HERBICIDAL COMPOUNDS
The present invention relates to certain substituted dihydro-hydantoin derivatives, lo
processes for their preparation, herbicidal compositions comprising them, and their use in
5 controlling plants or inhibiting plant growth.
Herbicidal dihydro-hydantoins of the formula
10
wherein A is a pyridine ring are taught in US Patent No, 4,600,430. Similar compounds wherein A
is a pyridazine ring are taught in IJS Patent No. 4,604,127,
Summary of the Invention
15
In a first aspect, the illvention provides compounds of the formula (I)
20 wherein
X is selected from S and 0;
Ra is selected from hydrogen and halogen,
25
Rh is selected from hydrogen, halogen, C,-C, alkyl, C,-C4 haloalkyl, C1-C6 alkoxy, C,-C3
alkoxy-C,-C, aldoxy a gro~pR 'R'I\I- a group R'C(O,I\I(R")-, a group R"s(o,)I\I(R",-, a group
R'R~NSO; a gro.lp R%"NC(O)- aryl opt orlally s.lbst~r~tebdy one or more groups
independently selected from halogen, nitro, cyano, C,-C, alkyl, C,-C3 alkoxy, C,-C, haloalkyl and
CI-C3 haloalkoxy, and heteroaryl optionally substituted substituted by one or more groups
independently selected from halogen, nitro, cyano, C,-C, alkyl, C,-C, alkoxy. C,--C3 haloalkyl and
CI-C3 haloalkoxy;
5
C . R 1s selected from hydrogen, halogen, C,-CG alkyl, C,-CG haloalkyl, C,-C, alkenyl, C I-CS
cyanoalkyl, Cl-Cs alkoxy, Cl-CG hydroxyalkyl, C,-CG alkenyloxy C,-CG alkyl and C,-C, cycloalkyl
optionally substituted by from 1 to 3 groups independently selected from cyano, C,-C, alkyl and
C,-C, alkoxy;
10
Rd is selected from hydrogen, halogen, cyano, C,-CG alkyl and C1-CG haloalkyl;
R' is selected from hydrogen, C1-C4 alkyl, Cl-C, alkoxy and C1-C4 haloalkyl and R2 is
selected from hydrogen, hydroxyl, C,-C4 alkyl. C,-C, alkoxy, C,-C4 alkoxy-C,-C4 alkyl, C,-C4
15 haloalkyl, C,-C, haloalkoxy and Cl-C4 cyanoalkyl, with the proviso that when R' is methyl, R2 is
not H;
or R' and R2 together with the nitrogen and carbon alorns to which they are attached
form a 3-7 membered saturated or partially unsat~~rateridn g optionally comprising from 1 to 3
20 heteroatoms independently selected from S, 0 and N and optionally substituted with from 1 to 3
groups independently selected from hydroxyl, =0, Cl-C, alkyl or C1-C0 haloalkyl.
R ~seSlec ted from halogen, hydroxyl, and any one of the followitlg groups
25
R%nd RG are independently selected from hydrogen, C,-C, alkyl, C1-CG haloalkyl, C,-CG
alkenyl, C2-CG alkynyl, or ~ " n d RG together with the carbon atoms to which they are attached
form a 3-6 membered saturated or partially unsaturated ring optionally comprising from 1 to 3
heteroatoms independently selected from S, 0 and N and optionally substituted with from 1 to 3
30 groups independently selected from halogen and C,-C, alkyl;
R' ano Rb are mdependent y selecreo from lhydroge~C~; -C, a~ky. C,-Cd I Iu~dlk y C; Cc
alkenyl C7-Coa lkynyl a CS-Clol ~eteroarygl roup wh ch can be mono- or b~cycIC cotnprlslng from
1 to 4 heteroatoms independently selected from N, 0 and S and optionally substituted with 1 to 3
groups independently selected from halogen, Cl-C3 alkyl, Cl-C, haloalkyl and Cl-C3 alkoxy, a C6-
C,O aryl group optionally substituted with 1 to 3 groups independently selected from halogen.
nitro, cyano, Cl-C3 alkyl, Cl-C3 alkoxy, C1-C3 haloalkyl and Cl-C3 haloalkoxy, or R7 and R8
5 together with the atoms to which they are attached form a 3-6 membered saturated or partially
unsaturated ring optionally comprising from 1 to 3 heteroatoms independently selected from S, 0
and N and optionally substituted with from 1 to 3 groups independently selected from halogen or
C1-Cs alkyl;
10 R9 is selected from C,-Ce alkyl and benzyl optionally substituted with 1 to 3 groups
independently selected from halogen, nitro, cyano, C,-C, alkyl, C,-C3 alkoxy, C1-C3 haloalkyl and
Cl-C3 haloalkoxy;
or an N-oxide or salt form thereof.
15
In a second aspect, the invention provides herbicidal compositions comprising a
compound of the invention together with at least one agriculturally acceptable adjuvant or diluent.
In a third aspect, the invention provides the use of a compound or a composition of the
20 invention for use as a herbicide.
In a fourth aspect, the invention provides a method of controlling weeds in crops of useful
plants, comprising applying to said weeds or to the locus of said weeds, or to said useful crop
plants, a compound or a coniposition of the invention.
25
In a fifth aspect, the invention relates to processes useful in the preparation of
compounds of the invention.
In a sixth aspect, the invention relates to intermediates useful in the preparation of
30 compounds of the invention.
Detailed Description
In particularly preferred embodiments of the invention, the preferred groups for X, Ra, Rb
35 RC, Rd, R1, RZ and R,, in any combination thereof, are as set out below.
Preferably X is 0
Preferably Ra is hydrogen.
Preferably. Rd is hydrogen.
Preferably R' is C,-C, alkyl, C,-C, alkoxy or C1-C4 haloalkyl. More preferably. R' is C,-C,
alkyl or C,-C, alkoxy Most preferably. R' is methyl or methoxy.
5
Preferably R' is C,-C3 alkyl, C,-C, alkoxy or C,-C, alkoxy-C,-C, alkyl. More preferably RZ
is methyl, methoxy, ethoxy or methoxymethyl.
Preferably, R3 is hydroxyl, halogen, Cl-CG alkylcarbonyloxy, C,-Cs alkoxycarbonyloxy or
10 aryloxycarbonyloxy wherein the aryl group may be substituted with 1 to 3 groups independently
selected from halogen, nitro, cyano. C,-C3 alkyl, C,-C3 alkoxy, C,-C, haloalkyl and C,-C3
haloalkoxy. Even more preferably, R3 is hydroxyl or halogen. Most preferably. R, is hydroxyl.
In one embodiment, X, Ra, Rd, R', Ri and R3 are as described above in any combination
15 and R~ and RC are as described below in any combination.
Preferably Rb is hydrogen, halogen, methoxy, heteroaryl substituted by halogen or
methoxy or aryl substituted by halogen or methoxy groups.
