROTECTION
LLC
Greensboro
NC
|
Family ID: |
41078008 |
Appl. No.: |
13/060219 |
Filed: |
July 24, 2009 |
PCT Filed: |
July 24, 2009 |
PCT NO: |
PCT/EP2009/059563 |
371 Date: |
May 9, 2011 |
Current U.S.
Class: |
514/362 ;
514/375; 514/378; 514/380; 514/422; 548/126; 548/217; 548/246;
548/248; 548/527 |
Current CPC
Class: |
C07D 409/12 20130101;
C07D 413/12 20130101; A01N 43/56 20130101; A01N 43/80 20130101;
C07D 413/14 20130101; A01N 43/82 20130101; A01N 43/36 20130101;
C07D 417/14 20130101; A01N 43/44 20130101; A01N 43/76 20130101 |
Class at
Publication: |
514/362 ;
548/246; 514/380; 548/248; 514/378; 548/527; 514/422; 548/217;
514/375; 548/126 |
International
Class: |
A01N 43/832 20060101
A01N043/832; A01N 43/80 20060101 A01N043/80; C07D 413/12 20060101
C07D413/12; C07D 409/12 20060101 C07D409/12; A01P 5/00 20060101
A01P005/00; A01N 43/76 20060101 A01N043/76; A01P 7/02 20060101
A01P007/02; A01P 7/04 20060101 A01P007/04; A01P 9/00 20060101
A01P009/00; C07D 413/14 20060101 C07D413/14; A01N 43/36 20060101
A01N043/36 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 22, 2008 |
GB |
0815437.9 |
Sep 4, 2008 |
GB |
0816133.3 |
Jan 14, 2009 |
GB |
0900561.2 |
Jan 22, 2009 |
IN |
127/DEL/2009 |
Jan 29, 2009 |
GB |
0901508.2 |
Mar 20, 2009 |
GB |
0904868.7 |
Mar 26, 2009 |
GB |
0905239.0 |
Apr 24, 2009 |
GB |
0907122.6 |
Jun 22, 2009 |
GB |
0910767.3 |
Jun 22, 2009 |
GB |
0910768.1 |
Jun 22, 2009 |
GB |
0910769.9 |
Jun 22, 2009 |
GB |
0910771.5 |
Claims
1. A compound of formula (I) ##STR00156## where A is aryl or
heteroaryl; B is a saturated or partially unsaturated heterocyclyl;
C is aryl or heteroaryl; G is oxygen or sulfur; m is 0, 1, 2, 3, 4
or 5; n is 0, 1, 2, 3, 4 or 5; o is 0, 1, 2, 3, 4 or 5; p is 1, 2,
3, 4 or 5; each R.sup.1 is independently C.sub.1-C.sub.8alkyl;
R.sup.2 is hydrogen, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8alkylcarbonyl-, or C.sub.1-C.sub.8alkoxycarbonyl-;
each R.sup.3 is independently halogen, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl,
C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, or
C.sub.1-C.sub.8alkoxycarbonyl-; each R.sup.4 is independently
halogen, cyano, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
hydroxy, C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl-, or
C.sub.1-C.sub.8haloalkylsulfonyl-, or if two R.sup.4 are attached
to the same carbon atom the two R.sup.4 together form .dbd.O,
.dbd.N--OR.sup.7 or .dbd.CR.sup.8R.sup.9; R.sup.5 is
C.sub.1-C.sub.8haloalkyl; each R.sup.6 is independently halogen,
cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-,
C.sub.1-C.sub.8alkoxycarbonyl-, C.sub.1-C.sub.8alkylthio-,
C.sub.1-C.sub.8haloalkylthio-, C.sub.1-C.sub.8alkylsulfinyl-,
C.sub.1-C.sub.8haloalkylsulfinyl-, C.sub.1-C.sub.8alkylsulfonyl-,
or C.sub.1-C.sub.8haloalkylsulfonyl-; X is S, SO, SO.sub.2,
S(NR.sup.10) or SO(NR.sup.10); R.sup.7 is hydrogen or
C.sub.1-C.sub.4alkyl; R.sup.8 and R.sup.9 are independently of each
other hydrogen or C.sub.1-C.sub.4alkyl; R.sup.10 is hydrogen,
cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.1-C.sub.8alkylcarbonyl-, C.sub.1-C.sub.8haloalkylcarbonyl-,
C.sub.1-C.sub.8alkoxycarbonyl-, C.sub.1-C.sub.8haloalkoxycarbonyl-,
C.sub.1-C.sub.8alkylsulfonyl-, C.sub.1-C.sub.8haloalkylsulfonyl-,
aryl-C.sub.1-C.sub.4alkylene- or aryl-C.sub.1-C.sub.4alkylene-
where the aryl moiety is substituted by one to three R.sup.11, or
heteroaryl-C.sub.1-C.sub.4alkylene- or
heteroaryl-C.sub.1-C.sub.4alkylene- where the heteroaryl moiety is
substituted by one to three R.sup.11, aryl or aryl substituted by
one to five R.sup.11, or heteroaryl or heteroaryl substituted by
one to five R.sup.11; and each R.sup.11 is independently halogen,
cyano, nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.1-C.sub.8alkoxy or C.sub.1-C.sub.8haloalkoxy, or
C.sub.1-C.sub.8alkoxycarbonyl-; or a salt or an N-oxide thereof;
provided that if A is a group of formula (A.I), (A.II), (A.III),
(A.IV) or (A.V) ##STR00157## where A.sup.1, A.sup.2, A.sup.3 and
A.sup.4 are independently of each other C--H or nitrogen; n is 0,
1, 2, 3, 4 or 5, and each R.sup.3 is independently halogen, cyano,
nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl,
C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, or
C.sub.1-C.sub.8alkoxycarbonyl-, B is not a group of formula (B.VI)
##STR00158## where R.sup.4a and R.sup.4b are both hydrogen.
2. A compound according to claim 1 where A is a group of formula
(A.I), (A.VI), (A.VII) or (A.VIII) ##STR00159## where A.sup.1,
A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are independently of
each other C--H or nitrogen; n is 0, 1, 2, 3, 4 or 5, and each
R.sup.3 is independently halogen, cyano, nitro,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8haloalkenyl,
C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-, or
C.sub.1-C.sub.8alkoxycarbonyl-.
3. A compound according to claim 1 where B is a group of formula
(B.I), (B.II), (B.III), (B.IV), (B.V), (B.VI) or (B.VII)
##STR00160## where R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d are
independently of each other hydrogen, halogen, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, hydroxy,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl-, or
C.sub.1-C.sub.8haloalkylsulfonyl-, o R.sup.4a and R.sup.4b and/or
R.sup.4c and R.sup.4d when attached to the same carbon atom
together form .dbd.O, N.dbd.OR.sup.7 or .dbd.CR.sup.8R.sup.9.
4. A compound according to claim 1 where C is a group of formula
(C.I) ##STR00161## where p is 1, 2, 3, 4 or 5; and each R.sup.6 is
independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, C.sub.1-C.sub.8alkoxycarbonyl-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl- or
C.sub.1-C.sub.8haloalkylsulfonyl-.
5. A method of controlling insects, acarines, nematodes or molluscs
which comprises applying to a pest, to a locus of a pest, or to a
plant susceptible to attack by a pest an insecticidally,
acaricidally, nematicidally or molluscicidally effective amount of
a compound of formula (I) as defined in claim 1.
6. An insecticidal, acaricidal, nematicidal or molluscicidal
composition comprising an insecticidally, acaricidally,
nematicidally or molluscicidally effective amount of a compound of
formula (I) as defined in claim 1.
Description
[0001] The present invention relates to certain tetracyclic
derivatives with a sulfur-containing four-membered ring connected
to the nitrogen atom of the amide group, to processes and
intermediates for preparing these derivatives, to insecticidal,
acaricidal, nematicidal and molluscicidal compositions comprising
these derivatives and to methods of using these derivatives to
control insect, acarine, nematode and mollusc pests.
[0002] Certain tetracyclic derivatives with a carbon only
four-membered ring connected to the nitrogen atom of the amide
group are disclosed in, for example, EP 1,731,512 and US
2007/066617 as having insecticidal properties. Certain tetracyclic
derivatives with a sulfur-containing four-membered ring connected
to the nitrogen atom of the amide group are disclosed in, for
example, PCT/EP2008/010701 as having insecticidal properties. The
compounds of PCT/EP2008/010701 have been excluded from the present
invention.
[0003] It has now been found that further tetracyclic derivatives
with a sulfur-containing four-membered ring connected to the
nitrogen atom of the amide group have insecticidal properties.
[0004] The present invention therefore provides a compound of
formula (I)
##STR00002##
where [0005] A is aryl or heteroaryl; [0006] B is a saturated or
partially unsaturated heterocyclyl; [0007] C is aryl or heteroaryl;
[0008] G is oxygen or sulfur; [0009] m is 0, 1, 2, 3, 4 or 5;
[0010] n is 0, 1, 2, 3, 4 or 5; [0011] o is 0, 1, 2, 3, 4 or 5;
[0012] p is 1, 2, 3, 4 or 5; [0013] each R.sup.1 is independently
C.sub.1-C.sub.8alkyl; [0014] R.sup.2 is hydrogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkylcarbonyl-, or
C.sub.1-C.sub.8alkoxycarbonyl-; [0015] each R.sup.3 is
independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl,
C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, or C.sub.1-C.sub.8alkoxycarbonyl-;
[0016] each R.sup.4 is independently halogen, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, hydroxy,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl-, or
C.sub.1-C.sub.8haloalkylsulfonyl-, or if two R.sup.4 are attached
to the same carbon atom the two R.sup.4 together form .dbd.O,
.dbd.N--OR.sup.7 or .dbd.CR.sup.8R.sup.9; [0017] R.sup.5 is
C.sub.1-C.sub.8haloalkyl; [0018] each R.sup.6 is independently
halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, C.sub.1-C.sub.8alkoxycarbonyl-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl-, or
C.sub.1-C.sub.8haloalkylsulfonyl-; [0019] X is S, SO, SO.sub.2,
S(NR.sup.10) or SO(NR.sup.10); [0020] R.sup.7 is hydrogen or
C.sub.1-C.sub.4alkyl; [0021] R.sup.8 and R.sup.9 are independently
of each other hydrogen or C.sub.1-C.sub.4alkyl; [0022] R.sup.10 is
hydrogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkylcarbonyl-,
C.sub.1-C.sub.8haloalkylcarbonyl-, C.sub.1-C.sub.8alkoxycarbonyl-,
C.sub.1-C.sub.8haloalkoxycarbonyl-, C.sub.1-C.sub.8alkylsulfonyl-,
C.sub.1-C.sub.8haloalkylsulfonyl-, aryl-C.sub.1-C.sub.4alkylene- or
aryl-C.sub.1-C.sub.4alkylene- where the aryl moiety is substituted
by one to three R.sup.11, or heteroaryl-C.sub.1-C.sub.4alkylene- or
heteroaryl-C.sub.1-C.sub.4alkylene- where the heteroaryl moiety is
substituted by one to three R.sup.11, aryl or aryl substituted by
one to five R.sup.11, or heteroaryl or heteroaryl substituted by
one to five R.sup.11; and [0023] each R.sup.11 is independently
halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkoxy or
C.sub.1-C.sub.8haloalkoxy, or C.sub.1-C.sub.8alkoxycarbonyl-;
[0024] or a salt or an N-oxide thereof; [0025] provided that if A
is a group of formula (A.I), (A.II), (A.III), (A.IV) or (A.V)
[0025] ##STR00003## [0026] where [0027] A.sup.1, A.sup.2, A.sup.3
and A.sup.4 are independently of each other C--H or nitrogen;
[0028] n is 0, 1, 2, 3, 4 or 5, and [0029] each R.sup.3 is
independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl,
C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, or C.sub.1-C.sub.8alkoxycarbonyl-,
[0030] B is not a group of formula (B.VI)
[0030] ##STR00004## [0031] where R.sup.4a and R.sup.4b are both
hydrogen.
[0032] The compounds of formula (I) may exist in different
geometric or optical isomers or tautomeric forms. This invention
covers all such isomers and tautomers and mixtures thereof in all
proportions as well as isotopic forms such as deuterated
compounds.
[0033] The compounds of the invention may contain one or more
asymmetric carbon atoms, and may exist as enantiomers (or as pairs
of diastereoisomers) or as mixtures of such.
[0034] Alkyl groups (either alone or as part of a larger group,
such as alkoxy-, alkylthio-, alkylsulfinyl-, alkylsulfonyl-,
alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight
or branched chain and are, for example, methyl, ethyl, propyl,
prop-2-yl, butyl, but-2-yl, 2-methyl-prop-1-yl or
2-methyl-prop-2-yl. The alkyl groups are, unless indicated to the
contrary, preferably C.sub.1-C.sub.6, more preferably
C.sub.1-C.sub.4, most preferably C.sub.1-C.sub.3 alkyl groups.
[0035] Alkylene groups can be in the form of a straight or branched
chain and are, for example, --CH.sub.2--, --CH.sub.2--CH.sub.2--,
--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH(CH.sub.3)--CH.sub.2--, or --CH(CH.sub.2CH.sub.3)--. The
alkylene groups are, unless indicated to the contrary, preferably
C.sub.1-C.sub.3, more preferably C.sub.1-C.sub.2, most preferably
C.sub.1 alkylene groups.
[0036] Alkenyl groups can be in the form of straight or branched
chains, and can be, where appropriate, of either the (E) or (Z)
configuration. Examples are vinyl and allyl. The alkenyl groups
are, unless indicated to the contrary, preferably C.sub.2-C.sub.6,
more preferably C.sub.2-C.sub.4, most preferably C.sub.2-C.sub.3
alkenyl groups.
[0037] Alkynyl groups can be in the form of straight or branched
chains. Examples are ethynyl and propargyl. The alkynyl groups are,
unless indicated to the contrary, preferably C.sub.2-C.sub.6, more
preferably C.sub.2-C.sub.4, most preferably C.sub.2-C.sub.3 alkynyl
groups.
[0038] Halogen is fluorine, chlorine, bromine or iodine.
[0039] Haloalkyl groups (either alone or as part of a larger group,
such as haloalkoxy-, haloalkylthio-, haloalkylsulfinyl-,
haloalkylsulfonyl-, haloalkylcarbonyl- or haloalkoxycarbonyl-) are
alkyl groups which are substituted by one or more of the same or
different halogen atoms and are, for example, difluoromethyl,
trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
[0040] Haloalkenyl groups are alkenyl groups which are substituted
by one or more of the same or different halogen atoms and are, for
example, 2,2-difluoro-vinyl or 1,2-dichloro-2-fluoro-vinyl.
[0041] Haloalkynyl groups are alkynyl groups which are substituted
by one or more of the same or different halogen atoms and are, for
example, 1-chloro-prop-2-ynyl.
[0042] Cycloalkyl groups or carbocyclic rings can be in mono- or
bi-cyclic form and are, for example, cyclopropyl, cyclobutyl,
cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups,
unless indicated to the contrary, are preferably C.sub.3-C.sub.8,
more preferably C.sub.3-C.sub.6 cycloalkyl groups.
[0043] Aryl groups are aromatic ring systems which can be in mono,
bi or tricyclic form. Examples of such rings include phenyl,
naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl
groups are phenyl and naphthyl, phenyl being most preferred. Where
an aryl moiety is said to be substituted, the aryl moiety is,
unless indicated to the contrary, preferably substituted by one to
four substituents, most preferably by one to three
substituents.
[0044] Heteroaryl groups are aromatic ring system containing at
least one heteroatom and consisting either of a single ring or of
two or more fused rings. Preferably, single rings will contain up
to three heteroatoms and bicyclic systems up to four heteroatoms
which will preferably be chosen from nitrogen, oxygen and sulfur.
Examples of monocyclic groups include pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl and thiadiazolyl. Examples of bicyclic groups include
quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl,
benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic
heteroaryl groups are preferred, pyridyl being most preferred.
Where a heteroaryl moiety is said to be substituted, the heteroaryl
moiety is, unless indicated to the contrary, preferably substituted
by one to four substituents, most preferably by one to three
substituents.
[0045] Heterocyclyl groups or heterocyclic rings are defined to
include heteroaryl groups and in addition their unsaturated or
partially unsaturated analogues. Examples of monocyclic groups
include thietanyl, pyrrolidinyl, tetrahydrofuranyl,
[1,3]dioxolanyl, piperidinyl, piperazinyl, [1,4]dioxanyl, and
morpholinyl or their oxidised versions such as 1-oxo-thietanyl and
1,1-dioxo-thietanyl. Examples of bicyclic groups include
2,3-dihydro-benzofuranyl, benzo[1,3]dioxolanyl, and
2,3-dihydro-benzo[1,4]dioxinyl. Where a heterocyclyl moiety is said
to be substituted, the heterocyclyl moiety is, unless indicated to
the contrary, preferably substituted by one to four substituents,
most preferably by one to three substituents.
[0046] Preferred values for A, A.sup.1, A.sup.2, A.sup.3, A.sup.4,
A.sup.5, A.sup.6, B, C, G, m, n, o, p, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, X, R.sup.7, R.sup.8, R.sup.9, R.sup.10
and R.sup.11 are, in any combination, as set out below.
[0047] Preferably A is a phenyl or a naphthyl group, or a
six-membered monocyclic heteroaryl group, or a bicyclic heteroaryl
group which comprises a six-membered ring. More preferably A is a
phenyl or a naphthyl group. Where A is bicyclic it is preferred
that the B ring and the amide group are connected to the same
six-membered ring moiety. Furthermore it is preferred that the B
ring and the amide group are attached to in para-position (as shown
in the groups of formula (A.I), (A.VI) and (A.VIII) below).
[0048] Preferably A is a group of formula (A.I), (A.VI), (A.VII) or
(A.VIII)
##STR00005##
where [0049] A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and
A.sup.6 are independently of each other C--H or nitrogen; [0050] n
is 0, 1, 2, 3, 4 or 5, and [0051] each R.sup.3 is independently
halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.2-C.sub.8alkenyl,
C.sub.2-C.sub.8haloalkenyl, C.sub.2-C.sub.8alkynyl,
C.sub.3-C.sub.10cycloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, or C.sub.1-C.sub.8alkoxycarbonyl-.