20 Even more preferably, R ~hySdro gen
I'referably, RC is C,-C, alkyl, C1-CG haloalkyl, C2-C8 alkenyl, C,-C6 cyanoalkyl or C3-CB
cycloalkyl optionally substituted by from 1 to 3 groups independently selected from cyano and C,-
C3 alkyl.
25
Even more preferably, R" is C,-CG alkyl, C,-C, haloalkyl, C,-C6 cyanoalkyl or C3-CG
cycloalkyl optionally substituted by from 1 to 3 groups independently selected from cyano and C,-
C3 alkyl.
30 Even more preferably lR"s methyl, ethyl, iso-propyl, (2-methyl)-prop-I-yl, (I-methyl)-
prop-I-yl, tert-butyl, (1.1-dimethyl)-prop-I-yl. (1,l-di1net1iyl)-but-I-yl, (I-methyl-I-ethyl)-prop-I-yl,
cyclobutyl, cyclopropyl, (1-rnethyl)cycloprop-I-yl, (I-methyl-I-cyano)-eth-I-yl, (l-methyl-l-ethyl-
2-cyano)-prop-I-yl, (1.1-dimethyl-2-cyano)-prop-I-yl, I-fluoroethyl, 1,l-difluoroethyl,
difluoromethyl, I-fluoro-I-methylethyl or trifluoromethyl.
35
Even more preferably, RC is tert-butyl, (I-methyl-I-cyano)-eth-I-yl, 1,l-difluoroethyl, 1-
fluoro-I-methylethyl or trifluoromethyl.
Most preferably, RC is trifluoromethyl
In particular, the substituted pyridine may be 4-tert-butyl-pyrid-2-yl, 4-((I-methyl-1-
cyano)-eth-I-yl)-pyrid-2.~1, 4-(I ,I-difluoroethy1)-pyrid-2-yl, 4-(I-fluoro-I-methylethyl)-pyrid-2-yl or
4-(trifluoromethyl)-pyrid-2-yl.
5 In a further embodiment, X, Ra, Rd, R', R2 and R3 are as described above in any
combination and Rb is R'R~NC(O)-o r R5~(0)N(R6)w-,h erein R%nd RF are as described above
and RCi s hydrogen, halo, C1-C4a lkyl or Cl-C4 haloalkyl. More preferably, R ~RS'R% c(o)-.
In a further embodiment, X, Ra, Rd, R'. R2 and R3 are as described above in any
10 combination and RD is halogen or C,-C4 alkyl and RC is C,-C3 haloalkyl, preferably trifluoromethyl
The compounds of formula (I) may exist as different geometric isomers, or in different
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.
15
The compounds of this invention may contain an asymmetric carbon atom and some of
the compounds of this invention may contain one or more asymmetric centers and may thus give
rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the
present invention includes such optical isomers and diastereomers; as well as the racemic and
20 resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S
stereoisomers and agrochelnically acceptable salts thereof. It is recognized that one optical
isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties
over the other. Thus when disclosing and claiming the invention, when one racemic mixture is
disclosed, it is clearly contemplated that both optical isomers, including diastereomers and
25 enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
Alkyl, as used herein refers to an aliphatic hydrocarbon chain and includes straight and
branched chains e. g. of 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isoliexyl.
30
Alkenyl, as used herein, refers to an aliphatic hydrocarbon chain having at least one
double bond, and preferably one double bond, and includes straight and branched chains e. g, of
2 to 8 carbon atoms such as ethenyl (vinyl), prop-I-enyl, prop-2-enyl (allyl), isopropenyl, but-lenyl,
but-2-enyl, but-3-enyl, 2-metliypropenyl.
35
Alkynyl, as used herein, refers to an aliphatic hydrocarbon chain having at least one triple
bond, and preferably one triple bond, and includes straight and branched chains e. g. of 2 to 8
carbon atoms such as ethynyl, prop-I-ynyl, prop-2-ynyl (propargyl) but-I-ynyl, but-2-ynyl and but-
3-ynyl.
Cycloalkyl, as used herein, refers to a cyclic, saturated hydrocarbon group having froni 3
to 6 ring carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl
and cyciohexyl.
5 Cycloalkenyl, as used herein, refers to a cyclic, partially unsaturated hydrocarbon group
having from 3 to 6 ring carbon atoms.
Alkoxy as used herein refers to the group -OR, wherein R is alkyl as defined above.
Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
10 sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy, n-hexyloxy, and isohexyloxy.
Alkenyloxy refers to the group -OR, wherein R is alkenyl as defined above. Examples of
alkenyloxy groups are ethenyloxy, propenyloxy, isopropenyloxy, but-I-enyloxy, but-2-enyloxy,
but-3-enyloxy, 2-methypropenyloxy etc.
15
Alkynyloxy refers to the group -OR, wherein R is alkynyl is as defined above. Examples
of alkynyloxy groups are ethynyloxy, propynyloxy, but-I-ynyloxy, but-2.-ynyloxy and but-3-
ynyloxy.
20 Alkoxyalkyl as used herein refers to the group -ROR, wherein each R is, independently,
an alkyl group as defined above.
Alkoxyalkenyl as used herein refers to the group -ROR', wherein R is an alkyl group as
defined above and R' is an alkenyl group as defined above.
25
Alkoxyalkynyl as used herein I-efers to the group -ROR', wherein R is an alkyl group as
defined above and R' is an alkynyl group as defined above.
Alkoxyalkoxy, as ued herein, refers to the group -OROR, wherein each R is,
30 Independently, an alkyl group as def~neda bove.
Cyanoalkyl as used herein refers to an alkyl group substituted with one or tnore cyano
groups.
35 Cyanoalkenyl as used herein refers to an alkenyl group substituted with one or more
cyano groups.
Cyanoalkynyl as used herern refers to an alkynyl group substituted w~tho ne or more
cyano groups
Cyanocycloalkyl as used herein refers to an cycloalkyl group substituted with one or
more cyano groups.
Cyanoalkoxy as used herein refers to the group -OR, wherein R is cyanoalkyl as defined
5 above.
Halogen, halide and halo refer to iodine, bromine, chlorine and fluorine.
Haloalkyl as used herein refers to an alkyl group as defined above wherein at least one
10 hydrogen atom has been replaced with a halogen atom as defined above. Examples of haloalkyl
groups include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and
trifluoromethyl. Preferred haloalkyl groups are fluoroalkyl groups (i.e haloalkyl gro~~pcso,n taining
fluorine as the only halogen). More highly preferred haloalkyl groups are perfluoroalkyl groups.
i.e alkyl groups wherein all the hydrogen atoms are replaced with fluorine atoms.
15
Haloalkenyl as used herein refers to an alkenyl group as defined above wherein at least
one hydrogen atom has been replaced with a halogen atom as defined above.
Haloalkynyl as used herein refers to an alkynyl group as defined above wherein at least
20 one hydrogen atom has been replaced with a halogen atom as defined above.
Haloalkoxy as used herein refers to the group -OR, wherein R is haloalkyl as defined
above.
25 Iialoalkenyloxy as used herein refers to the group -OR, wherein R is haloalkenyl as
defined above.
t-laloalkynyloxy as used herein refers to the group --OR, wherein K is haloalkynyl as
defined above.
30
Alkylthio as used herein refers to the group -SR, wherein R is an alkyl group as defined
above. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, tertbutylthio,
and the like
35 Alkylthioalkyl as used herein refers to the group -RSR, wherein each R is,
independently, an alkyl group as defined above.
Haloalkylth~oa s used here~nre fers to the group -SR, wherein R 1s a haloalkyl group as
def~neda bove
Alkylsulfinyl as used herein refers to the group -S(O)R, wherein R is an alkyl group as
defined above.
Alkylsulfonyl as used herein refers to the group-S(O)*R, wherein R is an alkyl group as
5 defined above.
Haloalkylsulfinyl as used herein refers to the group -S(O)R, wherein R is a haloalkyl
group as defined above.
10 Haloalkylsulfonyl as used herein refers to the group -S(O),R, wherein R is a haloalkyl
group as defined above.
Alkylsulfonyloxy, as used herein refers to the group -OSO,R, wherein R is an alkyl group
as defined above.
15
Alkylcarbonyl, as used herein refers to the group -COR, wherein R is an alkyl group as
defined above. Examples of alkylcarbonyl groups include ethanoyl, propanoyl, n-butanoyl, etc.
Alkenylcarbonyl, as used herein refers to the group -COR, wherein K is an alkenyl group
20 as defined above.
Alkynylcarbonyl, as used herein refers to the group -COK, wherein R is an alkynyl group
as defined above.
25 Iialoalkylcarbonyl, as used herein refers to the group--COR, wherein R is a haloalkyl
group as defined above.
Haloalkenylcarbonyl. as used herein refers to the group -COR, wherein R is a
lialoalkenyl group as defined above.
30
Iialoalkynylcarbonyl, as used lierein refers to the group -COR, wherein R is a
haloalkynyl group as defined above.
Alkoxycarbonyloxy as used herein, refers to the group -OC(O)OR, wherein R is an alkyl
35 group as defined above. Examples of alkoxycarbonyloxy groups are rnethoxycarbonyloxy,
ethoxycarbonyloxy, propoxycarbonyloxy, but-I-oxycarbonyloxy, but-2-oxycarbonyloxy and but-3-
oxycarbonyloxy.
Trialkylsilylalkynyl, as used herein, refers to the group -RSi(R'),, wherein R is an alkynyl
40 gioul, as tlefi~ltcal uove allu eacl! R IS, ~~~depcllclus~c~lelclylc.d flolrl all alny yloup as oeflnea
above
Formyl, as used herein, refers to the group -C(O)H.
Hydroxy or hydroxyl, as used herein, refers to the group -OH.
5
Nitro. as used herein, refers to the group -NO2.
Cyano as used herein, refers to the group -CN.
10 Aryl, as used herein, refers to an unsaturated aromatic carbocyclic group of from 6 to 10
carbon atoms having a single ring (e. g., phenyl) or multiple condensed (fused) rings, at least one
of which is aromatic (e.g., indanyl, naphthyl). Preferred aryl groups include phenyl, naphthyl and
the like. Most preferably, an aryl group is a phenyl group.
15 Aryloxy, as used herein, refers to the group -0-aryl, wherein aryl is as defined above.
Preferred aryloxy groups include phenoxy, naphthyloxy and the like.
Aryloxycarbonyloxy as used herein, refers to the group -OC(O)O-aryl wherein aryl is a
as defined above.
20
Benzyl, as used herein, refers to the group -CH2CGHB.
Benzyloxy, as used herein, refers to the group -OCH~CGH~.
25 Heterocyclyl, as used herein, refers to a non-aromatic ring system containing 3 to 10 ring
atoms, at least one ring heteroatom and consisting either of a single ring or of two or rnore fused
rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms
which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of such groups
include pyrrolidinyl, imidazolinyl, pyrazolidinyl, piperidyl, piperazinyl, quinuclidinyl, morpholinyl,
30 together with unsaturated or partially unsaturated analogues such as 4,5,6,7-tetrahydrobenzothiophenyl,
chromen-4-onyl, 9H-fluorenyl, 3.4-dihydro-21.4-benzo-1.4-dioxepinyl2, ,3..dihydrobenzofuranyl,
piperidinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 4,5-dihydro-isoxazolyl, tetrahydrofuranyl
and morpholinyl.
35 tieteroaryl, as used herein, refers to a ring system containing 5 to 10 ring atoms, 1 to 4
ring heteroatoms and consisting either of a single aromatic ring or of two or more fused rings, at
least one of which is aromatic. Preferably, single rings will contain up to three and bicyclic
systems up to four heteroatoms which will preferably be independently chosen from nitrogen,
oxygen and sulfur. Examples of such groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
40 IllaZlnyl, furanyl ttllopr~enylo, xazolyl lsoxazomyo8x, aa~azolylt i? azo y , lsotli azo yl th au~a~ulyl,
pyrrolyl pyrazolyl ~m~dazolylrl,,a zolyl and terrazolyl Examples of b~cycllcg roups are
benzothiophenyl, benzimidazolyl, benzothiadiazolyl, quinolinyl, cinnolinyl, quinoxalinyl and
pyrazolo[l,5-alpyrimidinyl.
'Saturated ring', as used herein, refers to a ring system in which the atoms in the ring are
5 linked by single bonds.
'Partially unsaturated ring', as used herein, refers to a ring system in which at least two
atoms in the ring are linked by a double bond. Partially unsaturated ring systems do not include
aromatic rings.
10
"Optionally substituted" as used herein means the group referred to can be substituted at
one or more positions by any one or any combination of the radicals listed thereafter. For most
groups, one or more hydrogen atoms are replaced by the radicals listed thereafter. For
halogenated groups, for example, haloalkyl groups, one or more halogen atoms are replaced by
15 the radicals listed thereafter.
Suitable salts include those derived from alkali or alkaline earth metals and those derived
trom ammonia and amines. Preterred cations include sodium, potassium, magnesium, and
ammonium cations of the formula N ' ( R ' % ~ ~ R ~ ' Rwh~e~re)i n R", RZOR. 2' and RZ2a re
20 independently selected from hydrogen. Cl-C6 alkyl and C,-CG hydroxyalkyl. Salts of the
compounds of Forrnula I can be prepared by treatment of cornpounds of Forrnula I with a metal
hydroxide, such as sodium hydroxide, or an amine, such as ammonia, trimethylamine,
diethanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, morpholine,
cyclododecylamine, or benzylamine. Amine salts are often preferred forms of the compounds of
25 Formula I because they are water-soluble and lend themselves to the preparation of desirable
aqueous based herbicidal compositions.