[0052] Preferably no more than two of A.sup.1, A.sup.2, A.sup.3,
A.sup.4, A.sup.5 and A.sup.6 are nitrogen.
[0053] Preferably A.sup.1 is C--H.
[0054] Preferably A.sup.2 is C--H.
[0055] Preferably A.sup.3 is C--H.
[0056] Preferably A.sup.4 is C--H.
[0057] Preferably A.sup.5 is C--H.
[0058] Preferably A.sup.6 is C--H.
[0059] More preferably A is a group of formula (A.Ia), (A.VIa),
(A.VIIa) or (A.VIIIa)
##STR00006##
[0060] Preferably B is a three- to five-membered saturated or
partially unsaturated heterocyclyl group. More preferably B is a
five-membered saturated or partially unsaturated heterocyclyl
group.
[0061] Preferably B is a group of formula (B.I), (B.II), (B.III),
(B.IV), (B.V), (B.VI) or (B.VII)
##STR00007##
where [0062] R.sup.4a, R.sup.4b, R.sup.4c and R.sup.4d are
independently of each other hydrogen, halogen, cyano,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl, hydroxy,
C.sub.1-C.sub.8alkoxy-, C.sub.1-C.sub.8haloalkoxy-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8-alkylsulfonyl-, or
C.sub.1-C.sub.8haloalkylsulfonyl-, or [0063] R.sup.4a and R.sup.4b
and/or R.sup.4c and R.sup.4d when attached to the same carbon atom
together form .dbd.O, N.dbd.OR.sup.7 or .dbd.CR.sup.8R.sup.9.
[0064] More preferably B is a group of formula (B.Ia), (B.IIa),
(B.IIIa), (B.IVa), (B.Va), (B.VIa) or (B.VIIa)
##STR00008##
where R.sup.12 is halogen.
[0065] Preferably C is a six-membered aryl or heteroaryl group.
[0066] Preferably C is a group of formula (C.I)
##STR00009##
where [0067] p is 1, 2, 3, 4 or 5; and [0068] each R.sup.6 is
independently halogen, cyano, nitro, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8haloalkyl, C.sub.1-C.sub.8alkoxy-,
C.sub.1-C.sub.8haloalkoxy-, C.sub.1-C.sub.8alkoxycarbonyl-,
C.sub.1-C.sub.8alkylthio-, C.sub.1-C.sub.8haloalkylthio-,
C.sub.1-C.sub.8alkylsulfinyl-, C.sub.1-C.sub.8haloalkylsulfinyl-,
C.sub.1-C.sub.8alkylsulfonyl- or
C.sub.1-C.sub.8haloalkylsulfonyl-.
[0069] More preferably C is a group of formula (C.Ia)
##STR00010##
[0070] Preferably G is oxygen.
[0071] Preferably m is 0, 1, 2, 3 or 4.
[0072] Preferably n is 0, 1 or 2.
[0073] Preferably o is 0, 1 or 2.
[0074] Preferably p is 1, 2 or 3.
[0075] Preferably each R.sup.1 is independently methyl.
[0076] Preferably R.sup.2 is hydrogen, methyl, ethyl,
methylcarbonyl- or methoxycarbonyl-, more preferably hydrogen,
methyl or ethyl, most preferably hydrogen.
[0077] Preferably each R.sup.3 is independently halogen, cyano,
C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl or
C.sub.1-C.sub.8alkoxy-, more preferably each R.sup.3 is
independently methyl.
[0078] Preferably each R.sup.4 is independently halogen,
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8alkylthio-,
C.sub.1-C.sub.8alkylsulfinyl- or C.sub.1-C.sub.8alkylsulfonyl-,
or
[0079] if two R.sup.4 are attached to the same carbon atom the two
R.sup.4 together form .dbd.O or .dbd.CR.sup.8R.sup.9.
[0080] Preferably R.sup.5 is chlorodifluoromethyl or
trifluoromethyl, most preferably trifluoromethyl.
[0081] Preferably each R.sup.6 is independently halogen, cyano,
nitro, C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8haloalkyl,
C.sub.1-C.sub.8alkoxy-, .sub.1-C.sub.8alkylthio-,
C.sub.1-C.sub.8alkylsulfinyl- or C.sub.1-C.sub.8alkylsulfonyl-.
[0082] Preferably X is S, SO or SO.sub.2.
[0083] Preferably R.sup.7 is hydrogen.
[0084] Preferably R.sup.8 and R.sup.9 are independently of each
other hydrogen or methyl.
[0085] Preferably R.sup.10 is hydrogen or cyano, more preferably
hydrogen.
[0086] Preferably each R.sup.11 is independently fluoro, chloro,
cyano, nitro, methyl, trifluoromethyl, methoxy or
trifluoromethoxy.
[0087] The compounds of the invention may be made by a variety of
methods, for example, as shown in Scheme 1.
##STR00011##
[0088] 1) A compound of formula (I) where G is oxygen, can be made
by reacting a compound of formula (III) where A, B, C, n, o, p,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined for a compound
of formula (I), G is oxygen and R is OH, C.sub.1-C.sub.8alkoxy, or
Br, Cl or F, with an amine of formula (II) where m, R.sup.1,
R.sup.2 and X are as defined for a compound of formula (I). When R
is OH, such reactions are usually carried out in the presence of a
coupling reagent, such as N,N'-dicyclohexylcarbodiimide ("DCC"),
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride
("EDC") or bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl"),
in the presence of a base, and optionally in the presence of a
nucleophilic catalyst. When R is Br, Cl or F, such reactions are
usually carried out in the presence of a base, and optionally in
the presence of a nucleophilic catalyst. Alternatively, when R is
Cl it is possible to conduct the reaction in a biphasic system
comprising an organic solvent, preferably ethyl acetate, and an
aqueous solvent, preferably a solution of sodium hydrogen
carbonate. When R is C.sub.1-C.sub.8alkoxy, it is sometimes
possible to convert the ester directly to the amide by heating the
ester and amine together in a thermal process. Suitable bases
include pyridine, triethylamine, 4-(dimethylamino)-pyridine
("DMAP") or diisopropylethylamine (Hunig's base). Suitable
nucleophilic catalysts include hydroxybenzotriazole ("HOBT").
Suitable solvents include dimethylacetamide, tetrahydrofuran,
dioxane, 1,2-dimethoxyethane, ethyl acetate and toluene. When R is
OH, the reaction is carried out preferably at a temperature of from
-20.degree. C. to +200.degree. C., more preferably from 50.degree.
C. to 150.degree. C., in particular at 100.degree. C. is Br, Cl or
F, the reaction is carried out preferably at a temperature of from
-20.degree. C. to +50.degree. C., more preferably from 0.degree. C.
to 50.degree. C., in particular at ambient temperature. Amines of
formula (II) are known from the literature (for example, from WO
2007/080131) or can be made by methods known to a person skilled in
the art.
[0089] 2) Compounds of formula (I) where G is sulfur, can be made
by reacting a compound of formula (III) where A, B, C, n, o, p,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined for a compound
of formula (I), G is oxygen and R is OH, C.sub.1-C.sub.8alkoxy, or
Br, Cl or F, with a thio-transfer reagent, such as Lawesson's
reagent or phosphorus pentasulfide, prior to reacting with the
amine of formula (II) as described under 1).
[0090] The compounds of formula (I) can be used to control
infestations of insect pests such as Lepidoptera, Diptera,
Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera,
Siphonaptera, Hymenoptera and Isoptera and also other invertebrate
pests, for example, acarine, nematode and mollusc pests. Insects,
acarines, nematodes and molluscs are hereinafter collectively
referred to as pests. The pests which may be controlled by the use
of the invention compounds include those pests associated with
agriculture (which term includes the growing of crops for food and
fiber products), horticulture and animal husbandry, companion
animals, forestry and the storage of products of vegetable origin
(such as fruit, grain and timber); those pests associated with the
damage of man-made structures and the transmission of diseases of
man and animals; and also nuisance pests (such as flies).
[0091] Examples of pest species which may be controlled by the
compounds of formula (I) include: Myzus persicae (aphid), Aphis
gossypii (aphid), Aphis fabae (aphid), Lygus spp. (capsids),
Dysdercus spp. (capsids), Nilaparvata lugens (planthopper),
Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs),
Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs),
Frankliniella occidentalis (thrip), Thrips spp. (thrips),
Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus
grandis (boll weevil), Aonidiella spp. (scale insects),
Trialeurodes spp. (white flies), Bemisia tabaci (white fly),
Ostrinia nubilalis (European corn borer), Spodoptera littoralis
(cotton leafworm), Heliothis virescens (tobacco budworm),
Helicoverpa armigera (cotton bollworm), Helicoverpa zea (cotton
bollworm), Sylepta derogata (cotton leaf roller), Pieris brassicae
(white butterfly), Plutella xylostella (diamond back moth), Agrotis
spp. (cutworms), Chilo suppressalis (rice stem borer), Locusta
migratoria (locust), Chortiocetes terminifera (locust), Diabrotica
spp. (rootworms), Panonychus ulmi (European red mite), Panonychus
citri (citrus red mite), Tetranychus urticae (two-spotted spider
mite), Tetranychus cinnabarinus (carmine spider mite),
Phyllocoptruta oleivora (citrus rust mite), Polyphagotarsonemus
latus (broad mite), Brevipalpus spp. (flat mites), Boophilus
microplus (cattle tick), Dermacentor variabilis (American dog
tick), Ctenocephalides felis (cat flea), Liriomyza spp.
(leafminer), Musca domestica (housefly), Aedes aegypti (mosquito),
Anopheles spp. (mosquitoes), Culex spp. (mosquitoes), Lucillia spp.
(blowflies), Blattella germanica (cockroach), Periplaneta americana
(cockroach), Blatta orientalis (cockroach), termites of the
Mastotermitidae (for example Mastotermes spp.), the Kalotermitidae
(for example Neotermes spp.), the Rhinotermitidae (for example
Coptotermes formosanus, Reticulitermes flavipes, R. speratu, R.
virginicus, R. hesperus, and R. santonensis) and the Termitidae
(for example Globitermes sulfureus), Solenopsis geminata (fire
ant), Monomorium pharaonis (pharaoh's ant), Damalinia spp. and
Linognathus spp. (biting and sucking lice), Meloidogyne spp. (root
knot nematodes), Globodera spp. and Heterodera spp. (cyst
nematodes), Pratylenchus spp. (lesion nematodes), Rhodopholus spp.
(banana burrowing nematodes), Tylenchulus spp. (citrus nematodes),
Haemonchus contortus (barber pole worm), Caenorhabditis elegans
(vinegar eelworm), Trichostrongylus spp. (gastro intestinal
nematodes) and Deroceras reticulatum (slug).
[0092] The invention therefore provides a method of controlling
insects, acarines, nematodes or molluscs which comprises applying
an insecticidally, acaricidally, nematicidally or molluscicidally
effective amount of a compound of formula (I), or a composition
containing a compound of formula (I), to a pest, a locus of pest,
preferably a plant, or to a plant susceptible to attack by a pest.
The compounds of formula (I) are preferably used against insects or
acarines.
[0093] The term "plant" as used herein includes seedlings, bushes
and trees.
[0094] Crops are to be understood as also including those crops
which have been rendered tolerant to herbicides or classes of
herbicides (e.g. ALS-, GS-, EPSPS-, PPO- and HPPD-inhibitors) by
conventional methods of breeding or by genetic engineering. An
example of a crop that has been rendered tolerant to
imidazolinones, e.g. imazamox, by conventional methods of breeding
is Clearfield.RTM. summer rape (canola). Examples of crops that
have been rendered tolerant to herbicides by genetic engineering
methods include e.g. glyphosate- and glufosinate-resistant maize
varieties commercially available under the trade names
RoundupReady.RTM. and LibertyLink.RTM..
[0095] Crops are also to be understood as being those which have
been rendered resistant to harmful insects by genetic engineering
methods, for example Bt maize (resistant to European corn borer),
Bt cotton (resistant to cotton boll weevil) and also Bt potatoes
(resistant to Colorado beetle). Examples of Bt maize are the Bt 176
maize hybrids of NK.RTM. (Syngenta Seeds). Examples of transgenic
plants comprising one or more genes that code for an insecticidal
resistance and express one or more toxins are KnockOut.RTM.
(maize), Yield Gard.RTM. (maize), NuCOTIN33B.RTM. (cotton),
Bollgard.RTM. (cotton), NewLeaf.RTM. (potatoes), NatureGard.RTM.
and Protexcta.RTM..
[0096] Plant crops or seed material thereof can be both resistant
to herbicides and, at the same time, resistant to insect feeding
("stacked" transgenic events). For example, seed can have the
ability to express an insecticidal Cry3 protein while at the same
time being tolerant to glyphosate.
[0097] Crops are also to be understood as being those which are
obtained by conventional methods of breeding or genetic engineering
and contain so-called output traits (e.g. improved storage
stability, higher nutritional value and improved flavor).
[0098] In order to apply a compound of formula (I) as an
insecticide, acaricide, nematicide or molluscicide to a pest, a
locus of pest, or to a plant susceptible to attack by a pest, a
compound of formula (I) is usually formulated into a composition
which includes, in addition to the compound of formula (I), a
suitable inert diluent or carrier and, optionally, a surface active
agent (SFA). SFAs are chemicals which are able to modify the
properties of an interface (for example, liquid/solid, liquid/air
or liquid/liquid interfaces) by lowering the interfacial tension
and thereby leading to changes in other properties (for example
dispersion, emulsification and wetting). It is preferred that all
compositions (both solid and liquid formulations) comprise, by
weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to
60%, of a compound of formula (I). The composition is generally
used for the control of pests such that a compound of formula (I)
is applied at a rate of from 0.1 g 10 kg per hectare, preferably
from 1 g to 6 kg per hectare, more preferably from 1 g to 1 kg per
hectare.
[0099] When used in a seed dressing, a compound of formula (I) is
used at a rate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g),
preferably 0.005 g to 10 g, more preferably 0.005 g to 4 g, per
kilogram of seed.
[0100] In another aspect the present invention provides an
insecticidal, acaricidal, nematicidal or molluscicidal composition
comprising an insecticidally, acaricidally, nematicidally or
molluscicidally effective amount of a compound of formula (I) and a
suitable carrier or diluent therefor. The composition is preferably
an insecticidal or acaricidal composition.
[0101] The compositions can be chosen from a number of formulation
types, including dustable powders (DP), soluble powders (SP), water
soluble granules (SG), water dispersible granules (WG), wettable
powders (WP), granules (GR) (slow or fast release), soluble
concentrates (SL), oil miscible liquids (OL), ultra low volume
liquids (UL), emulsifiable concentrates (EC), dispersible
concentrates (DC), emulsions (both oil in water (EW) and water in
oil (EO)), micro-emulsions (ME), suspension concentrates (SC),
aerosols, fogging/smoke formulations, capsule suspensions (CS) and
seed treatment formulations. The formulation type chosen in any
instance will depend upon the particular purpose envisaged and the
physical, chemical and biological properties of the compound of
formula (I).
[0102] Dustable powders (DP) may be prepared by mixing a compound
of formula (I) with one or more solid diluents (for example natural
clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite,
kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium
and magnesium carbonates, sulfur, lime, flours, talc and other
organic and inorganic solid carriers) and mechanically grinding the
mixture to a fine powder.
[0103] Soluble powders (SP) may be prepared by mixing a compound of
formula (I) with one or more water-soluble inorganic salts (such as
sodium bicarbonate, sodium carbonate or magnesium sulfate) or one
or more water-soluble organic solids (such as a polysaccharide)
and, optionally, one or more wetting agents, one or more dispersing
agents or a mixture of said agents to improve water
dispersibility/solubility. The mixture is then ground to a fine
powder. Similar compositions may also be granulated to form water
soluble granules (SG).
[0104] Wettable powders (WP) may be prepared by mixing a compound
of formula (I) with one or more solid diluents or carriers, one or
more wetting agents and, preferably, one or more dispersing agents
and, optionally, one or more suspending agents to facilitate the
dispersion in liquids. The mixture is then ground to a fine powder.
Similar compositions may also be granulated to form water
dispersible granules (WG).
[0105] Granules (GR) may be formed either by granulating a mixture
of a compound of formula (I) and one or more powdered solid
diluents or carriers, or from pre-formed blank granules by
absorbing a compound of formula (I) (or a solution thereof, in a
suitable agent) in a porous granular material (such as pumice,
attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths
or ground corn cobs) or by adsorbing a compound of formula (I) (or
a solution thereof, in a suitable agent) on to a hard core material
(such as sands, silicates, mineral carbonates, sulfates or
phosphates) and drying if necessary. Agents which are commonly used
to aid absorption or adsorption include solvents (such as aliphatic
and aromatic petroleum solvents, alcohols, ethers, ketones and
esters) and sticking agents (such as polyvinyl acetates, polyvinyl
alcohols, dextrins, sugars and vegetable oils). One or more other
additives may also be included in granules (for example an
emulsifying agent, wetting agent or dispersing agent).
[0106] Dispersible Concentrates (DC) may be prepared by dissolving
a compound of formula (I) in water or an organic solvent, such as a
ketone, alcohol or glycol ether. These solutions may contain a
surface active agent (for example to improve water dilution or
prevent crystallization in a spray tank).
[0107] Emulsifiable concentrates (EC) or oil-in-water emulsions
(EW) may be prepared by dissolving a compound of formula (I) in an
organic solvent (optionally containing one or more wetting agents,
one or more emulsifying agents or a mixture of said agents).
Suitable organic solvents for use in ECs include aromatic
hydrocarbons (such as alkylbenzenes or alkylnaphthalenes,
exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200;
SOLVESSO is a Registered Trade Mark), ketones (such as
cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl
alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as
N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of
fatty acids (such as C.sub.8-C.sub.10 fatty acid dimethylamide) and
chlorinated hydrocarbons. An EC product may spontaneously emulsify
on addition to water, to produce an emulsion with sufficient
stability to allow spray application through appropriate equipment.
Preparation of an EW involves obtaining a compound of formula (I)
either as a liquid (if it is not a liquid at room temperature, it
may be melted at a reasonable temperature, typically below
70.degree. C.) or in solution (by dissolving it in an appropriate
solvent) and then emulsifiying the resultant liquid or solution
into water containing one or more SFAs, under high shear, to
produce an emulsion. Suitable solvents for use in EWs include
vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes),
aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and
other appropriate organic solvents which have a low solubility in
water.