Acceptable salts can be formed from organic and inorganic acids, for example, acetic,
propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,
30 lhydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naplhthalenesul~or~ic,
benzenesulfonic, toluenesullonic, catnphorsulfonic, and similarly known acceptable acids when a
compound of this invention contains a basic moiety.
In another aspect the present invention provides intermediates useful in the preparation
35 of compounds of the invention.
In one embodiment, there are provided intermediates of the formula (11). wherein X, R',
R', Ra, Rb. RC and R~ are as defined above. These intermediates can also display herbicidal
activity.
In another embodiment, there are provided intermediates of the formula (Ill) wherein X, R', R',
5 Ra, R ~R,C a nd Rda re as defined above.
10 Compounds of the invention may be prepared by techniques known to the person skilled
in the art of organic chemistry. General methods for the production of compounds of formula (I)
are described below. Unless otherwise stated in the text, the substituents X, I?', R2, R3, Ra, Rb,
RC and re as defined hereinbefore. The starting materials used for the preparalion of the
compounds of the invention lnay be purchased lrotn usuai cotntnercial suppliers or may be
15 prepared by known methods. The starting materials as well as the intermediates may be purified
before use in the next step by state of the art methodologies such as chromatography,
crystallization, distillation and filtration.
For example, compounds of formula (IX) wherein R' is an alkyl or alkoxy group and R2 is
a hydrogen or alkyl group may be prepared by reaction of amino-pyridine (IV) with
20 phenylchloroformate to give carbamate product (V). The subsequent reaction with an
appropriately substutited amino-ester (VI) gives compounds of type (VII) and subsequent
cycl~sat~ognlv es compounds of type (VIII) and reduct~onw ~the g w~ths od~umb orohydrtde glves
compounas of type (IX) T f ~me ethyl ammo-ester (VI) may also be replaced by olller ammo esters
or amino-acids. Phenyl chloroformate may be replaced by other activating groups such as
phosgene or para-nitrophenyl chloroformate. The cyclisation to (VIII) may occur in sitir or require
heating for carboxylic acids or esters or treatment with a reagent such as th~onycl hloride for
carboxylic acids. Compounds of type (VII) can be converted to compounds of type (IX) directly by
5 treatment with a reducing reagent such as DIBAL-H or NaBH4. Esters of type (VII) may also be
reduced to their corresponding primary alcohols and then such alcohols can be re-oxidised to
compounds of type (IX) with oxidants such as Dess-Martin periodinane.
Phenyi chloroformate ?qii $4 o
DIPEA, UCM,
5% to room temp.
+ "Y N1i
R', .Nd;; O v N" 0
Alternatively, compounds of formula (IX) wherein K' is an alkyl group or alkoxy group
and R' is a hydrogen or alkyl group may be prepared by Palladium catalysed reaction of chloropyridine
(X) with urea (XI) to give (XII) (for a reference to a related reaction see W0'2006048249,
example 3.1) and then subsequent cyclisation gives compounds of type (IX)
15
K,:
N,!? i"d2dba3, Xantphos
CszCO3 HOAc/water 1 :I
Dioxane 90-1 OO°C
Cl 0
(XI (XI) 3,' iii
(XII) (IX)
Urea (XI) may be formed by reaction of ester (XIII) with Grignard reagents, reductive
amination of the product ketone (XIV) with amines and finally reaction of the subsequent product
amine (XV) with TMS-isocyanate to give compounds of type (XI). Alternatively (XV) can be
20 formed by a Grignard add~tiono f type R,MgCI to appropriate imines. Alternatively, a nitrile can
replace tne ester groLp of (XIII) In the react~onw ,trl tir~gnardre agents
. . . .
R1 NH2 HCI 09,
N t i 1<'.*Ao
I - (1) TW-NCO 0, (2) NaBH, ,, (2) water O\ Alternatively, reaction of compounds of type (XIV) with methoxylamine following by
5 reduction of the oxime ether formed gives compounds of type (XV) which can form compounds of
type (XI) wilere R1 is alkoxy. Alternatively, reaction ot compounds of type (XIV) where R2 is
hydrogen with methoxylamine followe by addition of Grignard reagents to the formed oxime also
can give compounds of type (XV).
Nli.
Nli? 4,
,a,i$? ( 1 ) i ' + p>qi (I)
0 , (2) NaCNBIi3 (2) water
\ O(XIW (XW (XI)
R,= alkoxy R7= alkoxy
10 Compounds of formula (XVIII) wherein R' is at1 llydroxy group (nay be prepared by the
Palladium catalysed reaction of chloro-pyridine (X) with urea (XVI) to give urea (XVII) (for a
reference to a related reaction see W02006048249, exalilple 3.1), which can react with aqueous
glyoxal solution to give product (XVIII). Compounds of formula (IX) where R2 is an alkoxy group
may be prepared by reacting compounds of formula (XVIII) with alcohols of type R4-OH under
15 acidic conditions.
,Hi dioxane
(XVII)
EtOH, reflux *
(aqueous
glyoxal)
R:, = OH
(.X VIII.)
Alternatively, compounds of formula (V) may be reacted with compounds of formula (XIX)
wherein ~ ' i sa hydrogen or alkyl group to give products of type (XX). Cyclisation with a suitable
20 reagent such as thionyl chloride gives compounds of formula (XXI), which can be alkylated with a
suitable base such as LiHMDS and a suitable alkylating agent such as methyl iodide (for R, =
Me) to give compound (VIII). Reduction as before gives compounds of type (IX).
Alternatively oxidative cleavage (using ozonolysis or Os04/Na104 or similar conditions) of
an appropriate vinyl compound such as (XXII) or derivatives thereof and cyclisation could give
the desired product.
oxidative cleavage
and cyclisation
Alternatively, compounds of type (XXIII) may be coupled with compounds of type (X)
under Palladium catalysed conditions to give compounds of type (VIII) and then standard
reduction with NaBH, for example gives products of type (IX).
Pd?dba3X, antpl~os
K2C03
Dioxane 130°C.
I-leating thcrlnally
or in a microwave
10
(X) (XXIII) (VIII) (IX)
Amino and chloro-pyr~d~news,h ere not comrnerc~allya vailable, may be made by
literature routes such as below and as deta~ledIn J March, Advanced Organlc Chem~stry,4 th ed
W~ley, New York, 1992
Hi>
NHdaq) .i -Halogenation R~eN,j f----.-
Nii, 0
(Iv) (X)
Suitable conditions for effecting these transformations are set out in J. March, Advanced
Organic Chemistry, 4th ed. Wiley, New York, 1992
5 The compounds of formula (I) according to the invention can be used as herbicides in
unmodified form, as obtained in the synthesis, but they are generally formulated into herbicidal
compositions in various ways using formulation adjuvants, such as carriers, solvents and surfaceactive
substances. Therefore, the invention also relates to a herbicidal composition which
comprises a herbicidally effective amount of a compound of formula (I) in addition to formulation
10 adjuvants. The formulations can be in various physical forms, e.g, in the form of dusting powdei-s,
gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent
pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oilflowables,
aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions,
emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible
15 organic solvent as carrier), impregnated polymer films or in other forms known eg. from the
Manual on Development and Use of FAO Specifications for Plant Protection Products, 5th
Edition. 1999. Such formulations can eitl~elb e used directly or they ate diluted prior to use. The
dilutions can be made, for example, with water, liquid fertilizers, micronutrients, biological
organisms, oil or solvents.
20 The formulations can be prepared e.g, by mixing the active ingredient with the
formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules,
solutions, dispersions or emulsions. The active ingredients can also be formulated with other
adjuvants, such as finely divided solids, rnineral oils, oils of vegetable or animal origin, modified
oils of vegetable or animal origin, organic solvents, water, surface-active substances or
25 combinations thereof. The active ingredients can also be contained in very fine microcapsules
consisting of a polymer. Microcapsules contain the active ingredients in a porous carrier. 1-his
enables the active ingredients to be released into the environment in controlled amounts (eg.
slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain
active ingredients in an amount of about from 25 to 95 % by weight of the capsule weight. The
30 active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or
liquid dispersion or in the form of a suitable solution. The encapsulating membranes comprise, for
example, natural or synthetic rubbers, cellulose, styrenelbutadiene copolymers, polyacrylonitrile,
polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers
and starch xanthates or other polymers that are known to the person skilled in the art in this
35 connection kiternat~velyv, ery f~rierl iicrocapsules can oe formed in wh ch tne active ingiedient 1s
contained in the form of finely divided particles in a solid matrix of base substance, but the
microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of the compositions
according to the invention are known per se. As liquid carriers there may be used: water, toluene.
xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid
anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate,
chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-
dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate,
diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether. N,Ndimethylformamide,
dimethyl sulfoxide, I,.?-dioxane, dipropylene glycol. dipropylene glycol methyl
ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidorie, ethyl acetate, 2-ethylhexanol,
ethylene carbonate, 1,1,1-trichloroethane. 2-heptanone, alpha-pinene, d-limonene, ethyl lactate.
ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone,
glycerol, glycerol acetate, glycerol diacetate, ylycerol triacetate, liexadecane, lhexylene glycol,
isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate,
lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl
ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane,
n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol,
polyethylene glycol (PEGdOO), propionic acid, propyl lactate, propylene carbonate, propylene
glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol,
xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl
acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol,
ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl
alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-
pyrrolidone and the like. Water is generally the carrier of choice for diluting the concentrates.
Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite
clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed
husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar
substanr:es, as described, for example, in CFR 180.1001. (c) R (d).
A large number of surface-active substances can advantageously be used in both solid
and liquid formulations, especially in those formulations which can be diluted with a carrier prior
to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can
be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical
surface-active substances include, for example, salts of alkyl sulfates, such as
diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate;
alkylphenollalkylene oxide addition products, such as nonylphenol ethoxylate;
alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as
sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium
a~bbtylnaphtfialencsulfo~iatde ~aky esters of s.~lfos.~cc~natsea lts, sucn as soa bm d (2-
ethylhexyl)sulfos~~ccinatseo; rbitol esters, such as sorbitoi oleate; quaternary amines, such as
lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene
glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and
di-alkylphosphate esters; and also further substances described e.g in "McCutcheon's
5 Detergents and Emulsifiers Annual" MC Publishing Corp., Ridgewood New Jersey, 1981
Further adjuvants that can usually be used in pesticidal formulations include
crystallization inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming
agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralizing or pHmodifying
substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up
10 enhancers, ~nicronutrientsp, lasticisers, glidants, lubricants, dispersants, thickeners, antifreezes,
microbicides, and also liquid and solid fertilizers.
The compositions according to the invention can additionally include an additive
comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures
of such oils and oil derivatives. The amount of oil additive in the composition according to the
15 invention is generally from 0.01 to 10 %, based on the spray mixture. For example, the oil
addilive car1 be added to the spray tank in the desired concentration after the spray mixture has
been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for
example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, such as AMIGOB
(RhGne-Poulenc Canada Inc.), alkyl esters of oils of vegetable origin, for example the methyl
20 derivatives, or an oil of animal origin, such as fish oil or beef tallow. A preferred additive contains,
for example, as active components essentially 80 % by weight alkyl esters of fish oils and 15 %
by weight methylated rapeseed oil, and also 5 % by weight of customary emulsifiers and pH
modifiers. Especially preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially
the methyl derivatives of C12-C18fa tty acids, for example (he methyl esters of lauric acid, palmitic
25 acid and oleic acid, being of importance. Those esters are known as methyl laurate (CAS-111-
82-O), methyl palmitate (CAS-112-39-0) and methyl oleate (CAS-112-62-9). A preferred fatty acid
methyl ester derivative is Emery@ 2230 and 2231 (Cognis Gmbli). Those and other oil
derivatives are also known from the Compendium of Herbicide Adjuvants, 5th Edition, So~ithern
Illinois University, 2000.
30 The application and action of the oil additives can be further improved by combination
with surface-active substances, such as non-ionic, anionic or cationic surfactants. Examples of
suitable anionic, non-ionic and cationic surfactants are listed on pages 7 and 8 of WO 97134485.
Preferred surface-active substances are anionic surfactants of the dodecylbenzylsulfonate type,
especially the calcium salts thereof, and also non-ionic surfactants of the fatty alcohol ethoxylate
35 type. Special preference is given to ethoxylated C12-Cz2fa tty alcohols having a degree of
ethoxylation of from 5 to 40. Examples of commercially available surfactants are the Genapol
types (Clariant AG). Also preferred are silicone surfactants, especially polyalkyl-oxide-modified
licpta~nctliylrr~loxanewsh icn are commerc~ayl ava lanle e 9 8s Silmt 1 -77%' anu also
perf,~orinateds ~rfaclanlsT he concentration of the surface-active substances in relatlon lo the
total additive is generally from 1 to 30 % by weight. Examples of oil additives consisting of
mixtures of oil or mineral oils or derivatives thereof with surfactants are Edenor ME SUal),
Turbocharge03 (Syngenta A(;, CH) or ActipronC (BP Oil UK Limited, GB).
If desired, it is also possible for the mentioned surface-active substances to be used in
5 the formulations on their own, that is to say, without oil additives.
Furthermore, the addition of an organic solvent to the oil additivelsurfactant mixture may
contribute to an additional enhancement of action. Suitable solvents are, for example, SolvessoBD
(ESSO) or Aromatic Solvent@ (Exxon Corporation). The concentration of such solvents can be
from 10 to 80 % by weight of the total weight. Oil additives that are present in admixture with
10 solvents are described, for example, in US-A-4,834,908. A commercially available oil additive
disclosed therein is known by the name MERGE@ (BASF Corporation). A further oil additive that
is preferred according to the invention is SCORE@ (Syngenta Crop Protection Canada).