[0108] Microemulsions (ME) may be prepared by mixing water with a
blend of one or more solvents with one or more SFAs, to produce
spontaneously a thermodynamically stable isotropic liquid
formulation. A compound of formula (I) is present initially in
either the water or the solvent/SFA blend. Suitable solvents for
use in MEs include those hereinbefore described for use in ECs or
in EWs. An ME may be either an oil-in-water or a water-in-oil
system (which system is present may be determined by conductivity
measurements) and may be suitable for mixing water-soluble and
oil-soluble pesticides in the same formulation. An ME is suitable
for dilution into water, either remaining as a microemulsion or
forming a conventional oil-in-water emulsion.
[0109] Suspension concentrates (SC) may comprise aqueous or
non-aqueous suspensions of finely divided insoluble solid particles
of a compound of formula (I). SCs may be prepared by ball or bead
milling the solid compound of formula (I) in a suitable medium,
optionally with one or more dispersing agents, to produce a fine
particle suspension of the compound. One or more wetting agents may
be included in the composition and a suspending agent may be
included to reduce the rate at which the particles settle.
Alternatively, a compound of formula (I) may be dry milled and
added to water, containing agents hereinbefore described, to
produce the desired end product.
[0110] Aerosol formulations comprise a compound of formula (I) and
a suitable propellant (for example n-butane). A compound of formula
(I) may also be dissolved or dispersed in a suitable medium (for
example water or a water miscible liquid, such as n-propanol) to
provide compositions for use in non-pressurized, hand-actuated
spray pumps.
[0111] A compound of formula (I) may be mixed in the dry state with
a pyrotechnic mixture to form a composition suitable for
generating, in an enclosed space, a smoke containing the
compound.
[0112] Capsule suspensions (CS) may be prepared in a manner similar
to the preparation of EW formulations but with an additional
polymerization stage such that an aqueous dispersion of oil
droplets is obtained, in which each oil droplet is encapsulated by
a polymeric shell and contains a compound of formula (I) and,
optionally, a carrier or diluent therefor. The polymeric shell may
be produced by either an interfacial polycondensation reaction or
by a coacervation procedure. The compositions may provide for
controlled release of the compound of formula (I) and they may be
used for seed treatment. A compound of formula (I) may also be
formulated in a biodegradable polymeric matrix to provide a slow,
controlled release of the compound.
[0113] A composition may include one or more additives to improve
the biological performance of the composition (for example by
improving wetting, retention or distribution on surfaces;
resistance to rain on treated surfaces; or uptake or mobility of a
compound of formula (I)). Such additives include surface active
agents, spray additives based on oils, for example certain mineral
oils or natural plant oils (such as soy bean and rape seed oil),
and blends of these with other bio-enhancing adjuvants (ingredients
which may aid or modify the action of a compound of formula
(I)).
[0114] A compound of formula (I) may also be formulated for use as
a seed treatment, for example as a powder composition, including a
powder for dry seed treatment (DS), a water soluble powder (SS) or
a water dispersible powder for slurry treatment (WS), or as a
liquid composition, including a flowable concentrate (FS), a
solution (LS) or a capsule suspension (CS). The preparations of DS,
SS, WS, FS and LS compositions are very similar to those of,
respectively, DP, SP, WP, SC and DC compositions described above.
Compositions for treating seed may include an agent for assisting
the adhesion of the composition to the seed (for example a mineral
oil or a film-forming barrier).
[0115] Wetting agents, dispersing agents and emulsifying agents may
be surface SFAs of the cationic, anionic, amphoteric or non-ionic
type.
[0116] Suitable SFAs of the cationic type include quaternary
ammonium compounds (for example cetyltrimethyl ammonium bromide),
imidazolines and amine salts.
[0117] Suitable anionic SFAs include alkali metals salts of fatty
acids, salts of aliphatic monoesters of sulfuric acid (for example
sodium lauryl sulfate), salts of sulfonated aromatic compounds (for
example sodium dodecylbenzenesulfonate, calcium
dodecylbenzenesulfonate, butylnaphthalene sulfonate and mixtures of
sodium di-isopropyl- and tri-isopropyl-naphthalene sulfonates),
ether sulfates, alcohol ether sulfates (for example sodium
laureth-3-sulfate), ether carboxylates (for example sodium
laureth-3-carboxylate), phosphate esters (products from the
reaction between one or more fatty alcohols and phosphoric acid
(predominately mono-esters) or phosphorus pentoxide (predominately
di-esters), for example the reaction between lauryl alcohol and
tetraphosphoric acid; additionally these products may be
ethoxylated), sulfosuccinamates, paraffin or olefine sulfonates,
taurates and lignosulfonates.
[0118] Suitable SFAs of the amphoteric type include betaines,
propionates and glycinates.
[0119] Suitable SFAs of the non-ionic type include condensation
products of alkylene oxides, such as ethylene oxide, propylene
oxide, butylene oxide or mixtures thereof, with fatty alcohols
(such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such
as octylphenol, nonylphenol or octylcresol); partial esters derived
from long chain fatty acids or hexitol anhydrides; condensation
products of said partial esters with ethylene oxide; block polymers
(comprising ethylene oxide and propylene oxide); alkanolamides;
simple esters (for example fatty acid polyethylene glycol esters);
amine oxides (for example lauryl dimethyl amine oxide); and
lecithins.
[0120] Suitable suspending agents include hydrophilic colloids
(such as polysaccharides, polyvinylpyrrolidone or sodium
carboxymethylcellulose) and swelling clays (such as bentonite or
attapulgite).
[0121] A compound of formula (I) may be applied by any of the known
means of applying pesticidal compounds. For example, it may be
applied, formulated or unformulated, to the pests or to a locus of
the pests (such as a habitat of the pests, or a growing plant
liable to infestation by the pests) or to any part of the plant,
including the foliage, stems, branches or roots, to the seed before
it is planted or to other media in which plants are growing or are
to be planted (such as soil surrounding the roots, the soil
generally, paddy water or hydroponic culture systems), directly or
it may be sprayed on, dusted on, applied by dipping, applied as a
cream or paste formulation, applied as a vapor or applied through
distribution or incorporation of a composition (such as a granular
composition or a composition packed in a water-soluble bag) in soil
or an aqueous environment.
[0122] A compound of formula (I) may also be injected into plants
or sprayed onto vegetation using electrodynamic spraying techniques
or other low volume methods, or applied by land or aerial
irrigation systems.
[0123] Compositions for use as aqueous preparations (aqueous
solutions or dispersions) are generally supplied in the form of a
concentrate containing a high proportion of the active ingredient,
the concentrate being added to water before use. These
concentrates, which may include DCs, SCs, ECs, EWs, MEs, SGs, SPs,
WPs, WGs and CSs, are often required to withstand storage for
prolonged periods and, after such storage, to be capable of
addition to water to form aqueous preparations which remain
homogeneous for a sufficient time to enable them to be applied by
conventional spray equipment. Such aqueous preparations may contain
varying amounts of a compound of formula (I) (for example 0.0001 to
10%, by weight) depending upon the purpose for which they are to be
used.
[0124] A compound of formula (I) may be used in mixtures with
fertilizers (for example nitrogen-, potassium- or
phosphorus-containing fertilizers). Suitable formulation types
include granules of fertilizer. The mixtures preferably contain up
to 25% by weight of the compound of formula (I).
[0125] The invention therefore also provides a fertilizer
composition comprising a fertilizer and a compound of formula
(I).
[0126] The compositions of this invention may contain other
compounds having biological activity, for example micronutrients or
compounds having fungicidal activity or which possess plant growth
regulating, herbicidal, insecticidal, nematicidal or acaricidal
activity.
[0127] The compound of formula (I) may be the sole active
ingredient of the composition or it may be admixed with one or more
additional active ingredients such as a pesticide, fungicide,
synergist, herbicide or plant growth regulator where appropriate.
An additional active ingredient may: provide a composition having a
broader spectrum of activity or increased persistence at a locus;
synergize the activity or complement the activity (for example by
increasing the speed of effect or overcoming repellency) of the
compound of formula (I); or help to overcome or prevent the
development of resistance to individual components. The particular
additional active ingredient will depend upon the intended utility
of the composition. Examples of suitable pesticides include the
following: [0128] a) Pyrethroids, such as permethrin, cypermethrin,
fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in
particular lambda-cyhalothrin), bifenthrin, fenpropathrin,
cyfluthrin, tefluthrin, fish safe pyrethroids (for example
ethofenprox), natural pyrethrin, tetramethrin, S-bioallethrin,
fenfluthrin, prallethrin or
5-benzyl-3-furylmethyl-(E)-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidene-
methyl)cyclopropane carboxylate; [0129] b) Organophosphates, such
as profenofos, sulprofos, acephate, methyl parathion,
azinphos-methyl, demeton-s-methyl, heptenophos, thiometon,
fenamiphos, monocrotophos, profenofos, triazophos, methamidophos,
dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone,
terbufos, fensulfothion, fonofos, phorate, phoxim,
pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or
diazinon; [0130] c) Carbamates (including aryl carbamates), such as
pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb,
ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb,
fenobucarb, propoxur, methomyl or oxamyl; [0131] d) Benzoyl ureas,
such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron or
chlorfluazuron; [0132] e) Organic tin compounds, such as cyhexatin,
fenbutatin oxide or azocyclotin; [0133] f) Pyrazoles, such as
tebufenpyrad and fenpyroximate; [0134] g) Macrolides, such as
avermectins or milbemycins, for example abamectin, emamectin
benzoate, ivermectin, milbemycin, spinosad, azadirachtin or
spinetoram; [0135] h) Hormones or pheromones; [0136] i)
Organochlorine compounds, such as endosulfan (in particular
alpha-endosulfan), benzene hexachloride, DDT, chlordane or
dieldrin; [0137] j) Amidines, such as chlordimeform or amitraz;
[0138] k) Fumigant agents, such as chloropicrin, dichloropropane,
methyl bromide or metam; [0139] l) Neonicotinoid compounds, such as
imidacloprid, thiacloprid, acetamiprid, nitenpyram, dinotefuran,
thiamethoxam, clothianidin, nithiazine or flonicamid; [0140] m)
Diacylhydrazines, such as tebufenozide, chromafenozide or
methoxyfenozide; [0141] n) Diphenyl ethers, such as diofenolan or
pyriproxifen; [0142] o) Indoxacarb; [0143] p) Chlorfenapyr; [0144]
q) Pymetrozine; [0145] r) Spirotetramat, spirodiclofen or
spiromesifen; [0146] s) Diamides, such as flubendiamide,
chlorantraniliprole or cyantraniliprole; [0147] t) Sulfoxaflor; or
[0148] u) Metaflumizone.
[0149] In addition to the major chemical classes of pesticide
listed above, other pesticides having particular targets may be
employed in the composition, if appropriate for the intended
utility of the composition. For instance, selective insecticides
for particular crops, for example stemborer specific insecticides
(such as cartap) or hopper specific insecticides (such as
buprofezin) for use in rice may be employed. Alternatively
insecticides or acaricides specific for particular insect
species/stages may also be included in the compositions (for
example acaricidal ovo-larvicides, such as clofentezine,
flubenzimine, hexythiazox or tetradifon; acaricidal motilicides,
such as dicofol or propargite; acaricides, such as bromopropylate
or chlorobenzilate; or growth regulators, such as hydramethylnon,
cyromazine, methoprene, chlorfluazuron or diflubenzuron).
[0150] Examples of fungicidal compounds which may be included in
the composition of the invention are
(E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoaceta-
mide (SSF-129),
4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethyl-benzimidazole-1-sulfonamid-
e,
.alpha.-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-.gamma.-butyrolacto-
ne, 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide
(IKF-916, cyamidazosulfamid),
3-5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide
(RH-7281, zoxamide),
N-allyl-4,5,-dimethyl-2-trimethylsilylthiophene-3-carboxamide
(MON65500),
N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)propionamide
(AC382042), N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide,
acibenzolar (CGA245704), alanycarb, aldimorph, anilazine,
azaconazole, azoxystrobin, benalaxyl, benomyl, biloxazol,
bitertanol, blasticidin S, bromuconazole, bupirimate, captafol,
captan, carbendazim, carbendazim chlorhydrate, carboxin,
carpropamid, carvone, CGA41396, CGA41397, chinomethionate,
chlorothalonil, chlorozolinate, clozylacon, copper containing
compounds such as copper oxychloride, copper oxyquinolate, copper
sulfate, copper tallate and Bordeaux mixture, cymoxanil,
cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulfide
1,1'-dioxide, dichlofluanid, diclomezine, dicloran, diethofencarb,
difenoconazole, difenzoquat, diflumetorim,
O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole,
dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap,
dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine,
doguadine, edifenphos, epoxiconazole, ethirimol,
ethyl-(Z)-N-benzyl-N-([methyl(methyl-thioethylideneaminooxycarbonyl)amino-
]thio)-.beta.-alaninate, etridiazole, famoxadone, fenamidone
(RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid
(KBR2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate,
fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil,
flumetover, fluoroimide, fluquinconazole, flusilazole, flutolanil,
flutriafol, folpet, fuberidazole, furalaxyl, furametpyr, guazatine,
hexaconazole, hydroxyisoxazole, hymexazole, imazalil,
imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole,
iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl
carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054,
LY211795, LY248908, mancozeb, maneb, mefenoxam, mepanipyrim,
mepronil, metalaxyl, metconazole, metiram, metiram-zinc,
metominostrobin, myclobutanil, neoasozin, nickel
dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace,
organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid,
oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron,
phenazin oxide, phosetyl-Al, phosphorus acids, phthalide,
picoxystrobin (ZA1963), polyoxin D, polyram, probenazole,
prochloraz, procymidone, propamocarb, propiconazole, propineb,
propionic acid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon,
pyroxyfur, pyrrolnitrin, quaternary ammonium compounds,
quinomethionate, quinoxyfen, quintozene, sipconazole (F-155),
sodium pentachlorophenate, spiroxamine, streptomycin, sulfur,
tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole,
thifluzamid, 2-(thiocyanomethylthio)benzothiazole,
thiophanate-methyl, thiram, timibenconazole, tolclofos-methyl,
tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide,
tricyclazole, tridemorph, trifloxystrobin (CGA279202), triforine,
triflumizole, triticonazole, validamycin A, vapam, vinclozolin,
zineb and ziram.
[0151] The compounds of formula (I) may be mixed with soil, peat or
other rooting media for the protection of plants against
seed-borne, soil-borne or foliar fungal diseases.
[0152] Examples of suitable synergists for use in the compositions
include piperonyl butoxide, sesamex, safroxan and dodecyl
imidazole.
[0153] Suitable herbicides and plant-growth regulators for
inclusion in the compositions will depend upon the intended target
and the effect required.
[0154] An example of a rice selective herbicide which may be
included is propanil. An example of a plant growth regulator for
use in cotton is PIX.TM..
[0155] Some mixtures may comprise active ingredients which have
significantly different physical, chemical or biological properties
such that they do not easily lend themselves to the same
conventional formulation type. In these circumstances other
formulation types may be prepared. For example, where one active
ingredient is a water insoluble solid and the other a water
insoluble liquid, it may nevertheless be possible to disperse each
active ingredient in the same continuous aqueous phase by
dispersing the solid active ingredient as a suspension (using a
preparation analogous to that of an SC) but dispersing the liquid
active ingredient as an emulsion (using a preparation analogous to
that of an EW). The resultant composition is a suspoemulsion (SE)
formulation.
[0156] The following Examples illustrate, but do not limit, the
invention.
PREPARATION EXAMPLES
[0157] The following abbreviations were used in this section:
s=singlet; bs=broad singlet; d=doublet; dd=double doublet;
dt=double triplet; t=triplet, tt=triple triplet, q=quartet,
sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl;
M.p.=melting point; RT=retention time, [M+H].sup.-=molecular mass
of the molecular cation, [M-H].sup.-=molecular mass of the
molecular anion.
[0158] The following LC-MS methods were used to characterize the
compounds:
TABLE-US-00001 Method A MS ZQ Mass Spectrometer from Waters (single
quadrupole mass spectrometer), ionization method: electrospray,
polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00,
source temperature (.degree. C.) 100, desolvation temperature
(.degree. C.) 250, cone gas flow (L/Hr) 50, desolvation gas flow
(L/Hr) 400, mass range: 150 to 1000 Da. LC HP 1100 HPLC from
Agilent: solvent degasser, quaternary pump, heated column
compartment and diode-array detector. Column: Phenomenex Gemini
C18, length (mm) 30, internal diameter (mm) 3, particle size
(.mu.m) 3, temperature (.degree. C.) 60, DAD wavelength range (nm):
200 to 500, solvent gradient: A = 0.05% v/v formic acid in water
and B = 0.04% v/v formic acid in acetonitrile/methanol (4:1). Time
(min) A % B % Flow (ml/min) 0.0 95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0
100 1.7 2.9 95 5.0 1.7 Method B MS ZMD Mass Spectrometer from
Waters (single quadrupole mass spectrometer), ionization method:
electrospray, polarity: positive ionization, capillary (kV) 3.00,
cone (V) 30.00, extractor (V) 3.00, source temperature (.degree.