In addition to the oil additives listed above, for the purpose of enhancing the action of the
compositions according to the invention it is also possible for formulations of alkylpyrrolidones
15 (e.g AgrimaxO) to be added to the spray mixture. Formulations of synthetic lattices, e.g.
polyacrylamide, polyvinyl compounds or poly-I-p-menthetie (e.g. Bond@, Courier@ or Emerald@)
may also be used. It is also possible for solutions that contain propionic acid, for example
Eurogkem Pen-e-trateO, to be added to the spray mixture as action-enhancing agent.
The herbicidal compositions generally comprise from 0.1 to 99 YO by weight, especially
20 from 0.1 to 95 % by weight, compounds of formula (I) and from 1 to 99.9 % by weight of a
formulation adjuvant which preferably includes from 0 to 25 % by weight of a surface-active
substance. Whereas commercial products will preferably be formulated as concentrates, the end
user will normally employ dilute formulations.
The rates of application of compounds of formula (I) may vary within wide limits and
25 depend on the nature of the soil, the method of application (pre- or post-emergence; seed
dressir~ga; pplication to the seed furrow; no tillage application etc.), the crop plant, the grass or
weed to be controlled, the prevailing climatic conditions. and other factors governed by the
method of application, the time of application and the target crop. The compounds of formula (I)
according to the invention are generally applied at a rate of from 10 to 2000 glha, especially from
30 50 to 1000 glha.
Preferred formulations have especially the following compositions (% = percent by
weight):
Emulsifiable concentrates:
active ingredient: 1 to 95 %, preferably 60 to 90 %
35 surface-act~vea a- ent 1 to 30 %. oreferablv 5 to 20 % . ,
llqlria carrier 1 lo 80 "/L, preferably 1 lo 35 U/r
Dusts:
active ingredient:
solid carrier:
0.1 to 10 %, preferably 0.1 to 5 %
99.9 to 90 %. preferably 99.9 to 99 %
Suspension c o n c e n m :
5 active ingredient: 5 to 15 YO, preterably 10 to 50 YO
water: 94 to 24 %, preferably 88 to 30 %
surface-active agent: 1 to 40 %, preferably 2 to 30 %
Wettable powders:
active ingredient: 0.5 to 90 %, preferably 1 to 80 %
10 surface-active agent: 0.5 to 20 %, preferably 1 to 15 %
solid carrier: 5 to 95 %, preferably 15 to 90 %
Granules:
active ingredient:
solid carrier:
0.1 to 30 O h , preferably 0.1 to 15 %
99.5 to 70 %, preferably 97 to 85 %
15 The following Examples further illustrate, but do not limit, the invention.
Formulation Examples for herbicides of formula (I) (% = % by weiqhtl
F1. Emulsifiable concentrates a) b) C) d)
active ingredient 5% 10 % 25 % 50 %
calcium dodecylbenzenesulfonate 6% 8% 6% 8%
20 castor oil polyglycol ether 4% 4% 4%
(36 niol of ethylene oxide)
octylphenol polyglycol ether 4% 2%
(7~8m ol of ethylene oxide)
NMP 10 % 20 %
25 arom. hydrocarbon mixture 85 % 78 % 55 % 16 %
c9-c12
Elnulsions of any desired concentration can be obtained fro111 such concentrates by dilution with
water.
F2. Solutions a) b) C) d)
30 active ingredient 5% 10 % 50 % 90 %
1-methoxy-3-(3-methoxypropoxy)-
propane 20 % 20 %
polyethylene glycol MW 400 20 % 10 %
NMP 30 % 10 %
The solut~onsa re su~tablefo r use in the form of m~crodrops
F3. Wettable powders a)
active ingredient 5 O h
sodium lignosulfonate 4 %
5 sodium lauryl sultate 2%
sodium diisobutylnaphthalenesulfonate
octylphenol polyglycol ether
(7-8 mol of ethylene oxide)
10 highly dispersed silicic acid I 'YO
kaolin 88 %
The active ingredient is mixed thoroughly with the adjuvants and the mixture is thoroughly ground
in a suitable mill, affording wettable powders which can be diluted with water to give suspensions
of any desired concentration.
15 F4. Coated qranules a) b) c)
active ingredient 0.1 % 5 O/O 15 %
highly dispersed silicic acid 0.9 % 2% 2%
iriorga~iicc arrier 99.0 % 93 % 83 %
(diameter 0.1 - 1 mm)
20 e.g. CaC03 or SiO,
The active ingredient is dissolved in methylene chloride and applied to the carrier by spraying,
and the solvent is then evaporated off in vacuo.
F5. Coated gIa_nuls
active ingredient
25 polyethylene glycol MW 200
highly dispersed silicic acid
inorganic carrier
(diameter 0.1 - 1 mm)
e.g CaCO, or Si02
30 The finely ground active ingredient is uniformly applied, in a mixer, to the carrier moistened with
polyethylene glycol. Non-dusty coated granules are obtained in this manner.
F6. Extruder qranules
active ingredient
sodium lignosulfonate
35 carboxymethylcellulose
kao n Y/ U % Y 3 "/o 90 VO 79 'A.
The actlve ingredtent 1s mixed and ground with the adjuvants, and the mlxtilre is motstened with
water The mixture is extruded and then drted in a stream of atr
F7. Dusts
active ingredient
5 talcum
kaolin
a) b) c)
0.1 % 1 % 5 %
3Y.Y % 49 % 35 %
GOO % 50 % 60 %
Ready-to-use dusts are obtained by mixing the active ingredient with the carriers and grinding the
mixture in a suitable mill.
F8. - .Suspension concentrates
10 active ingredient
ethylene glycol
nonylphenol polyglycol ether
(15 mol of ethylene oxide)
sodium lignosulfonate
15 carboxymethylcelIulose
37 % aqueous formaldehyde
solution
silicone oil erliulsior~
water
20 The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension
concentrate from which suspensions of any desired concentration can be obtained by dil~ition
with water.
The invention also provides a method of controlling plants which comprises applying to
the plants or to the locus thereof a herbicidally effective amount of a compound of formula (I).
25 The invention also provides a method of inhibiting plant growth which co~ilprisesa pplying
to the plants or to the locus thereof a herbicidally effective amount of a cornpound of formula (I).
1-lie invention also provides a method of controlling weeds in crops of useful plants,
comprising applying to said weeds or to the locus of said weeds, or to said useful plants or to the
locus of said useful plants, a compound or a composition of the invention.
30 The invention also provides a method of selectively controlling grasses and/or weeds in
crops of useful plants which comprises applying to the useful plants or locus thereof or to the
area of cultivation a herbicidally effective amount of a compound of formula (I).