C.) 150, desolvation temperature (.degree. C.) 320, cone gas flow
(L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 800
Da. LC Alliance 2795 LC HPLC from Waters: quaternary pump, heated
column compartment and diode-array detector. Column: Waters
Atlantis dc18, length (mm) 20, internal diameter (mm) 3, particle
size (.mu.m) 3, temperature (.degree. C.) 40, DAD wavelength range
(nm): 200 to 500, solvent gradient: A = 0.1% v/v formic acid in
water and B = 0.1% v/v formic acid in acetonitrile. Time (min) A %
B % Flow (ml/min) 0.0 80 20 1.7 5.0 0.0 100 1.7 5.6 0.0 100 1.7 6.0
80 20 1.7 Method C MS ZQ Mass Spectrometer from Waters (single
quadrupole mass spectrometer), ionization method: electrospray,
polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00,
extractor (V) 3.00, source temperature (.degree. C.) 100,
desolvation temperature (.degree. C.) 200, cone gas flow (L/Hr)
200, desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da. LC
1100er Series HPLC from Agilent: quaternary pump, heated column
compartment and diode-array detector. Column: Waters Atlantis dc18,
length (mm) 20, internal diameter (mm) 3, particle size (.mu.m) 3,
temperature (.degree. C.) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B =
0.1% v/v formic acid in acetonitrile. Time (min) A % B % Flow
(ml/min) 0.0 90 10 1.7 5.5 0.0 100 1.7 5.8 0.0 100 1.7 5.9 90 10
1.7 Method D MS ZMD Mass Spectrometer from Waters (single
quadrupole mass spectrometer), ionization method: electrospray,
polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00,
extractor (V) 3.00, source temperature (.degree. C.) 150,
desolvation temperature (.degree. C.) 320, cone gas flow (L/Hr) 50,
desolvation gas flow (L/Hr) 400, mass range: 150 to 800 Da. LC
Alliance 2795 LC HPLC from Waters: quaternary pump, heated column
compartment and diode-array detector. Column: Waters Atlantis dc18,
length (mm) 20, internal diameter (mm) 3, particle size (.mu.m) 3,
temperature (.degree. C.) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B =
0.1% v/v formic acid in acetonitrile. Time (min) A % B % Flow
(ml/min) 0.0 80 20 1.7 2.5 0.0 100 1.7 2.8 0.0 100 1.7 2.9 80 20
1.7 Method E MS ZQ Mass Spectrometer from Waters (single quadrupole
mass spectrometer), ionization method: electrospray, polarity:
positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor
(V) 3.00, source temperature (.degree. C.) 100, desolvation
temperature (.degree. C.) 200, cone gas flow (L/Hr) 200,
desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da. LC
1100er Series HPLC from Agilent: quaternary pump, heated column
compartment and diode-array detector. Column: Waters Atlantis dc18,
length (mm) 20, internal diameter (mm) 3, particle size (.mu.m) 3,
temperature (.degree. C.) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B =
0.1% v/v formic acid in acetonitrile. Time (min) A % B % Flow
(ml/min) 0.0 80 20 1.7 2.5 0.0 100 1.7 2.8 0.0 100 1.7 2.9 80 20
1.7 Method F MS ZQ Mass Spectrometer from Waters (single quadrupole
mass spectrometer), ionization method: electrospray, polarity:
negative ionization, capillary (kV) 3.00, cone (V) 45.00, source
temperature (.degree. C.) 100, desolvation temperature (.degree.
C.) 250, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400,
mass range: 150 to 1000 Da. LC HP 1100 HPLC from Agilent: solvent
degasser, binary pump, heated column compartment and diode-array
detector. Column: Phenomenex Gemini C18, length (mm) 30, internal
diameter (mm) 3, particle size (.mu.m) 3, temperature (.degree. C.)
60, DAD wavelength range (nm): 200 to 500, solvent gradient: A =
0.05% v/v formic acid in water and B = 0.04% v/v formic acid in
acetonitrile/methanol (4:1). Time (min) A % B % Flow (ml/min) 0.0
95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0 100 1.7 2.9 95 5.0 1.7 3.1 95 5
1.7
Example 1.1
Method A for Preparing the Compounds of the Invention from a
Carboxylic Acid
##STR00012##
[0160] To a solution of the appropriate carboxylic acid (30
.mu.mol), for example,
4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-
-isoxazol-3-yl]-2-methyl-benzoic acid (Example 1.7) for Compound
No. A5 of Table A, in dimethylacetamide (0.4 ml) was added a
solution of the appropriate amine (30 .mu.mol), for example,
3-methyl-thietan-3-ylamine (preparation described in, for example,
WO 2007/080131) for Compound No. A5 of Table A, in
dimethylacetamide (0.145 ml) followed by diisopropylethylamine
(Hunig's Base) (0.02 ml, 100 .mu.mol) and a solution of
bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl") (15.3 mg)
in dimethylacetamide (0.2 ml). The reaction mixture was stirred at
80.degree. C. for 16 hours. Then the mixture was diluted with
acetonitrile (0.6 ml) and a sample was used for the LC-MS analysis.
The remaining mixture was further diluted with
acetonitrile/dimethylformamide (4:1) (0.8 ml) and purified by HPLC
to give the desired compound.
[0161] This method was used to make:
[0162] Compound Nos. A1, A2, A15 and A16 of Table A from
4-[5-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-
-1-carboxylic acid (preparation described in, for example, WO
2007/079162),
[0163] Compound Nos. A3 and A4 of Table A from
4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benz-
oic acid (Example 2.2),
[0164] Compound Nos. A5-A8 of Table A from
4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-2-methyl-benzoic acid (preparation described in, for
example, WO 2009/005015),
[0165] Compound Nos. A9-A11 of Table A from
4-[5-(3,5-dichloro-phenyl)-2-oxo-5-trifluoromethyl-oxazolidin-3-yl]-2-met-
hyl-benzoic acid (preparation described in, for example, in WO
2007/123853),
[0166] Compound Nos. A12-A14 of Table A from
4-[5-(3,5-dichloro-phenyl)-1-methyl-5-trifluoromethyl-4,5-dihydro-1H-pyra-
zol-3-yl]-2-methyl-benzoic acid (preparation described in, for
example, JP 2008/133273),
[0167] Compound Nos. A18-A21 of Table A from
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid (Example 4.5),
[0168] Compound Nos. A22-A25 of Table A from
7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-b-
enzo[1,2,5]thiadiazole-4-carboxylic acid (Example 5.8),
[0169] Compound Nos. A26-A29 of Table A from
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzooxazole-7-carboxylic acid (Example 6.11),
[0170] Compound Nos. A32-A35 of Table A from
4-[4-chloro-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid (preparation of corresponding methyl
ester described in, for example, WO 2009/005015),
[0171] Compound Nos. A36-A38 of Table A from
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid (Example 9.6),
[0172] Compound Nos. A42-A45 of Table A were made from
4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid (preparation of similar
compounds described in, for example, WO 2009/005015),
[0173] Compound Nos. A46-A49 of Table A were made from
4-[4-(3,5-dichlorophenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-
-methyl-benzoic acid (Example 10.6),
[0174] Compound Nos. A51-A54 of Table A were made from
4-[5-(3,5-dichlorophenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid (Example 12.2),
[0175] Compound Nos. A55-A58 of Table A were made from
4-{5-(3,5-dichlorophenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-is-
oxazol-3-yl}-2-methyl-benzoic acid (Example 13.3), and
[0176] Compound Nos. A59-A62 of Table A were made from
4-[5-(3,5-dichlorophenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-2-methyl-benzoic acid (Example 14.2).
[0177] Compound Nos. A63, A68, A69 and A70 of Table A were made
from
5'-(3,5-Dichloro-phenyl)-5'-trifluoromethyl-4',5'-dihydro[3,3']biisoxazol-
yl-5-carboxylic acid (Example 15.5).
[0178] Compound Nos. A64-A67 of Table A were made from
5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2--
methyl-2H-pyrazole-3-carboxylic acid (Example 16.2)
Example 1.2
Method B for Preparing the Compounds of the Invention from a
Carboxylic Acid
##STR00013##
[0180] To a solution of the appropriate carboxylic acid, for
example,
4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-2-methy-
l-benzoic acid (105 mg) (Example 3.2), in dichloromethane (3 ml)
was added oxalyl chloride (0.025 ml). After addition of
N,N-dimethylformamide ("DMF") (2 drops) the reaction mixture was
stirred at ambient temperature for 2 hours. The reaction mixture
was concentrated to give the acid chloride as a yellow solid, which
was used without further purification. Triethylamine (0.175 ml) and
the appropriate amine, for example, 3-methyl-thietan-3-ylamine (117
mg) (preparation as described in, for example, WO 2007/080131) were
added to a solution of the acid chloride residue in dichloromethane
(2 ml). The reaction mixture was stirred at ambient temperature for
16 hours. The reaction mixture was diluted with water and ethyl
acetate and the phases were separated. The organic phase was washed
successively with saturated aqueous hydrogen carbonate (1M) and
brine, dried over sodium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (eluent:
cylohexane/ethyl acetate) to afford Compound No. A17 of Table A (8
mg) as a colorless solid. M.p. 180-181.degree. C.
[0181] This method was used to make:
[0182] Compound No. A17 of Table A from
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-2-meth-
yl-benzoic acid (Example 3.2),
[0183] Compound No. A30 of Table A from
4-[5-(3,5-dichloro-phenyl)-4-ethylidene-5-trifluoromethyl-4,5-dihydro-iso-
xazol-3-yl]-2-methyl-benzoic acid (Example 7.2),
[0184] Compound No. A31 of Table A from
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid (Example 8.2),
[0185] Compound No. A39 of Table A from
4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid (preparation described in, for
example, WO 2009/005015),
[0186] Compound No. A40 of Table A from
4-[5-(3,5-dichloro-phenyl)-4-methylthio-5-trifluoromethyl-4,5-dihydro-iso-
xazol-3-yl]-2-methyl-benzoic acid (preparation described in, for
example, WO 2009/005015),
[0187] Compound No. A41 of Table A from
4-[5-(3,5-dichloro-phenyl)-4-methyl-sulfinyl-5-trifluoromethyl-4,5-dihydr-
o-isoxazol-3-yl]-2-methyl-benzoic acid (which was obtained by
oxidation of
4-[5-(3,5-dichloro-phenyl)-4-methylthio-5-trifluoromethyl-4,5-dihydro-iso-
xazol-3-yl]-2-methyl-benzoic acid with, for example,
3-chloroperoxybenzoic acid), and
[0188] Compound No. A50 of Table A from
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-naphthalene-1-carboxylic acid (Example 11.1).
Example 2.1
Preparation of
4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benz-
oic acid methyl ester
##STR00014##
[0190] A mixture of 4-azido-2-methyl-benzoic acid methyl ester
(made in analogy to methods described in, for example, Journal of
Organic Chemistry, 2006, 71(15), 5822-5825) (820 mg, 3.4 mmol) and
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (500 mg, 2.6 mmol) in
toluene (20 ml) was heated at 130.degree. C. for 48 hours. The
reaction mixture was concentrated and the residue purified by
column chromatography on silica gel (eluent: 3% v/v ethyl acetate
in hexane) to give
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-[1,2,3]triazol-1-
-yl]-2-methyl-benzoic acid methyl ester as a gummy oil (200
mg).
Example 2.2
Preparation of
4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benz-
oic acid
##STR00015##
[0192] To a solution of
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-[1,2,3]triazol-1-
-yl]-2-methyl-benzoic acid methyl ester (Example 2.1) (3.6 g, 8.33
mmol) in methanol (10 ml) was added aqueous potassium hydroxide
(40% w/v) (35 ml) and the reaction mixture heated at 80.degree. C.
for 15 hours. The reaction mixture was then diluted with water and
extracted with ethyl acetate. The aqueous phase was acidified by
addition of aqueous hydrochloric acid (1M) and extracted again with
ethyl acetate (3.times.200 ml). The combined organic extracts were
washed with brine and concentrated. The residue was purified by
column chromatography on silica gel (eluent: 15% v/v ethyl acetate
in hexane) to give
4-[2-(3,5-dichloro-phenyl)-2-trifluoromethyl-aziridin-1-yl]-2-methyl-benz-
oic acid as a white solid (1.2 g). 1H-NMR (DMSO-d6, 400 MHz): 12.57
(s, 1H), 7.70 (d, 1H), 7.65 (s, 3H), 6.99 (s, 1H), 6.97 (d, 1H),
3.27 (s, 1H), 3.05 (s, 1H), 2.45 (s, 3H).
Example 3.1
Preparation of
5-(3,5-dichloro-phenyl)-3-(3,4-dimethyl-phenyl)-5-trifluoromethyl-[1,4,2]-
dioxazole
##STR00016##
[0194] A solution of 3,4-dimethyl-benzaldehyde oxime (commercially
available) (1.56 g) and N-chlorosuccinimide ("NCS") (1.4 g) in
dimethylformamide (30 ml) was stirred at ambient temperature under
an atmosphere of nitrogen for 3 hours. A solution of
3,5-dichloro-2,2,2-trifluoro-acetophenone (commercially available)
(1 g) and triethylamine (1.46 ml) in dimethylformamide (12 ml) was
then added dropwise and the reaction mixture was stirred at ambient
temperature for 16 hours. The reaction mixture was diluted with
water and extracted three times with diethyl ether. The combined
organic extracts were washed with brine, dried over sodium sulfate
and concentrated. The residue was purified by column chromatography
on silica gel (eluent: cyclohexane/ethyl acetate) to give
5-(3,5-dichloro-phenyl)-3-(3,4-dimethyl-phenyl)-5-trifluoromethyl-[1,4,2]-
dioxazole (1.18 g).
Example 3.2
Preparation of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-2-meth-
yl-benzoic acid
##STR00017##
[0196] Periodic acid (2.2 g) was dissolved under an atmosphere of
nitrogen in dimethylformamide (35 ml). After 15 minutes,
chromium(VI) oxide (55 mg) was added followed by
5-(3,5-dichloro-phenyl)-3-(3,4-dimethyl-phenyl)-5-trifluoromethyl-[1,4,2]-
dioxazole (Example 3.1) (1 g) and the reaction mixture was stirred
at ambient temperature for 16 hours. The solids were removed by
filtration and the filtrate was concentrated. The residue was
diluted with aqueous sodium carbonate (1M) (100 ml) and
dichloromethane (100 ml) and the phases were separated. The aqueous
layer was extracted twice with dichloromethane and then acidified
to pH 1 by addition of aqueous hydrochloric acid (concentrated).
The aqueous layer was extracted three times with dichloromethane.
The combined organic extracts were dried over sodium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: cyclohexane/ethyl acetate, then methanol) to
afford a mixture of isomers. The mixture of isomers were separated
by reverse phase HPLC to give
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-2-meth-
yl-benzoic acid (792 mg) as a solid. M.p. 114-134.degree. C. 1H-NMR
(DMSO-d6, 400 MHz): 13.5 (bs, 1H), 7.8-8.0 (m, 6H), 2.6 (s,
3H).
Example 4.1
Preparation of 4-bromo-2-methyl-benzoic acid tent-butyl ester
##STR00018##
[0198] 4-Bromo-2-methyl-benzoic acid (commercially available) (50
g) was suspended in dichloromethane (500 ml). A catalytic amount of
dimethylformamide ("DMF") and oxalyl chloride (23 ml) were added to
the suspension. The reaction mixture was stirred at ambient
temperature for 3 hours. The reaction mixture was concentrated and
the residue dissolved in dry tetrahydrofuran (800 ml). The solution
was cooled to 2.degree. C. and added to a solution of potassium
tert-butoxide (39.2 g) in dry tetrahydrofuran (300 ml) dropwise at
5-10.degree. C. The reaction mixture was stirred at ambient
temperature for 30 minutes and then poured onto a mixture of ice
and water. The mixture was extracted with ethyl acetate. The
organic extract was washed with water, dried over sodium sulfate
and concentrated to give 4-bromo-2-methyl-benzoic acid tert-butyl
ester (65.3 g) as yellow oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz):
7.70 (d, 1H), 7.40 (s, 1H), 7.35 (d, 1H), 2.58 (s, 3H), 1.60 (s,
9H).
Example 4.2
Preparation of 4-formyl-2-methyl-benzoic acid tert-butyl ester
##STR00019##
[0200] A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester
(Example 4.1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to
-100.degree. C. A solution of butyl lithium (1.6M in hexane) (163
ml) was added dropwise at -100.degree. C. Dimethylformamide ("DMF")
(1.14 ml) was added at -100.degree. C. The reaction mixture was
stirred at -95.degree. C. for 75 minutes. The reaction was quenched
by addition of aqueous ammonium chloride (saturated) (8 ml) at
-90.degree. C. The mixture was stirred for 10 minutes at
-90.degree. C., warmed to 0.degree. C. and poured onto a mixture of
ice and water. The mixture was allowed to warm to ambient
temperature and then extracted twice with ethyl acetate. The
combined organic phases were washed with water, dried over sodium
sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid
tert-butyl ester (60.3 g) as yellow oil. .sup.1H-NMR (CDCl.sub.3,
400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H),
1.65 (s, 9H).
Example 4.3
Preparation of
(4-tert-butoxycarbonyl-3-methyl-benzylidene)-N-methyl-nitrone
##STR00020##
[0202] To a solution of 4-formyl-2-methyl-benzoic acid tert-butyl
ester (Example 4.2) (1.57 g) in tetrahydrofuran/water (3:1) (20 ml)
was added sodium acetate (0.67 g) and N-methyl-hydroxylamine
hydrochloride (0.69 g). The reaction mixture was stirred at
50.degree. C. for 15 hours. The reaction mixture was diluted with
ethyl acetate and water. The phases were separated and the organic
layer was washed with water, dried over sodium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: methanol/ethyl acetate 5:5) to give
(4-tert-butoxycarbonyl-3-methyl-benzylidene)-N-methyl-nitrone (1.43
g) as yellow oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.10 (s, 1H),
8.02 (d, 1H), 7.85 (d, 1H), 7.35 (s, 1H), 3.90 (s, 3H), 2.60 (s,
3H).
Example 4.4
Preparation of
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid tert-butyl ester
##STR00021##
[0204] To a solution of
(4-tert-butoxycarbonyl-3-methyl-benzylidene)-N-methyl-nitrone
(Example 4.3) (1.42 g) in toluene (10 ml) was added
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (2.17 g). The reaction
mixture was heated in a microwave at 120.degree. C. for 3.5 hours.
The toluene was evaporated and the residue was purified by column
chromatography on silica gel (eluent: ethyl acetate/heptane 5:95 to
50:50) to give
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid tert-butyl ester as a mixture of
diastereoisomers (1.73 g). .sup.1H-NMR (CDCl.sub.3, 400 MHz):
7.80-7.10 (m, 6H), 3.85-3.55 (m, 1H), 3.32-2.50 (m, 9H), 1.60 (m,
9H).
Example 4.5
Preparation
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid
##STR00022##
[0206] To a solution of
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid tert-butyl ester (Example 4.4) (0.67 g) in
dichloromethane (15 ml) was added trifluoroacetic acid ("TFA")
(1.05 ml). The reaction mixture was stirred at ambient temperature
for 16 hours. The dichloromethane was evaporated and ethyl acetate
was added. The mixture was washed with water, dried over sodium
sulfate and concentrated. The residue was purified by preparative
HPLC to give
4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]--
2-methyl-benzoic acid as a mixture of diastereoisomers (0.56 g).
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.05 (m, 1H), 7.45-7.15 (m, 5H),
3.90-3.60 (m, 1H), 3.35-2.60 (m, 9H).
Example 5.1
Preparation of 4-bromo-7-bromomethyl-benzo[1,2,5]thiadiazole
##STR00023##
[0208] Bromine (9.78 ml) was added to a solution of
4-methylbenzo[c][1,2,5]thiadiazole (commercially available) (15 g)
in aqueous hydrobromic acid (48% w/v) (100 ml). The reaction
mixture was heated at reflux temperature for 2 hours. The reaction
mixture was allowed to cool to ambient temperature and diluted with
aqueous sodium metabisulfite (20 g in 250 ml water). The mixture
was extracted twice with dichloromethane. The combined organic
phases were washed with water and brine, dried over sodium sulfate,
and concentrated to give a mixture of brominated products. This
mixture was suspended in .alpha.,.alpha.,.alpha.-trifluorotoluene
(250 ml) and N-bromosuccinimide ("NBS") (13.88 g) and
2,2'-azobis(2-methylpropionitrile) ("AIBN") (0.640 g) were added.
The reaction mixture was heated at 90.degree. C. for 3 hours. The
reaction mixture was allowed to cool to ambient temperature and was
diluted with dichloromethane (600 ml) and aqueous hydrochloric acid
(1M) (300 ml). The phases were separated and the organic layer was
washed successively with aqueous hydrochloric acid (1M)
(2.times.250 ml), water (200 ml) and brine (200 ml), dried over
sodium sulfate and concentrated to give
4-bromo-7-bromomethyl-benzo[1,2,5]thiadiazole (29.05 g) as a yellow
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.82 (d, 1H), 7.54 (d,
1H), 4.94 (s, 2H) ppm.
Example 5.2
Preparation of (7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol
##STR00024##
[0210] A mixture of 4-bromo-7-bromomethyl-benzo[1,2,5]thiadiazole
(Example 5.1) (29.05 g), potassium carbonate (65.2 g) and water
(400 ml) was stirred at 110.degree. C. for 16 hours. The reaction
mixture was cooled to ambient temperature and quenched by addition
of aqueous hydrochloric acid (2M) (400 ml). Ethyl acetate (600 ml)
was added to the mixture. The phases were separated and the organic
layer was washed successively with aqueous hydrochloric acid (2M)
(400 ml), water (250 ml) and brine (250 ml), dried over sodium
sulfate and concentrated to give
(7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (20.22 g) as a
orange solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.87 (d, 1H), 7.57
(d, 1H), 5.14 (s, 2H) ppm.
Example 5.3
Preparation of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde
##STR00025##
[0212] To a solution of
(7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (Example 5.2) (20.22
g) in dichloromethane (185 ml) was added manganese(IV) oxide (71.7
g). The suspension was stirred at ambient temperature for 16 hours.
The reaction mixture was filtered through a plug of Celite.RTM..
The filtrate was concentrated to give
7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (16.65 g) as an
orange solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): 10.74 (s, 1H),
8.11-8.05 (m, 2H) ppm.
Example 5.4
Preparation of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde
oxime
##STR00026##
[0214] To a solution of
7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (Example 5.3) (16.65
g) in ethanol (150 ml) were added hydroxylamine hydrochloride (9.52
g), sodium hydrogen carbonate (11.51 g) and water (15 ml). The
reaction mixture was stirred at ambient temperature for 16 hours.
The reaction mixture was diluted with ethyl acetate (1500 ml) and
water (400 ml). After separation of the phases, the aqueous layer
was extracted with ethyl acetate (200 ml). The combined organic
layers were washed with water (200 ml) and brine (200 ml), dried
over sodium sulfate and concentrated to give
7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (16.65 g) as a
brown solid. .sup.1H-NMR (DMSO-d6, 400 MHz): 11.94 (s, 1H), 8.66
(s, 1H), 8.09-9.90 (m, 2H) ppm.
Example 5.5
Preparation of
7-bromo-N-hydroxy-benzo[1,2,5]thiadiazole-4-carbimidoyl
chloride
##STR00027##
[0216] To a solution of
7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (Example 5.4)
(16.65 g) in dimethylformamide (150 ml) was added
N-chlorosuccinimide ("NCS") (10.34 g). The reaction mixture stirred
at ambient temperature for 16 hours. Water (750 ml) was added to
the reaction mixture and the solids were isolated by filtration to
obtain 7-bromo-N-hydroxy-benzo[1,2,5]thiadiazole-4-carbimidoyl
chloride (15.77 g) as a yellow solid which was used without further
purification.
Example 5.6
Preparation of
4-bromo-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-benzo[1,2,5]thiadiazole
##STR00028##
[0218] To a solution of
7-bromo-N-hydroxy-benzo[1,2,5]thiadiazole-4-carbimidoyl chloride
(Example 5.5) (10.01 g) in 2-propanol (140 ml) was added
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (6.87 g) and sodium
hydrogen carbonate (5.99 g). The reaction mixture was stirred at
65.degree. C. for 3 hours. The reaction mixture was concentrated
and the residue was purified by column chromatography
(heptane/ethyl acetate 9:1) to give
4-bromo-7-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol--
3-yl]-benzo[1,2,5]thiadiazole (7.4 g). .sup.1H-NMR (DMSO-d6, 400
MHz): 8.17-7.53 (m, 5H), 4.70 (d, 1H), 4.49 (d, 1H) ppm.
Example 5.7
Preparation of
7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-b-
enzo[1,2,5]thiadiazole-4-carboxylic acid methyl ester
##STR00029##
[0220] Triethylamine (7.8 ml) and methanol (72 ml) were added at
ambient temperature to a solution of
4-bromo-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-benzo[1,2,5]thiadiazole (Example 5.6) (7.96 g) in
dimethylformamide (72 ml).
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
("PdCl.sub.2(dppf)") (654 mg) was added and the reaction mixture
was stirred in a pressure reactor in an atmosphere of carbon
monoxide (3 bar) at 87.degree. C. for 16 hours. The reaction
mixture was cooled to ambient temperature, filtered through a plug
of Celite.RTM. and concentrated. The residue was purified by column
chromatography on silica gel (eluent: heptane/ethyl acetate) to
give
7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-b-
enzo[1,2,5]thiadiazole-4-carboxylic acid methyl ester (4.01 g) as
an orange oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.43-7.57 (m,
5H), 4.66 (d, 1H), 4.27 (d, 1H), 4.09 (s, 3H) ppm.
Example 5.8
Preparation of
7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-b-
enzo[1,2,5]thiadiazole-4-carboxylic acid
##STR00030##
[0222] To a solution of
7-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-be-
nzo[1,2,5]thiadiazole-4-carboxylic acid methyl ester (Example 5.7)
(4.01 g) in tetrahydrofuran (30 ml) was added aqueous sodium
hydroxide (1M) (25.3 ml). The reaction mixture was stirred at
ambient temperature for 1.5 hours. Aqueous hydrochloric acid (1M)
(100 ml) was added and the mixture diluted with ethyl acetate (150
ml). After separation of the layers, the aqueous layer was
extracted with ethyl acetate (2.times.75 ml). The combined organic
layers were washed with water (75 ml) and brine (75 ml), dried over
sodium sulfate and concentrated. The residue was purified by column
chromatography (dichloromethane/methanol) to give
7-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-be-
nzo[1,2,5]thiadiazole-4-carboxylic acid (1.29 g) as yellow solid.
.sup.1H-NMR (DMSO-d6, 400 MHz): 13.67 (bs, 1H), 8.37-7.26 (m, 5H),
4.76 (d, 1H), 4.53 (d, 1H) ppm.
Example 6.1
Preparation of 3-hydroxy-2-nitro-benzoic acid methyl ester
##STR00031##
[0224] 3-Hydroxy-2-nitro-benzoic acid (commercially available)
(31.5 g) was suspended in acetonitrile (100 ml). Oxalyl chloride
(22 ml) in acetonitrile (20 ml) was added dropwise upon which a
vigorous gas stream evolved. After 15 minutes the reaction slowed
down and therefore, the reaction mixture was heated with a warm
water bath (40.degree. C.) for 40 minutes. The mixture was
concentrated and the residue was re-dissolved in dichloromethane
(100 ml). A mixture of methanol (50 ml) and triethylamine (20 ml)
in dichloromethane (30 ml) was added dropwise while cooling the
mixture with an ice bath. The reaction mixture was stirred at
ambient temperature for 16 hours. The mixture was concentrated and
the residue was purified by column chromatography on silica gel
(eluent: 10-55% v/v ethyl acetate in heptane) to give
3-hydroxy-2-nitro-benzoic acid methyl ester (15.9 g). 1H-NMR (400
MHz, CDCl.sub.3): 10.15 (bs, 1H), 7.60 (t, 1H), 7.27 (d, 1H), 7.08
(d, 1H), 3.93 (s, 3H) ppm.
Example 6.2
Preparation of 4-bromo-3-hydroxy-2-nitro-benzoic acid methyl
ester
##STR00032##
[0226] To a solution of 3-hydroxy-2-nitrobenzoic acid methyl ester
(Example 6.1) (11 g) in chloroform (220 ml) was added dropwise
bromine (18.7 g). The reaction mixture was heated at reflux for 16
hours. The reaction mixture was allowed to cool to ambient
temperature and the reaction quenched by addition of aqueous sodium
metabisulfite (22 g in 100 ml water) and the mixture was stirred
for 15 minutes. The phases were separated and the organic phase was
washed with brine, dried over sodium sulfate and concentrated. The
residue was crystallized from diethyl ether/heptane to give
4-bromo-3-hydroxy-2-nitro-benzoic acid methyl ester (6.6 g). 1H-NMR
(400 MHz, CDCl.sub.3): 9.92 (s, 1H), 7.84 (d, 1H), 7.09 (d, 1H),
3.93 (s, 3H) ppm.
Example 6.3
Preparation of 2-amino-4-bromo-3-hydroxy-benzoic acid methyl
ester
##STR00033##
[0228] To a solution of 4-bromo-3-hydroxy-2-nitro-benzoic acid
methyl ester (Example 6.2) (3.13 g) in tetrahydrofuran (40 ml) was
added a solution of sodium dithionite (10.23 g) in water (40 ml).
The reaction mixture was stirred at 60.degree. C. for 2 hours. Then
the reaction was diluted with ethyl acetate (80 ml) and aqueous
hydrochloric acid (1M) (30 ml) and the mixture vigorously shaken.
The phases were separated and the aqueous phase was extracted with
ethyl acetate (60 ml). The combined organic extracts were washed
with brine, dried over sodium sulfate and concentrated to give
2-amino-4-bromo-3-hydroxy-benzoic acid methyl ester (2.46 g).
1H-NMR (400 MHz, CDCl.sub.3): 7.35 (d, 1H), 6.72 (d, 1H), 6.05 (s,
1H), 5.47 (s, 1H), 3.87 (s, 3H) ppm.
Example 6.4
Preparation of 7-bromo-2-methyl-benzo[d]oxazole-4-carboxylic acid
methyl ester
##STR00034##
[0230] To a solution of 2-amino-4-bromo-3-hydroxy-benzoic acid
methyl ester (Example 6.3) (2.46 g) in toluene (250 ml) was added
sequentially triethylamine (1.53 ml), pyridinium p-toluenesulfonate
("PPTS") (0.75 g) and acetyl chloride (0.78 ml). The reaction
mixture was heated at reflux for 16 hours. The reaction mixture was
cooled to ambient temperature and diluted with aqueous hydrochloric
acid (1M) (100 ml) and ethyl acetate (200 ml). The phases were
separated and the organic extract was washed with aqueous
hydrochloric acid (1M) (150 ml) and brine (150 ml) and then dried
over sodium sulfate. The solids were removed by filtration and the
filtrate was concentrated to give 7-bromo-2
methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (2.94 g).
1H-NMR (400 MHz, CDCl.sub.3): 7.87 (d, 1H), 7.52 (d, 1H), 4.04 (s,
3H), 2.77 (s, 3H) ppm.
Example 6.5
Preparation of (7-bromo-2-methyl-benzo[d]oxazol-4-yl)-methanol
##STR00035##
[0232] To a solution of 7-bromo-2
methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (Example 6.4)
(8.64 g) in tetrahydrofuran (250 ml) was added dropwise a solution
of diisobutylaluminium hydride ("DIBAL-H") (1M in hexane) (80 ml)
under a nitrogen atmosphere at 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 20 minutes. Then the ice-bath was
removed and the reaction mixture was allowed to warm to ambient
temperature. After 40 minutes the mixture was cooled with an
ice-bath and the reaction was quenched by the slow addition of
water (5.0 ml). The mixture was poured onto aqueous sodium hydrogen
carbonate (saturated) (300 ml) and extracted with diethyl ether
(400 ml). The aqueous phase was further extracted with diethyl
ether (2.times.300 ml). The combined organic extracts were washed
with brine, dried over sodium sulfate and concentrated. The residue
was triturated in a mixture of diisopropyl ether and heptane (3:1)
to give (7-bromo-2-methyl-benzo[d]oxazol-4-yl)-methanol (4.45 g).
1H-NMR (400 MHz, CDCl.sub.3): 7.41 (d, 1H), 7.17 (d, 1H), 4.98 (s,
3H), 3.06 (s, 1H), 2.67 (s, 3H) ppm.
Example 6.6
Preparation of 7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde
##STR00036##
[0234] To a solution of (7-bromo-2-methyl-benzo[d]oxazol-4-yl)
methanol (Example 6.5) (5.16 g) in dichloromethane (300 ml) was
added manganese(IV) oxide (59.9 g) and the suspension stirred at
ambient temperature for 16 hours. The reaction mixture was filtered
through a plug of silica gel and the filtrate concentrated to give
7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde (3.23 g). LC-MS:
RT=1.83 min, [M+H].sup.+=240.0/242.0, method A.
Example 6.7
Preparation of (E)-7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde
oxime
##STR00037##
[0236] To a suspension of
7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde (Example 6.6) (3.23
g) in a mixture of methanol and water (7:3) (60 ml) were added
successively hydroxylamine hydrochloride (1.03 g) and triethylamine
(2.06 ml) and the reaction mixture was stirred at ambient
temperature for 1 hour. The reaction mixture was diluted with ethyl
acetate (200 ml) and water (200 ml). The phases were separated and
the aqueous phase was extracted with ethyl acetate (150 ml). The
combined organic extracts were washed with brine (200 ml), dried
over sodium sulfate and concentrated to give
(E)-7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde oxime (3.61 g)
as a brown solid. 1H-NMR (400 MHz, CDCl.sub.3): 9.47 (s, 1H) 7.47
(d, 1H), 7.33 (d, 1H), 2.74 (s, 3H) ppm.
Example 6.8
Preparation of
(Z)-7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl
chloride
##STR00038##
[0238] To a solution of
(E)-7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde oxime (Example
6.7) (3.61 g) in dimethylformamide (30 ml) was added
N-bromosuccinimide ("NCS") (7.54 g) and the reaction mixture
stirred at ambient temperature for two hours. Water (300 ml) was
added to the mixture and the solids were isolated by filtration to
give (Z)-7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl
chloride (3.63 g) as an orange solid. 1H-NMR (DMSO-d6, 400 MHz):
12.76 (s, 1H) 7.69 (d, 1H), 7.58 (d, 1H), 2.68 (s, 3H) ppm.
Example 6.9
Preparation of
7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol--
3-yl)-2-methyl-benzo[d]oxazole
##STR00039##
[0240] To a solution of
7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl chloride
(Example 6.8) (3.63 g) in 2-propanol (100 ml) was added
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (3.43 g) and sodium
hydrogen carbonate (1.44 g). The reaction mixture was stirred at
65.degree. C. for 16 hours. The reaction mixture was concentrated
and the residue was purified by column chromatography on silica gel
(eluent: 2-25% v/v ethyl acetate in heptane) to give
7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol--
3-yl)-2-methyl-benzo[d]oxazole (3.7 g). 1H-NMR (400 MHz,
CDCl.sub.3): 7.71-7.42 (m, 5H), 4.50 (d, 1H), 4.06 (d, 1H), 2.73
(s, 3H) ppm.
Example 6.10
Preparation of
4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2--
methyl-benzo[d]oxazole-7-carboxylic acid methyl ester
##STR00040##
[0242] To a solution of
7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol--
3-yl)-2-methyl-benzo[d]oxazole (Example 6.9) (3.5 g) in
dimethylformamide (40 ml) was added successively triethylamine (2.5
ml), methanol (60 ml) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
("PdCl2(dppf)") (259 mg). The reaction mixture was stirred in a
pressure reactor in an atmosphere of carbon monoxide (4 bar) at
80.degree. C. for 16 hours. The reaction mixture was cooled to
ambient temperature, filtered over a plug of Celite.RTM. and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: 15-55% v/v ethyl acetate in heptane) to give
4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2--
methyl-benzo[d]oxazole-7-carboxylic acid methyl ester (2.75 g).
1H-NMR (400 MHz, CDCl.sub.3): 7.95-7.42 (m, 5H), 4.56 (d, 1H), 4.12
(d, 1H), 4.02 (s, 3H), 2.77 (s, 3H) ppm.
Example 6.11
Preparation of
4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2--
methyl-benzo[d]oxazole-7-carboxylic acid
##STR00041##
[0244] To a solution of
4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2--
methyl-benzo[d]oxazole-7-carboxylic acid methyl ester (Example
6.10) (2.75 g) in tetrahydrofuran (50 ml) was added aqueous sodium
hydroxide (1M) (8.7 ml) and methanol (5 ml). The reaction mixture
was stirred at ambient temperature for 2.5 hours. The reaction
mixture was diluted with aqueous hydrochloric acid (1M) (150 ml)
and ethyl acetate (200 ml) and the phases separated. The organic
phase was washed with brine, dried over sodium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: 1-6% v/v methanol in dichloromethane) to give
4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2--
methyl-benzo[d]oxazole-7-carboxylic acid (2.12 g) as yellow solid.
1H-NMR (400 MHz, CDCl.sub.3): 8.05-7.43 (m, 5H), 4.57 (d, 1H), 4.13
(d, 1H), 2.79 (s, 3H) ppm.