The term "herbicide" as used herein means a compound that controls or modifies the
growth of plants The term "herbicidally effecttve amount" means the quantlty of such a
35 compo~i>odr combinat on of sdch compounds lhal 1s capable of prod~c~na gco nrroll~ngo r
modifying effect on the growth of plants. Controlling or modifying effects include all deviation from
natural development, for example: killing, retardation, leaf burn, albinism, dwarfing and the like.
The term "plants" refers to all physical parts of a plant, including seeds, seedlings, saplings,
roots, tubers, stems, stalks, foliage, and fruits. The term "locus" is intended to include soil, seeds,
5 and seedlings, as well as established vegetation and includes not only areas where weeds may
already be growing, but also areas where weeds have yet to emerge, and also to areas under
cultivation with respect to crops of useful plants. "Areas under cultivation" include land on which
the crop plants are already growing and land intended for cultivation with such crop plants. The
term "weeds" as used herein means any undesired plant, and thus includes not only
10 agronomically important weeds as described below, but also volunteer crop plants.
The compounds of the invention can be applied before or after planting of the crops,
before weeds emerge (pre-emergence application) or after weeds emerge (post-emergence
application), and are particularly effective when applied post-emergence to the weeds.
Crops of useful plants in which the composition according to the invention can be used
15 include, but are not limited to, perennial crops, such as citrus fruit, grapevines, nuts, oil palms,
olives, pome fruit, stone fruit and rubber, and annual arable crops, such as cereals, for example
barley and wheat, cotton, oilseed rape, maize, rice, soy beans, sugar beet, sugar cane,
sunflowers, ornamentals, switchgrass, turf and vegetables, especially cereals, maize and soy
beans.
20 The grasses and weeds to be controlled may be both monocotyledonous species, for
example Agrostis, Alopecurus, Avena, Brachiaria, Bromus, Cenchrus, Cyperus, Digitaria,
Echinochloa, Eriochloa. Lolium, Monochoria, Panicum, Poa, Rottboellia, Sagittaria, Scirpus,
Setaria, Sida and Sorghum, and dicotyledonous species, for example Abutilon, Amaranthus,
Chenopodium, Chrysanthemum, Euphorbia, Galium, Ipomoea. Kochia. Nasturtium, Polygonum,
25 Sida, Sinapis, Solanum, Stellaria, Veronica, Viola and Xanthium.
Crops are to be understood as also including those crops which have been rendered
tolerant to herbicides or classes of herbicides (eg auxins or AILS-, CPSPS-, PPO- and HPPDinhibitors)
by conventional methods of breeding or by genetic engineering. An example of a crop
that has been rendered tolerant to imidazolinones, eg. irriazamox, by conventional methods of
30 breeding is ClearfieldB summer rape (canola). Exanlples of crops that have been rendered
tolerant to herbicides by genetic engineering methods include eg. glyphosate- and glufosinateresistant
lnaize varieties cornrriercially available under the trade names RoundupReadyB and
LibertyLinkB, respectively.
Crops are also to be understood as being those which have been rendered resistant to
35 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
oeetle) txaniples of Ot tnalze are tne Ut 1 /I3 ma re hybrids ol NK@ (Syngenta Seeos, I he Ut
toxln 1s a proteln that 1s formed naturally by Bacll us rliur~ng~enssios1 1b acter~aE xamp es of
24
toxins, or transgenic plants able to synthesize such toxins, are described in EP-A-451 878, EP-A-
374 753, WO 93107278, WO 95134656, WO 031052073 and EP-A-427 529. Examples of
transgenic plants comprising one or more genes that code for an insecticidal resistance and
express one or more toxins are Knockout8 (maize), Yield GardB (maize), N L I C O T I N ~ ~ B ~
5 (cotton). Bollgardm (cotton), NewLeam (potatoes), NatureGardB and Protexcta8. 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.
Crops are also to be understood as being those which are obtained by conventional
10 methods of breeding or genetic engineering and contain so-called output traits (eg, improved
storage stability, higher nutritional value and improved flavor).
Any method of application to weedslcrop of useful plant, or locus thereof, which is
routinely used in agriculture may be used, for example application by spray or broadcast method
typically after suitable dilution of a compound of formula (I) (whether said compound is formulated
15 andlor in combination with one or more further active ingredients andlor safeners, as described
herein).
The compounds of formula (I) according to the invention can also be used in combination
with other active ingredients, eg. other herbicides, andlor insecticides, andlor acaricides, andlor
nematocides, andlor niolluscicides, and/or fungicides, andlor plant growth regulators. Such
20 mixtures, and the use of such mixtures to control weeds and/or undesired plant growth, form yet
further aspects of the invention. For the avoidance of doubt, mixtures of invention also include
mixtures of two or more different compounds of formula (I). In particular, the present invention
also relates to a composition of the invention which comprises at least one further herbicide in
addition to the compound of formula (I).
25 When a compound of formula (I) is combined with at least one additional herbicide, the
following mixtures of the compound of formula (I) are preferred. Compound of formula (I) +
acetochlor, colnpound of formula (I) + acifluorfen, compound of formula (I) acifluorfen-sodiuni,
cornpound of formtrla (I) + aclonifen, compound of formula (I) + acrolein, compound of formula (I)
+ alachlor, compound of formula (I) + alloxydim, compound of formula (I) + allyl alcohol,
30 compound of formula (I) + ametryn, compound of formula (I) 4- amicarbazone, compound of
formula (I) + amidosulfuron, compound of formula (I) + aminocyclopyrachlor, compound of
formula (I) + aminopyralid, compound of formula (I) + amitrole, compound of formula (I) +
ammonium sulfamate, compound of formula (I) + anilofos, compound of formula (I) + asulam,
compound of formula (I) + atrazine, formula (I) + aviglycine, formula (I) + azafenidin, compound
35 of formula (I) + azimsulfuron, compound of formula (I) + BCPC, compound of formula (I) +
beflubutamid, compound of formula (I) + benazolin, formula (I) + bencarbazone, compound of
compound of formula (I) + bentazone, compound of formula (I) 4. benzfendizone, compound of
formula (I) + benzobicyclon, compound of formula (I) + benzofenap, compound of formula (I) +
bicyclopyrone, compound of formula (I) + bifenox, compound of formula (I) + bilanafos,
compound of formula (I) + bispyribac, compound of formula (I) + bispyribacsodium, compound of
5 formula (I) + borax, compound of formula (I) + bromacil, compound of formula (I) + bromobutide,
formula (I) + bromophenoxim, compound of formula (I) + bromoxynil, compound of formula (I) +
butachlor, compound of formula (I) + butafenacil, compound of formula (I) + butamifos,
compound of formula (I) + butralin, compound of formula (I) + butroxydim, compound of formula
(I) + butylate, compound of formula (I) + cacodylic acid, compound of formula (I) + calcium
10 chlorate, compound of formula (I) + cafenstrole, compound of formula (I) + carbetamide,
compound of formula (I) + carfentrazone, compound of formula (I) .+ carfentrazone-ethyl,
compound of formula (I) + CDEA, compound of formula (I) + CEPC, compound of formula (I) +
chlorflurenol, compound of formula (I) + chlorflurenol-methyl, compound of formula (I) ichloridazon,
compound of formula (I) + chlorimuron, compound of formula (I) + chlorimuron-ethyl,
15 compound of formula (I) + chloroacetic acid, compound of formula (I) + chlorotoluron, compound
of formula (I) + chlorpropham, compound of formula (I) + chlorsulfuron, compound of formula (I) +
chlorthal, compound of formula (I) 4. chlorthal-dimethyl, compound of formula (1) + cinidon-ethyl,
compound of fortiiula (I) + cintnethylin, compound of forlnula (I) 4- cinosulfuron, compound of
formula (I) + cisanilide, compound of formula (I) + clethodim, compound of formula (I) +
20 clodinafop, compound of forlnula (I) + clodinafop-propa~gylc, ompound of formula (I) +
clomazone, compound of formula (I) + clomeprop, compound of formula (I) + clopyralid,
compound of formula (I) + cloransulam, compound of formula (I) + cloransulam-methyl.