Example 7.1
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihy-
dro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester
##STR00042##
[0246] To a solution of N,N-diisopropylamine (0.24 ml) in dry
tetrahydrofuran (6 ml) stirred under argon at 0.degree. C., was
added butyl lithium (2.5M in hexane) (0.80 ml). The solution was
stirred at 0.degree. C. for 30 minutes then was cooled to
-85.degree. C. To this solution was added a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid methyl ester (preparation described in, for
example, EP 1,731,512) (404 mg) in dry tetrahydrofuran (3 ml). The
reaction mixture was stirred at -85.degree. C. until deprotonation
was completed as monitored by thin layer chromatography. Then, to
this solution was added acetaldehyde (0.14 ml) and the reaction
mixture was stirred at -85.degree. C. for 1.5 hours. The reaction
was quenched by addition of aqueous ammonium chloride (saturated)
at -85.degree. C. The mixture allowed to warm to ambient
temperature and was then extracted with dichloromethane. The
combined organic extracts were dried over magnesium sulfate and
concentrated. The residue was purified by chromatography on silica
gel (eluent: heptane/diethyl ether 60:40) to give
4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihy-
dro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a
white solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.98-7.96 (d, 1H),
7.60-7.45 (m, 5H), 4.09-4.08 (m, 1H), 3.96-3.91 (m, 1H), 3.91 (s,
3H), 2.63 (s, 3H), 1.07 and 0.94 (d, 3H).
Example 7.2
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-ethylidene-5-trifluoromethyl-4,5-dihydro-iso-
xazol-3-yl]-2-methyl-benzoic acid
##STR00043##
[0248] A mixture of
4-[5-(3,5-dichloro-phenyl)-4-(1-hydroxy-ethyl)-5-trifluoromethyl-4,5-dihy-
dro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (Example 7.1)
(0.242 g, 0.51 mmol), lithium hydroxide monohydrate (0.06 g, 1.4
mmol), tetrahydrofuran (5 ml) and water (5 ml) was stirred at
ambient temperature for 2 days. Then further portions of lithium
hydroxide monohydrate were added to complete the reaction. In
total, 545 mg of lithium hydroxide monohydrate were added over 5
days. The mixture was concentrated and the residue dissolved in
water. The solution was acidified by addition of aqueous
hydrochloric acid (1N) and extracted with ethyl acetate. The
combined organic extracts were dried over magnesium sulfate and
concentrated to give a residue which was used without further
purification in the following step. LC-MS showed the presence of
4-[5-(3,5-dichloro-phenyl)-4-ethylidene-5-trifluoromethyl-4,5-dihydro-iso-
xazol-3-yl]-2-methyl-benzoic acid: RT=2.20 min, m/z=442/444/446
(M-H.sup.+).
Example 8.1
Preparation of
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid methyl ester
##STR00044##
[0250] A sealed tube purged with argon was charged with
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid methyl ester (preparation described
in, for example, WO 2007/079162) (468 mg), palladium(II) acetate
(23 mg), N-bromosuccinimide ("NBS") (23 mg) and acetic acid (5 ml).
The tube was heated at 100.degree. C. under vigorous stirring for
24 hours. The reaction mixture was cooled to ambient temperature,
diluted with water then extracted with ethyl acetate (3.times.25
ml). The combined organic extracts were washed with water and
brine, treated with charcoal, dried over sodium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: dichloromethane/cyclohexane) to afford
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl]-naphthalene-1-carboxylic acid methyl ester. MS [MH+]
548.
Example 8.2
Preparation of
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid
##STR00045##
[0252] To a solution of
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid methyl ester (Example 8.1)
(400 mg) in tetrahydrofuran (3.5 ml) was added a solution of
potassium hydroxide (1.9 g) in methanol (3.5 ml) and water (3.5
ml). The reaction mixture was stirred at ambient temperature for 2
hours. The reaction mixture was then acidified by addition of
aqueous hydrochloric acid (4N) and the mixture extracted with ethyl
acetate (3.times.10 ml). The combined organic extracts were washed
with water (3.times.10 ml) and brine, dried over sodium sulfate and
concentrated to give
8-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-naphthalene-1-carboxylic acid (342 mg). LC-MS: RT=2.41 min,
[M-H].sup.-=532/534, Method A.
Example 9.1
Preparation of 5-bromo-1-naphtoic acid
##STR00046##
[0254] To a solution of 1-naphtoic acid (commercially available)
(15 g) in acetic acid (37 ml) was added dropwise bromine (4.5 ml).
The reaction mixture was heated at reflux for 4 hours. The reaction
mixture was then cooled to ambient temperature and stored at
ambient temperature for 16 hours. The solids were isolated by
filtration and washed with acetic acid and then ethanol to give
5-bromo-1-naphtoic acid (10.8 g) as a white solid. 1H-NMR (DMSO,
400 MHz): 8.85 (d, 1H), 8.40 (d, 1H), 8.21 (d, 1H), 7.98 (d, 1H),
7.76 (m, 1H), 7.55 (m, 1H).
Example 9.2
Preparation of 5-bromo-1-naphtoic acid tert-butyl ester
##STR00047##
[0256] To a suspension of 5-bromo-1-naphtoic acid (Example 9.1)
(10.8 g) in dichloromethane (93 ml) containing 3 drops of
dimethylformamide was added oxalyl chloride (4 ml) and the reaction
mixture stirred at ambient temperature for 6 hours. The solution
was concentrated to afford a white solid which was re-dissolved in
tetrahydrofuran. The solution was cooled to 2.degree. C. and a
solution of potassium tert-butoxide (7.2 g) in tetrahydrofuran (148
ml) was added dropwise and the reaction mixture stirred at ambient
temperature for 3 hours. The solution was poured onto ice and
extracted with ethyl acetate. The combined organic extracts were
washed with water, dried over sodium sulfate and concentrated. The
residue was purified by column chromatography on silica gel
(eluent: cyclohexane/ethyl acetate) to give 5-bromo-1-naphtoic acid
tert-butyl ester (12 g). 1H-NMR (CDCl.sub.3, 400 MHz): 8.82 (d,
1H), 8.46 (d, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.60 (m, 1H), 7.40
(m, 1H), 1.70 (s, 9H).
Example 9.3
Preparation of 5-formyl-1-naphtoic acid tent-butyl ester
##STR00048##
[0258] To a solution of 5-bromo-1-naphtoic acid tert-butyl ester
(Example 9.2) (6.1 g) in dry tetrahydrofuran (54 ml) cooled to
-100.degree. C. was added a solution of butyl lithium (1.6M in
hexane) (12.5 ml) dropwise at -100.degree. C., followed by addition
of dimethylformamide ("DMF") (2.77 ml) at -100.degree. C. The
reaction mixture was stirred at -95.degree. C. for 75 minutes. The
reaction was quenched by addition of aqueous ammonium chloride
(saturated) (8 ml) at -90.degree. C. The mixture was stirred for 10
minutes at -90.degree. C., warmed to 0.degree. C. and poured onto a
mixture of ice and water. The mixture was allowed to warm to
ambient temperature and then extracted twice with ethyl acetate.
The combined organic extracts were washed with water, dried over
sodium sulfate and concentrated to give 5-formyl-1-naphtoic acid
tert-butyl ester (3 g) as yellow oil. 1H-NMR (CDCl.sub.3, 400 MHz):
10.35 (s, 1H), 9.50 (s, 1H), 9.18 (d, 1H), 8.15 (d, 1H), 8.00 (d,
1H), 7.65-7.75 (m, 2H), 1.65 (s, 9H).
Example 9.4
Preparation of 5-(hydroxyimino-methyl)-1-naphtoic acid tert-butyl
ester
##STR00049##
[0260] To a solution of 5-formyl-1-naphtoic acid tert-butyl ester
(Example 9.3) (1.5 g) in ethanol (7.6 ml) was added aqueous
hydroxylamine (50% w/v) (0.48 ml) and the reaction mixture was
stirred at ambient temperature for 16 hours. The reaction mixture
was concentrated and the residue was purified by column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to
give 5-(hydroxyimino-methyl)-1-naphtoic acid tert-butyl ester (1.4
g). 1H-NMR (CDCl.sub.3, 400 MHz): 8.90 (d, 1H), 8.81 (s, 1H), 8.62
(d, 1H), 8.10 (d, 1H), 7.80 (d, 1H), 7.50-7.65 (m, 2H), 1.70 (s,
9H).
Example 9.5
Preparation of
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid tert-butyl ester
##STR00050##
[0262] To a solution of 5-(hydroxyimino-methyl)-1-naphtoic acid
tert-butyl ester (Example 9.4) (1.4 g) in dimethylformamide (3.4
ml) was added at 0.degree. C. N-chloro-succinimide ("NCS") (759
mg). The reaction mixture was warmed to ambient temperature and
stirred at ambient temperature for 30 minutes. The reaction mixture
was diluted with water and extracted with ethyl acetate. The
combined organic extracts were washed with water and brine, dried
over sodium sulfate and concentrated. The residue was purified by
column chromatography on silica gel (eluent: cyclohexane/ethyl
acetate) to give 5-(chloroxime-methyl)-1-naphtoic acid tert-butyl
ester. The 5-(chloroxime-methyl)-1-naphtoic acid tert-butyl ester
was dissolved in dimethylformamide (2 ml) and a solution of
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (1.7 g) and triethylamine
in dimethylformamide (2 ml) was added dropwise. The reaction
mixture was stirred at ambient temperature for 16 hours. The
reaction mixture was diluted with water and extracted with ethyl
acetate. The combined organic extracts were dried over sodium
sulfate and concentrated. The residue was purified by column
chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to
give
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid tert-butyl ester. 1H-NMR (CDCl.sub.3,
400 MHz): 8.90 (s, 1H), 8.62 (d, 1H), 7.45-7.70 (m, 5H), 7.45 (s,
1H), 7.80 (d, 1H), 4.30 (d, 1H), 3.90 (d, 1H), 1.70 (s, 9H).
Example 9.6
Preparation of
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid
##STR00051##
[0264] To a stirred solution of
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid tent-butyl ester (Example 9.5) (1.0 g)
in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) and
the reaction mixture was stirred at ambient temperature for 4
hours. The reaction mixture was concentrated to give a solid which
was washed with cyclohexane to give
5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid (0.76 g). 1H-NMR (DMSO, 400 MHz): 8.95
(m, 2H), 8.20 (d, 1H), 7.90 (d, 1H), 7.65-7.80 (m, 5H), 4.50 (q,
2H).
Example 10.1
Preparation of 4-bromo-3-methyl-benzylamine
##STR00052##
[0266] To a solution of 4-bromo-3-methyl-benzonitrile (commercially
available) (15 g) in diethyl ether (150 ml) under an argon
atmosphere was added a solution of lithium aluminum hydride in
diethyl ether (1M) (150 ml) at ambient temperature. The reaction
mixture was stirred at 40.degree. C. for 2 hours. Then the reaction
mixture was cooled to 0.degree. C. and quenched by successive
addition of water (10.5 ml), aqueous sodium hydroxide (20% w/v)
(7.5 ml) and water (37.5 ml). The phases were separated. The
organic phase was filtered through a plug of silica gel and the
filtrate concentrated to give 4-bromo-3-methyl-benzylamine (15.11
g) as a yellow oil. 1H-NMR (400 MHz, CDCl.sub.3): 7.47 (d, 1H),
7.19 (s, 1H), 6.98 (d, 1H), 3.80 (s, 2H), 2.39 (s, 3H) ppm.
Example 10.2
Preparation of N-(4-bromo-3-methyl-benzyl)-formamide
##STR00053##
[0268] To a solution of 4-bromo-3-methyl-benzylamine (Example 10.1)
(15.11 g) in ethyl formate (150 ml) was added triethylamine (1.5
ml) at ambient temperature. The reaction mixture was stirred at
reflux for 16 hours. The reaction mixture was concentrated and the
residue was triturated with diisopropyl ether/heptane (1:1) (100
ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a
white solid. 1H-NMR (400 MHz, CDCl.sub.3): 8.28 (s, 1H), 7.49 (m,
1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39
(s, 3H) ppm.
Example 10.3
Preparation of 1-bromo-4-isocyanomethyl-2-methyl-benzene
##STR00054##
[0270] To a solution of N-(4-bromo-3-methyl-benzyl)-formamide
(Example 10.2) (4.3 g) in dichloromethane (70 ml) was added a
solution of phosphorus oxychloride (2.8 g) in dichloromethane (15
ml) at 0-5.degree. C. The reaction mixture was stirred at ambient
temperature for 16 hours. The reaction mixture was poured onto a
mixture of ice and water (400 ml), and sodium hydrogen carbonate
(saturated) (100 ml) and ethyl acetate (250 ml) were added. The
phases were separated and the organic phase was washed with brine,
dried over sodium sulfate and concentrated to give
1-bromo-4-isocyanomethyl-2-methyl-benzene (4.52 g) as a brown oil.
1H-NMR (400 MHz, CDCl.sub.3): 7.54 (m, 1H), 7.22 (s, 1H), 7.03 (m,
1H), 4.57 (s, 2H), 2.42 (s, 3H) ppm.
Example 10.4
Preparation of
2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-
-dihydro-2H-pyrrole
##STR00055##
[0272] A mixture of
1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation
described in, for example, EP 1,731,512) (8.03 g),
1-bromo-4-isocyanomethyl-2-methyl-benzene (Example 10.3) (4.16 g)
and copper(I) oxide (0.13 g) in toluene (50 ml) was stirred at
110.degree. C. for 16 hours. The reaction mixture was concentrated
and the residue purified by chromatography on silica gel (eluent:
ethyl acetate/heptane) to give
2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluorome-
thyl-3,4-dihydro-2H-pyrrole (2.39 g). 1H-NMR (400 MHz, CDCl.sub.3):
7.39-6.86 (m, 7H), 5.39-4.98 (m, 1H), 3.24-2.77 (m, 1H), 2.35 (m,
3H), 2.32-2.09 (m, 1H) ppm.
Example 10.5
Preparation of
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]--
2-methyl-benzoic acid ethyl ester
##STR00056##
[0274] To a solution of
2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-
-dihydro-2H-pyrrole (Example 10.4) (7.0 g) in a mixture of ethanol
(60 ml) and dimethylformamide (20 ml), was added
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
("PdCl.sub.2(dppf)") (0.8 g) and sodium acetate (1.4 g) at ambient
temperature. The reaction mixture was stirred in a pressure reactor
in an atmosphere of carbon monoxide (6 bar) at 85.degree. C. for 16
hours. The reaction mixture was cooled to ambient temperature, the
ethanol was evaporated and aqueous sodium hydrogen carbonate
(saturated) (200 ml) and ethyl acetate (250 ml) were added. The
phases were separated and the organic phase was dried over sodium
sulfate and concentrated. The residue was purified by
chromatography on silica gel (eluent: 0-4% v/v methanol in
dichloromethane) to give
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]--
2-methyl-benzoic acid ethyl ester (2.8 g). 1H-NMR (CDCl.sub.3, 400
MHz): 8.04-7.06 (m, 7H), 5.46-5.06 (m, 1H), 4.35 (m, 2H), 3.27-3.79
(m, 1H), 2.59 (m, 3H), 2.38-2.10 (m, 1H), 1.39 (m, 3H) ppm.
Example 10.6
Preparation of
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]--
2-methyl-benzoic acid
##STR00057##
[0276] To a solution of
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]--
2-methyl-benzoic acid ethyl ester (Example 10.5) (2.8 g) in ethanol
(40 ml) was added a solution of sodium hydroxide (0.51 g) in water
(15 ml). The reaction mixture was stirred at reflux for 1 hour.
After cooling to ambient temperature aqueous hydrochloric acid (1M)
(20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The
phases were separated and the organic phase was washed with brine,
dried over sodium sulfate and concentrated. The residue was
recrystallised from diisopropyl ether to give
4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-
-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1H-NMR
(d.sub.6-DMSO, 400 MHz): 13.07 (s, 1H), 7.91-7.58 (m, 6H), 4.85 (d,
1H), 4.44 (d, 1H), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Example 11.1
Preparation of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-naphthalene-1-carboxylic acid
##STR00058##
[0278] A sealed tube purged with argon was charged with
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-n-
aphthalene-1-carboxylic acid (preparation described in, for
example, WO 2007/079162) (454 mg), methyl boronic acid (180 mg),
palladium(II) acetate (224 mg), benzoquinone (90 mg), silver
carbonate (275 mg), potassium hydrogen phosphate (8265 mg) and
tent-butanol (4 ml). The tube was heated at 100.degree. C. under
vigorous stirring for 24 hours. The reaction mixture was
concentrated and the residue acidified by addition of aqueous
hydrochloric acid (1N). The mixture was extracted with ethyl
acetate (3.times.25 ml). The combined organic layers were washed
with water and brine, treated with charcoal, dried over sodium
sulfate and concentrated. The residue was purified by preparative
reverse phase HPLC to give
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-
-3-yl]-2-methyl-naphthalene-1-carboxylic acid (100 mg). LC-MS:
RT=2.41 min, [M-H].sup.-=466/468, Method A. 1H-NMR (CDCl.sub.3, 400
MHz): 8.8 (m, 1H), 8.1 (m, 1H), 7.7-7.4 (m, 6H), 4.3 (d, 1H), 3.9
(d, 1H), 2.6 (s, 3H).
Example 12.1
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-benzoic acid tert-butyl ester
##STR00059##
[0280] To a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid tert-butyl ester (preparation of similar
compounds described in, for example, EP 1,731,512) (2.83 g) in
tetrahydrofuran (25 ml) that was stirred at -78.degree. C. for 5
minutes under argon, was slowly added lithium
bis(trimethylsilyl)amide ("LiHMDS") (1M in hexane) (6.9 ml). After
3 hours at -78.degree. C., a cold (-20.degree. C.) solution of
2-benzenesulfonyl-3-phenyl-oxaziridine (commercially available)
(2.34 g) in tetrahydrofuran (10 ml) was added quickly. The
temperature was kept below -65.degree. C. for 4 hours and 30
minutes. The reaction was quenched by addition of aqueous ammonium
chloride (saturated) at -78.degree. C. tert-Butyl methyl ether
("TBME") was added and the phases were separated. The organic layer
was washed successively with ammonium chloride and brine, dried
over magnesium sulfate and concentrated. The residue was purified
by column chromatography on silica gel (eluent: heptane/TBME 9:1)
to give
4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-benzoic acid tert-butyl ester (738 mg) as a white
solid.
Example 12.2
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-benzoic acid
##STR00060##
[0282] To a solution of
4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-benzoic acid tent-butyl ester (Example 12.1) (500
mg) in dichloromethane (20 ml) was added trifluoroacetic acid
("TFA") (4 ml) and the reaction mixture was stirred at ambient
temperature for 16 hours. To the reaction mixture was diluted with
water and the phases were separated. The organic layer was washed
with water and brine, dried over magnesium sulfate and
concentrated. The residue was suspended in diisopropyl
ether/pentane (1:3). The solids were isolated by filtration and
washed with pentane to give
4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-benzoic acid (395 mg) as a white solid. M.p.
215-217.degree. C. 1H-NMR (CDCl.sub.3, 400 MHz): 7.98 (d, 1H), 7.72
(s, 1H), 7.69 (s, 1H), 7.52 (s, 2H), 7.40 (s, 1H), 5.76 (s, 1H),
2.61 (s, 3H).
Example 13.1
Preparation of
4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoromethyl-1-hydroxyimino-but-2-eny-
l]-2-methyl-benzoic acid tert-butyl ester
##STR00061##
[0284] To a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid tert-butyl ester (preparation of similar
compounds described in, for example, EP 1,731,512) (5 g) in dry
tetrahydrofuran (110 ml) under at atmosphere of argon was added
lithium bis(trimethylsilyl)amide ("LiHMDS") (1M in tetrahydrofuran)
(11 ml) at ambient temperature. Then, more lithium
bis(trimethylsilyl)amide ("LiHMDS") (1M in tetrahydrofuran) (6 ml
in total) was added portionwise to the reaction mixture until
completion of the reaction was observed. Then, the reaction mixture
was quenched by addition of aqueous ammonium chloride (saturated).
The mixture was extracted several times with diethyl ether. The
combined organic extracts were dried over magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: heptane/diethyl ether 9:1) to give
4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoromethyl-1-hydroxyimino-but-2-eny-
l]-2-methyl-benzoic acid tert-butyl ester (2 g).
Example 13.2
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester
##STR00062##
[0286] To a solution of
4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoromethyl-1-hydroxyimino-but-2-eny-
l]-2-methyl-benzoic acid tert-butyl ester (Example 13.1) (1 g) in a
mixture of ethanol/water/tetrahydrofuran (1:2:2) (25 ml) was added
sodium nitrite (500 mg). The reaction mixture was acidified to pH
1.5 by addition of aqueous hydrochloric acid (2M). The reaction
mixture was stirred at ambient temperature for 24 hours. Further
sodium nitrite (400 mg) was added and the reaction mixture
acidified to pH 1.5 by addition of further aqueous hydrochloric
acid (2M) and the reaction mixture was stirred at ambient
temperature for 2 hours. Further sodium nitrite (100 mg) was added
and the reaction mixture acidified to pH 1.5 by addition of further
aqueous hydrochloric acid (2M) and the reaction mixture was stirred
at ambient temperature for 24 hours. Further sodium nitrite (200
mg) was added and the reaction mixture acidified to pH 1.5 by
addition of further aqueous hydrochloric acid (2M) and the reaction
mixture was stored at ambient temperature for 48 hours. The
reaction mixture was diluted with dichloromethane and water. The
phases were separated and the organic layer was washed successively
with water and brine, dried over magnesium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: heptane/diethyl ether 9:1) to give
4-{5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl}-2-methyl-benzoic acid tert-butyl ester (512 mg) as
yellow solid.
Example 13.3
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl]-2-methyl-benzoic acid
##STR00063##
[0288] To a solution of
4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 13.2)
(634 mg) in dichloromethane (4 ml) was added trifluoroacetic acid
("TFA") (0.2 ml) and the reaction mixture was stirred at ambient
temperature for 8 hours. Further trifluoroacetic acid (0.2 ml) was
added and the reaction mixture was stirred at ambient temperature
for 16 hours. The reaction mixture was diluted with ethyl acetate
and water and the phases were separated. The organic layer was
washed successively with water and brine, dried over magnesium
sulfate, and concentrated to give
4-[5-(3,5-dichloro-phenyl)-4-hydroxyimino-5-trifluoromethyl-4,5-dihydro-i-
soxazol-3-yl]-2-methyl-benzoic acid (554 mg) as a yellow foam.
1H-NMR (CDCl.sub.3, 400 MHz): 8.94 (s, 1H), 8.10 (d, 1H), 7.90 (m,
2H), 7.59 (m, 2H), 7.44 (m, 1H), 2.69 (s, 3H).
Example 14.1
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid tert-butyl ester
##STR00064##
[0290] To a solution of
4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-benzoic acid tert-butyl ester (preparation of similar
compounds described in, for example, EP 1,731,512) (500 mg) in
tetrahydrofuran (6 ml) that was stirred at -78.degree. C. for 15
minutes under argon, was slowly added lithium
bis(trimethylsilyl)amide ("LiHMDS") (1M in hexane) (1.1 ml). The
reaction mixture was stirred at -78.degree. C. for 1.5 hours. Then
N-fluorobenzenesulfonimide ("NFSI") (433 mg) was added quickly and
the reaction mixture was stirred at -78.degree. C. for 2 hours. The
reaction was quenched by addition of aqueous ammonium chloride
(saturated) at -78.degree. C. tert-Butyl methyl ether ("TBME") was
added and the phases were separated. The organic layer was washed
successively with aqueous ammonium chloride (saturated) and brine,
dried over magnesium sulfate and concentrated. The residue was
purified by column chromatography on silica gel (eluent:
dichloromethane/heptane 1:2) to give
4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-is-
oxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (200 mg) as a
colorless oil.
Example 14.2
Preparation of
4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid
##STR00065##
[0292] To a solution of
4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 14.1) (310
mg) in dichloromethane (3.1 ml) was added trifluoroacetic acid
("TFA") (0.62 ml). The reaction mixture was stirred at ambient
temperature for 16 hours. The reaction mixture was concentrated and
the residue taken up in dichloromethane and water. The phases were
separated and the organic layer was washed successively with water
and brine, dried over magnesium sulfate, and concentrated to give a
1:1 mixture of the diastereoisomers of
4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isox-
azol-3-yl]-2-methyl-benzoic acid (255 mg) as a white solid. 1H-NMR
(CDCl.sub.3, 400 MHz): 8.13 (2.times.d, 1H), 7.68 (m, 2H), 7.60
(2.times.s, 1H), 7.52 (2.times.s, 1H), 7.48 (m, 1H), 6.48 and 6.35
(2.times.d, 1H), 2.70 and 2.68 (2.times.s, 3H).
Example 15.1
5-(3,5-Dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazole-3-carboxylic
acid ethyl ester
##STR00066##
[0294] A solution of ethyl chlorooximidoacetate (9.0 g, 59.1 mmol)
in ethylacetate (30 ml) was added at ambient temperature with a
syringe pump over a period of 40 h to a suspension of
1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl) benzene (prepared
according to WO 2005/085216) (9.5 g, 39.4 mmol) and sodium hydrogen
carbonate (15.9 g, 189 mmol) in ethylacetate (85 ml). The reaction
mixture was diluted with ethylacetate and washed with water. The
organic phase was separated dried over sodium sulfate and
concentrated. The residue was purified by chromatography over
silica (cyclohexane/ethylacetate; 4/1) to give 8.9 of a yellow oil.
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.45 (m, 3H), 4.49 (q, 2H), 3.96
(d, 1H), 3.59 (d, 1H), 1.40 (t, 3H).
Example 15.2
[5-(3,5-Dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-methanol
##STR00067##
[0296] Lithiumborohydride (0.86 g, 39.7 mmol) was added in portions
at ambient temperature to a solution of
5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carboxy-
lic acid ethyl ester (8.8 g, 24.8 mmol) in tetrahydrofuran (100 ml)
and a small amount of methanol (1.5 ml). After stirring for 2 h at
40.degree. C. the reaction mixture was cooled to 20.degree. C.,
made acidic with 2N hydrochloric acid and stirred for 1 h. Solid
potassium carbonate was added until the reaction mixture was
slightly alkaline. After extraction with ethylacetate the organic
phase was separated, dried over sodium sulfate and concentrated to
give 7.98 g of a white material which was used in the next step
without further purification .sup.1H-NMR (CDCl.sub.3, 400 MHz):
7.38-7.48 (m, 3H), 4.47 (d, 2H), 3.82 (d, 1H), 3.43 (d, 1H), 1.93
(t, 1H).
Example 15.3
5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbalde-
hyde
##STR00068##
[0298] Manganese dioxide (17.7 g, 203 mmol) was added to a solution
of
[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-met-
hanol (7.98 g, 25.4 mmol) in chloroform (170 ml). After stirring
for 4 h at 60.degree. C. the reaction mixture was cooled to
20.degree. C. and filtered. The filtrate was concentrated and the
residue was purifided by chromatography over silica
(cyclohexane/ethylacetate; 3/1) to give 4.1 g of a yellow oil.
1H-NMR (CDCl.sub.3, 400 MHz): 9.93 (s, 1H) 7.42-7.48 (m, 3H), 3.88
(d, 2H), 3.50 (d, 1H).
Example 15.4
5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbalde-
hyde oxime
##STR00069##
[0300] To a solution of
5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbald-
ehyde (2 g) in EtOH (4 mL) and H.sub.2O (2 drops), was added
aqueous NH.sub.2OH (50% in water, 0.48 mL). The solution was
stirred at room temperature for 3 hours then allowed to stand at
room temperature for 16 hours. Then the solution was stirred again
and more hydroxylamine (0.04 mL) was added. After 3 hours, the
reaction was quenched by addition of water. After extraction with
ethylacetate, the organic phase was separated, dried over magnesium
sulfate and concentrated to give 2.02 g of a yellow solid which was
used in the next step without further purification. 1H-NMR
(CDCl.sub.3, 400 MHz) shows a mixture of diastereoisomers: 8.07 and
7.94 (s, 1H), 7.43-7.38 (m, 3H), 3.88 (d, 1H), 3.50 (d, 1H).
Example 15.5
5'-(3,5-Dichloro-phenyl)-5'-trifluoromethyl-4',5'-dihydro[3,3']biisoxazoly-
l-5-carboxylic acid
##STR00070##
[0302] To a solution of
5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbald-
ehyde oxime (500 mg) in dimethylformamide (10 mL) under argon at
room temperature, was added N-chlorosuccinimide (225 mg). The
solution was stirred at room temperature for 30 minutes then was
allowed to stand at room temperature for 14 hours. The reaction was
then quenched by addition of water. After extraction with
dichloromethane, the organic phase was separated, dried over
magnesium sulfate and concentrated to give an orange residue which
was used in the next step without further purification.
[0303] To a solution of tert-butyl propiolate (2 mL) in chloroform
(10 mL) was added a solution of the preceeding residue in
chloroform (10 mL), at room temperature. Then triethylamine (0.3
mL) was added. The solution was stirred at room temperature for 30
minutes then was allowed to stand at room temperature for 14
hours.
[0304] The reaction was then quenched by addition of water. After
extraction with dichloromethane, the organic phase was separated,
dried over magnesium sulfate and concentrated to give a yellow oil.
The residue was purified by chromatography over silica
(heptane/dichloromethane; 1/0 to 1/1) to give 393 mg of
5'-(3,5-Dichloro-phenyl)-5'-trifluoromethyl-4',5'-dihydro-[3,3']biisoxazo-
lyl-5-carboxylic acid tert-butyl ester as a colorless oil.
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.46 (m, 2H) 7.44-7.43 (m, 1H),
7.23 (s, 1H), 4.15 (d, 1H), 3.78 (d, 1H), 1.60 (s, 9H).
[0305] Similarly to example 14.2, the
5'-(3,5-Dichloro-phenyl)-5'-trifluoromethyl-4',5'-dihydro-[3,3']biisoxazo-
lyl-5-carboxylic acid tert-butyl ester (393 mg) was deprotected
with trifluoroacetic acid to give the
5'-(3,5-Dichloro-phenyl)-5'-trifluoromethyl-4',5'-dihydro-[3,3']biisoxazo-
lyl-5-carboxylic acid (331 mg) as a white solid. .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.65 (bs, 1H) 7.46 (m, 2H), 7.44-7.42 (m,
2H), 4.17 (d, 1H), 3.81 (d, 1H).
Example 16.1
5-Formyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester
##STR00071##
[0307] To a solution of 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid
methyl ester (2 g) in carbon tetrachloride (100 mL) under argon,
was added N-bromosuccinimide (5 g). The reaction mixture was
refluxed under argon for 10 minutes then benzoyl peroxide (75% in
water, 300 mg) was added. After 1 hour at reflux, more benzoyl
peroxide (75% in water, 130 mg) was added and the reaction was
refluxed for a further hour. The reaction mixture was then cooled
to room temperature, and the solution was filtered. The filtrate
was concentrated to give a yellow residue that was then dissolved
in water (16 mL). To this solution was added K.sub.2CO.sub.3 (500
mg) at room temperature and the reaction mixture was heated at 90 C
for one hour.
[0308] The reaction was then diluted with ethyl acetate, the
aqueous phase was acidified to pH=1 with HCl 1M. After extraction
with ethyl acetate, the organic phase was separated, dried over
magnesium sulfate and concentrated to give a yellow oil. The
residue was purified by chromatography over silica (heptane/diethyl
ether; 1/0 to 8/2) to give
5-Formyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (210
mg) as a white solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 9.94 (s,
1H) 7.30 (s, 1H), 4.26 (s, 3H), 3.90 (s, 3H).
Example 16.2
5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2--
methyl-2H-pyrazole-3-carboxylic acid
##STR00072##
[0310] To a solution of 5-Formyl-2-methyl-2H-pyrazole-3-carboxylic
acid methyl ester (210 mg) in ethanol (10 mL), was added aqueous
NH.sub.2OH (50% in water, 0.10 mL). The solution was stirred at
room temperature for 4 hours then was concentrated to give a white
solid which was then dissolved in dimethylformamide (4 mL). To this
solution was added N-chlorosuccinimide (180 mg). The solution was
stirred at room temperature for 4 hours. This solution was slowly
added to a solution of
1,3-Dichloro-5-(1-trifluoromethyl-vinyl)-benzene (750 mg) (prepared
according to WO 2005/085216) in dimethylformamide (6 mL). When the
addition was completed, triethylamine (0.2 mL) was added. The
solution was stirred at room temperature for 4 hours then the
reaction was then quenched by addition of water. After extraction
with diethyl ether, the organic phase was separated, dried over
magnesium sulfate and concentrated to give an orange oil. The
residue was purified by chromatography over silica (heptane/diethyl
ether; 1/0 to 7/3) to give 300 mg of
5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz-
ol-3-yl]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a
white solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.48 (m, 2H),
7.39-7.38 (m, 1H), 7.23 (s, 1H), 4.17 (s, 3H), 4.14 (d, 1H), 3.89
(s, 3H), 3.75 (d, 1H).
[0311] Similarly to example 7.2,
5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-2H-pyrazole-3-carboxylic acid was obtained from the
5-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-
-methyl-2H-pyrazole-3-carboxylic acid methyl ester. .sup.1H-NMR
(CDCl.sub.3, 400 MHz): 7.49 (m, 2H), 7.41 (m, 1H), 7.35 (s, 1H),
4.19 (s, 3H), 4.15 (d, 1H), 3.76 (s, 3H).
TABLE-US-00002 TABLE A Comp Mole- LC-MS No. Structure RT (min)
cular ion method A1 ##STR00073## 2.25 [M + H].sup.+ = 538 A A2
##STR00074## 2.15 [M + H].sup.+ = 524 A A3 ##STR00075## 1.98 [M +
H].sup.+ = 475 D A4 ##STR00076## 1.85 [M + H].sup.+ = 461 D A5
##STR00077## 2.06 [M + H].sup.+ = 580 E A6 ##STR00078## 1.95 [M +
H].sup.+ = 566 E A7 ##STR00079## 2.05 [M + H].sup.+ = 585 E A8
##STR00080## 2.04 [M + H].sup.+ = 585 E A9 ##STR00081## 1.87 [M +
H].sup.+ = 519 E A10 ##STR00082## 1.55 [M + H].sup.+ = 521 E A11
##STR00083## 1.79 [M + H].sup.+ = 505 E A12 ##STR00084## 2.05 [M +
H].sup.+ = 516 E A13 ##STR00085## 1.7 [M + H].sup.+ = 518 E A14
##STR00086## 1.96 [M + H].sup.+ = 502 E A15 ##STR00087## 2.11 [M +
H].sup.- = 555 A A16 ##STR00088## 2.05 [M + H].sup.+ = 539 A A17
##STR00089## 2.20 [M + H].sup.+ = 491 A A18 ##STR00090## 3.17 [M +
H].sup.+ = 520.1 E A19 ##STR00091## 3.51 [M + H].sup.+ = 536.9 E
A20 ##STR00092## 4.04 [M + H].sup.+ = 518.9 E A21 ##STR00093## 3.86
[M + H].sup.+ = 504.9 E A22 ##STR00094## 5.52 [M + H].sup.+ = 564 E
A23 ##STR00095## 4.31 [M + H].sup.+ = 547 E A24 ##STR00096## 3.18
[M + H].sup.+ = 549 E A25 ##STR00097## 4.05 [M + H].sup.+ = 533 E
A26 ##STR00098## 3.47 [M + H].sup.+ = 562 C A27 ##STR00099## 4.12
[M + H].sup.+ = 544 C A28 ##STR00100## 3.18 [M + H].sup.+ = 546 C
A29 ##STR00101## 3.91 [M + H].sup.+ = 530 C A30 ##STR00102## 2.18
[M + H + HCOOH].sup.+ = 559/561/563 E A31 ##STR00103## 2.26 [M +
H].sup.- = 539 A A32 ##STR00104## 3.53 [M + H].sup.+ = 555 E A33
##STR00105## 4.06 [M + H].sup.+ = 537 E A34 ##STR00106## 3.3 [M +
H].sup.+ = 539 E A35 ##STR00107## 3.91 [M + H].sup.+ = 523 E A36
##STR00108## 4.05 [M + H].sup.+ = 539 C A37 ##STR00109## 3.27 [M +
H].sup.+ = 540 C A38 ##STR00110## 3.87 [M + H].sup.+ = 524 C A39
##STR00111## 2.14 [M + H].sup.+ = 547/549 F A40 ##STR00112## 2.16
[M + H].sup.+ = 579/581 F A41 ##STR00113## 2.05 [M + H].sup.+ =
565/567 F A42 ##STR00114## 2.06 [M + H].sup.+ = 635/637 E A43
##STR00115## 2.35 [M + H].sup.+ = 617/619 E A44 ##STR00116## 1.94
[M + H].sup.+ = 619/621 E A45 ##STR00117## 2.15 [M + H].sup.+ =
603/605 E A46 ##STR00118## 3.04 [M + H].sup.+ = 519.0 C A47
##STR00119## 3.59 [M + H].sup.+ = 501.0 C A48 ##STR00120## 2.82 [M
+ H].sup.+ = 503.0 C A49 ##STR00121## 3.40 [M + H].sup.+ = 487.0 C
A50 ##STR00122## 2.23 [M + H].sup.+ = 603/605 A A51 ##STR00123##
2.43 [M + H].sup.+ = 537 B A52 ##STR00124## 2.93 [M + H].sup.+ =
519 B A53 ##STR00125## 2.17 [M + H].sup.+ = 521 B A54 ##STR00126##
2.75 [M + H].sup.+ = 505 B A55 ##STR00127## 2.6 [M + H].sup.+ = 591
B A56 ##STR00128## 3.11 [M + H].sup.+ = 532 B A57 ##STR00129## 2.35
[M + H].sup.+ = 534 B A58 ##STR00130## 2.94 [M + H].sup.+ = 518 B
A59 ##STR00131## 2.85 [M + H].sup.+ = 580 B A60 ##STR00132## 3.4 [M
+ H].sup.+ = 521 B A61 ##STR00133## 3.22 [M + H].sup.+ = 507 B A62
##STR00134## 2.55 [M + H].sup.+ = 523 B A63 ##STR00135## 4.7 [M +
H].sup.+ = 466 C A64 ##STR00136## 3.36 [M + H].sup.+ = 510.81 C A65
##STR00137## 3.94 [M + H].sup.+ = 492.87 C A66 ##STR00138## 3.82 [M
+ H].sup.+ = 478.88 C A67 ##STR00139## 3.05 [M + H].sup.+ = 494.87
C A68 ##STR00140## 4.48 [M + H].sup.+ = 498 C A69 ##STR00141## 4.59
[M + H].sup.+ = 479.95 C A70 ##STR00142## 4.13 [M + H].sup.+ =
481.84 C
[0312] Table A provides compounds of formula (I), their structure,
retention time, molecular ion and the LC-MS method.
Example 17.1
3-Bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole
##STR00143##
[0314] To a solution of dibromoformaldoxime (6.23 g, Tetrahedron
Lett., 1984, 487) in ethyl acetate (150 ml) was added
1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl) benzene (6.3 g,
prepared according to WO 2005/085216) and sodium bicarbonate (9.5
g). The reaction was stirred at room temperature for 96 h. Water
was added, then the two layers were then separated. The aqueous
layer was extracted with ethyl acetate and the combined organic
layers were dried over sodium sulfate and concentrated to afford a
white solid (6.23 g). 1H-NMR (CDCl.sub.3, 400 MHz): 7.47-7.43 (m,
3H), 3.95 (d, 1H), 3.58 (d, 1H)
Example 17.2
3-Chloro-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole
##STR00144##
[0316] Concentrated hydrochloric acid (2.5 ml) was added on sodium
chloride to generate dry HCl gas. This was pushed with argon to
bubble into a solution of
3-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole
(182 mg) in tetrahydrofuran (5 ml). The reaction was stirred
overnight at room temperature then water and diethyl ether ether
were added. The two layers were then separated. The aqueous layer
was extracted with diethyl etherether. The combined organic layers
were washed with water, dried over dodium sulfate and concentrated
to afford a residue, which was taken up in cyclohexane and
filtered; The filtrate was concentrated in vacuo then dried under
high vacuum to afford a white solid (132 mg). 1H-NMR (CDCl.sub.3,
400 MHz): 7.44-7.37 (m, 3H), 3.84 (d, 1H), 3.50 (d, 1H)
Example 17.3
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3--
methyl-1H-pyrazole-4-carboxylic acid ethyl ester
##STR00145##
[0318] To a solution of 3-methyl-4-ethyl ester pyrazole (616 mg) in
acetonitrile (15 ml) under argon was added sodium hydride (60% in
oil, 160 mg). The reaction mixture was stirred for 1 hour at room
temperature with addition of 5 ml tetrahydrofuran to help
solubilising the nucleophile. 10 ml of the resulting solution was
added slowly to a solution of chloroisoxazoline (Example 17.2, 630
mg) in acetonitrile (10 ml) at room temperature. The resulting red
solution was stirred at rt for 30 min. 5 ml of the pyrazole sodium
salt solution was added again and the mixture was stirred a further
1.5 hour. Another 0.2 ml of the pyrazole sodium salt solution
solution was added and after 30 min the reaction was quenched by
adding water and dichloromethane. The two layers were separated.
The aqueous layer was extracted with dichloromethane. The combined
organic layers were washed with brine, dried over Na2SO4 and
concentrated. The crude residue was purified by column
chromatography (from c-Hex (100%) to c-Hex:EtOAc (80:20)) to afford
the title intermediate (872 mg) as the major regioisomer (along
with
1-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5--
methyl-1H-pyrazole-4-carboxylic acid ethyl ester). 1H-NMR
(CDCl.sub.3, 400 MHz): 8.5 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H), 4.35
(d, 1H), 4.30 (q, 2H), 3.95 (d, 1H), 2.50 (s, 3H), 1.35 (t,
3H).
Example 17.4
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3--
methyl-1H-pyrazole-4-carboxylic acid
##STR00146##
[0320] To a solution of ethyl ester of example 17.3 (493 mg) in 10
ml THF:water (4:1) was added sodium hydroxide (68 mg). The reaction
mixture was stirred at room temperature for 3 hours before adding 2
ml of methanol. The reaction was stirred overnight before
evaporation of the solvent in vacuo. The aqueous layer was
extracted with ethyl acetate before being acidified. It was then
extracted several times with ethyl acetate. The combined organic
layers were dried over sodium sulfate and concentrated to afford a
mixture of regioisomeric acids (224 mg, 3-methyl major and 5-methyl
minor). 1H-NMR (CDCl.sub.3, 400 MHz): 8.5 (s, 1H), 7.5 (m, 2H),
7.45 (m, 1H), 4.35 (d, 1H), 3.85 (d, 1H), 2.50 (s, 3H).
Example 18.1
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-1H-
-pyrazole-3-carboxylic acid methyl ester
##STR00147##
[0322] To a solution of pyrazole-3-carboxylic acid methyl ester
(504 mg) in acetonitrile (25 ml) under argon was added sodium
hydride (160 mg). The reaction mixture was stirred at room
temperature for 1 h. 15 mf of this solution was added dropwise to a
solution of chloroisoxazoline of example 17.2 (630 mg) in
acetonitrile (10 ml). It was then stirred at room temperature for 1
h; 10 ml of pyrazole solution was added again and the mixture was
stirred for 1.5 hour. The reaction was quenched by adding water and
dichloromethane. The two layers were separated. The aqueous layer
was extracted with dichloromethane. The combined organic layers
were washed with brine, dried over sodium sulfate and concentrated.
The crude residue was purified by column chromatography (from c-Hex
(100%) to c-Hex:EtOAc (80:20)) to afford the title intermediate
(680 mg). 1H-NMR (CDCl3, 400 MHz): 8.15 (s, 1H), 7.5 (m, 2H), 7.45
(m, 1H), 4.45 (d, 1H), 4.10 (d, 1H), 3.95 (s, 3H).
Example 18.2
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-1H-
-pyrazole-3-carboxylic acid
##STR00148##
[0324] To a solution of methyl ester of example 18.1 (408 mg) in 5
ml THF:water (4:1) was added sodium hydroxide (60 mg). The reaction
was stirred 2 hours at room temperature before evaporation of the
solvent in vacuo. The aqueous layer was extracted with ethyl
acetate before being acidified. It was then extracted several times
with ethyl acetate. The combined organic layers were dried over
sodium sulfate and concentrated to afford the title acid (369 mg)
as a yellowish solid. 1H-NMR (CDCl.sub.3, 400 MHz): 8.20 (s, 1H),
7.50 (m, 2H), 7.45 (m, 1H), 7.05 (s, 1H), 4.45 (d, 1H), 4.10 (d,
1H).
Example 19.1
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-1H-
-pyrazole-4-carboxylic acid methyl ester
##STR00149##
[0326] To a solution of pyrazole-4-carboxylic acid methyl ester
(756 mg) in acetonitrile (30 ml) under argon was added sodium
hydride (240 mg). The reaction mixture was stirred at room
temperature for 1 h. 15 mf of this solution was added dropwise to a
solution of chloroisoxazoline of example 17.2 (630 mg) in
acetonitrile (10 ml). It was then stirred at room temperature for 1
h; 15 ml of pyrazole solution was added again and the mixture was
stirred over the weekend. The reaction was quenched by adding water
and dichloromethane. The two layers were separated. The aqueous
layer was extracted with dichloromethane. The combined organic
layers were washed with brine, dried over sodium sulfate and
concentrated. The crude residue was purified by column
chromatography (from c-Hex (100%) to c-Hex:EtOAc (80:20)) to afford
the title intermediate (810 mg) as a yellow solid. 1H-NMR (CDCl3,
400 MHz): 8.60 (s, 1H), 8.10 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H),
4.35 (d, 1H), 4.00 (d, 1H), 3.75 (s, 3H).
Example 19.2
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-1H-
-pyrazole-4-carboxylic acid
##STR00150##
[0328] To a solution of methyl ester of example 19.1 (513 mg) in
12.5 ml THF:water (4:1) was added sodium hydroxide (75 mg). The
reaction mixture was stirred at room temperature for 3 hours before
adding 2 ml of methanol. The reaction was stirred overnight before
evaporation of the solvent in vacuo. The aqueous layer was
extracted with ethyl acetate before being acidified. It was then
extracted several times with ethyl acetate. The combined organic
layers were dried over sodium sulfate and concentrated to afford
the title acid (452 mg) as a yellow solid. 1H-NMR (CDCl.sub.3, 400
MHz): 8.55 (s, 1H), 8.05 (s, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 4.35
(d, 1H), 4.00 (d, 1H).
Example 19.3
Method C for Preparing the Compounds of the Invention from a
Carboxylic Acid
##STR00151##
[0330] To a solution/suspension of the appropriate carboxylic acid,
for example,
1-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo-
l-3-yl]-1H-pyrazole-4-carboxylic acid (example 19.2, 98 mg) in
dichloromethane (10 ml) was added the appropriate amine, for
example, thietan-3-ylamine (trifluoracetic acid salt, 118 mg),
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) (80 mg) and triethylamine (0.125 ml). The
resulting mixture was stirred at rt overnight. It was then quenched
with aqueous diluted hydrochloric acid. The organic layer was
washed with water before being dried over sodium sulfate and
concentrated. The residue was purified by column chromatography on
silica gel (eluent: from c-Hex:EA (95:5) to c-Hex:EA (75:25)) to
afford Compound No. B4 of Table B (72 mg) as a colorless solid.
M.p. 85-87.degree. C.
[0331] This method was used to make:
[0332] Compound Nos. B1, B2 of Table B from
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-
-methyl (5-methyl regioisomer)-1H-pyrazole-4-carboxylic acid
(preparation described in Example 17.4),
[0333] Compound Nos. B3 of Table B from
1-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-1-
H-pyrazole-3-carboxylic acid (preparation described in Example
18.2),
TABLE-US-00003 TABLE B Comp No. Structure M.p. .sup.1H-NMR B1
##STR00152## 177-180.degree. C. (CDCl.sub.3, 400 Mhz): 8.32 (s,
1H), 7.50 (m, 2H), 7.45 (m, 1H), 6.21 (br d, 1H), 5.47 (m, 1H),
4.30 (d, 1H), 3.95 (d, 1H), 3.40 (m, 4H), 2.50 (s, 3H). B2
##STR00153## 77.degree. C. (CDCl.sub.3, 400 Mhz): 7.78 (s, 1H),
7.50 (m, 2H), 7.45 (m, 1H), 6.15 (br d, 1H), 5.39 (m, 1H), 4.36 (d,
1H), 4.00 (d, 1H), 3.40 (m, 4H), 2.85 (s, 3H). B3 ##STR00154##
77-80.degree. C. (CDCl.sub.3, 400 Mhz): 8.12 (s, 1H), 7.50 (m, 2H),
7.45 (m, 1H), 7.19 (br d, 1H), 7.00 (s, 1H), 5.42 (m, 1H), 4.39 (d,
1H), 4.00 (d, 1H), 3.45 (m, 4H), 2.50 (s, 3H). B4 ##STR00155##
85-87.degree. C. (CDCl.sub.3, 400 Mhz): 8.49 (s, 1H), 7.98 (s, 1H),
7.50 (m, 2H), 7.45 (m, 1H), 6.22 (br d, 1H), 5.40 (m, 1H), 4.32 (d,
1H), 3.98 (d, 1H), 3.42 (m, 4H)
[0334] Table B provides compounds of formula (I), their structure,
melting points and .sup.1H-NMR data.
Biological Examples
[0335] This Example illustrates the insecticidal and acaricidal
properties of compounds of formula (I). The tests were performed as
follows:
[0336] Spodoptera littoralis (Egyptian Cotton Leafworm):
[0337] Cotton leaf discs were placed on agar in a 24-well
microtiter plate and sprayed with test solutions at an application
rate of 200 ppm. After drying, the leaf discs were infested with 5
L1 larvae. The samples were checked for mortality, feeding
behavior, and growth regulation 3 days after treatment (DAT).
[0338] The following compound gave at least 80% control of
Spodoptera littoralis: A1, A2, A5, A6, A7, A8, A10, A11, A12, A13,
A14, A15, A16, A17, A18, A19, A21, A22, A23, A24, A25, A30, A31,
A32, A33, A34, A35, A39, A40, A41A42, A43, A44, A45, A46, A47, A48,
A49, A50, A51, A53, A54, A55, A59, A60, A61, A62.
[0339] Heliothis virescens (Tobacco Budworm):
[0340] Eggs (0-24 h old) were placed in 24-well microtiter plate on
artificial diet and treated with test solutions at an application
rate of 200 ppm (concentration in well 18 ppm) by pipetting. After
an incubation period of 4 days, samples were checked for egg
mortality, larval mortality, and growth regulation.
[0341] The following compound gave at least 80% control of
Heliothis virescens: A1, A2, A3, A4, A5, A6, A7, A8, A10, A11, A12,
A13, A14, A15, A16, A18, A19, A21, A22, A24, A25, A30, A31, A32,
A33, A34, A35, A37, A38, A39, A40, A42, A43, A44, A45, A46, A47,
A48, A49, A50, A51, A55, AA57, A58, A59, A60, A61, A62.
[0342] Plutella xylostella (Diamond Back Moth):
[0343] 24-well microtiter plate (MTP) with artificial diet was
treated with test solutions at an application rate of 200 ppm
(concentration in well 18 ppm) by pipetting. After drying, the
MTP's were infested with L2 larvae (7-12 per well). After an
incubation period of 6 days, samples were checked for larval
mortality and growth regulation.
[0344] The following compound gave at least 80% control of Plutella
xylostella: A1, A2, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14,
A15, A16, A17, A18, A19, A20, A21, A22, A24, A25, A30, A31, A32,
A33, A34, A35, A37, A38, A39, A40, A42, A43, A44, A45, A46, A47,
A48, A49, A50, A51, A52, A53, A54, A55, A57, A58, A59, A60, A61,
A62, B3.
[0345] Diabrotica balteata (Corn Root Worm):
[0346] A 24-well microtiter plate (MTP) with artificial diet was
treated with test solutions at an application rate of 200 ppm
(concentration in well 18 ppm) by pipetting. After drying, the
MTP's were infested with L2 larvae (6-10 per well). After an
incubation period of 5 days, samples were checked for larval
mortality and growth regulation.
[0347] The following compound gave at least 80% control of
Diabrotica balteata: A1, A2, A5, A6, A7, A10, A11, A12, A13, A14,
A15, A16, A17, A18, A19, A21, A22, A24, A25, A30, A31, A32, A33,
A34, A35, A38, A39, A40, A42, A43, A44, A45, A46, A47, A48, A49,
A50, A59, A60, A61, A62.
[0348] Thrips tabaci (Onion Thrips):
[0349] Sunflower leaf discs were placed on agar in a 24-well
microtiter plate and sprayed with test solutions at an application
rate of 200 ppm. After drying, the leaf discs were infested with an
aphid population of mixed ages. After an incubation period of 7
days, samples were checked for mortality.
[0350] The following compounds gave at least 80% control of Thrips
tabaci: A1, A2, A5, A6, A7, A8, A10, A12, A13, A14, A15, A16, A17,
A18, A19, A21, A24, A25, A30, A31, A32, A33, A34, A35, A39, A42,
A43, A44, A45, A46, A47, A48, A49, A50, A51, A53, A54, A57, A58,
A59, A60, A61, A62.
[0351] Tetranychus urticae (Two-Spotted Spider Mite):
[0352] Bean leaf discs on agar in 24-well microtiter plates were
sprayed with test solutions at an application rate of 200 ppm.
After drying, the leaf discs are infested with mite populations of
mixed ages. 8 days later, discs are checked for egg mortality,
larval mortality, and adult mortality.
[0353] The following compound gave at least 80% control of
Tetranychus urticae: A1, A2, A4, A5, A6, A7, A8, A10, A11, A12,
A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A30, A31, A32,
A33, A34, A35, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48,
A49, A50, A51, A53, A54, A55, A57, A59, A60, A61, A62.
[0354] Compound Nos. A26, A27, A28, A29, A36 and A56 of Table A
were tested using the same protocols and showed little or no effect
on mortality, feeding behavior, or growth regulation under the test
conditions.
* * * * *