compound of formula (I) + CMA, compound of formula (I) + 4-CPB, compound of formula (I) +
CPMF, compound of formula (I) + 4-CPP, compound of formula (I) 4. CPPC, compound of
25 formula (I) + cresol, compound of formula (I) + cumyluron, compound of formula (I) + cyanamide,
compound of formula (I) + cyanazine, compound of formula (I) + cycloate, compound of formula
(I) + cyclosulfamuron, compound of formula (I) + cycloxydim, compound of formula (I) +
cyhalofop, compound of formula (I) + cyhalofop-butyl, compound of formula (I) + 2,4-D,
compound of formula (I) 3- 3,4-DA, compound of formula (I) daimuron, compound of formula (I)
30 + dalapon, compound of forlnula (I) + dazomet, compound of formula (I) 4. 2,4-DB, compound of
formula (I) + 3,4-DB, compound of formula (I) + 2,4-DEB, compound of formula (I) .+
desmedipham, formula (I) + desmetryn, compound of formula (I) + dicamba, compound of
formula (I) + dichlobenil, compound of formula (I) + ortho-dichlorobenzene, compound of formula
(I) + para-dichlorobenzene, compound of formula (I) + dichlorprop, compound of formula (I) +
35 dichlorprop-P, compound of formula (I) + diclofop, compound of formula (I) + diclofop-methyl,
compound of formula (I) + diclosulam, compound of formula (I) + difenzoquat, compound of
formula (I) + difenzoquat metilsulfate, compound of formula (I) + diflufenican, compound of
formula (I) + diflufenzopyr, compound of formula (I) + dimefuron, compound of formula (I) +
dimepiperate, compound of formula (I) + dimethachlor, compound of formula (I) + dimethametryn,
40 conipouno of f01111dld( I) + d llielrie~lal(1~ ic ompo~ndo f formula (I) + dimetnenam 0-P, compound
of formula (I) 4 dlmethlp 11 compourlo of formula (I) + dlmetnylarsln c ac~o compouno of formtrla
(I) + dinitramine, compound of formula (I) + dinoterb, compound of formula (I) + diphenamid,
formula (I) + dipropetryn, compound of formula (I) + diquat, compound of formula (I) + diquat
dibromide, compound of formula (I) + dilliiopyr, compound of forniula (I) + diuron, compound of
formula (I) + DNOC, compound of formula (I) + 3,4-DP, compound of formula (I) + DSMA,
5 compound of formula (I) + EBEP, compound of formula (I) + endothal, compound of formula (I) +
EPTC, compound of formula (I) + esprocarb, compound of formula (I) + ethalfluralin, compound
of formula (I) + ethametsulfuron, compound of formula (I) + ethametsulfuron-methyl, formula (I) +
ethephon, compound of formula (I) + ethofumesate, compound of formula (I) + ethoxyfen,
compound of formula (I) + ethoxysulfuron, compound of formula (I) + etobenzanid, compound of
10 formual (I) + fenoxaprop, compound of formula (I) + fenoxaprop-P, compound of formula (I) +
fenoxaprop-ethyl, compound of formula (I) + fenoxaprop-P-ethyl, compound of formula (I) +
fentrazamide, compound of formula (I) + ferrous sulfate, compound of formula (I) + flamprop-M,
compound of formula (I) + flazasulfuron, compound of formula (I) 4- florasulam, compound of
formula (I) + fluazifop, compound of formula (I) + fluazifop-butyl, compound of formula (I) +
15 fluazifop-P, compound of formula (I) + fluazifop-P-butyl, formula (I) + fluazolate, compound of
formula (I) + flucarbazone, compound of formula (I) + flucarbazone-sodium. compound of formula
(I) + flucetosulfuron, compound of formula (I) + fluchloralin, compound of formula (I) + flufenacet,
compound of forniula (I) -1- flufenpyr, compound of forrnula (I) + flufenpyr-ethyl, forrnula (I) -1-
flumetralin, compound of formula (I) + flumetsulam, compound of formula (I) + flumiclorac,
20 compound of fortiiula (I) + flu~niclorac-pentylc, ompound of formula (I) + flumioxaziri, formula (I) +
flumipropin, compound of formula (I) -1- fluometuron, compound of formula (I) + fluoroglycofen,
compound of formula (I) + fluoroglycofen-ethyl, formula (I) + fluoxaprop, formula (I) .t flupoxam,
formula (I) + flupropacil, compound of formula (I) + flupropanate, compound of formula (I) +
flupyrsulfuron, compound of formula (I) + flupyrsulfuron-methyl-sodium, compound of formula (I)
25 -1- flurenol, compound of formula (I) + fluridone, compound of formula (I) + flurochloridone,
compound of formula (I) + fluroxypyr, compound of formula (I) + flurtamone, compound of formula
(I) + fluthiacet, compound of formula (I) + fluthiacet-methyl, compound of formula (I) + fomesafen,
compound of formula (I) + foramsulfuron, compound of formula (I) + fosamine, compound of
formula (I) + glufosinate, compound of formula (I) + glufosinate-ammonium. compound of formula
30 (1) -1- glyphosate, compound of formula (I) + lialauxifen, compound of formula (I) + halauxifenmethyl,
compound of formula (I) + halosulfuron, compound of formula (I) + halosulfitror~-nietllyl,
compound of formula (I) + haloxyfop, compound of formula (I) + haloxyfop-P, compound of
formula (I) + HC-252, compound of formula (I) + hexazinone, compoi~ndo f formula (I) +
imazamethabenz, compound of formula (I) + imazamethabenz-methyl, compound of formula (I) +
35 imazamox, compound of formula (I) + imazapic, compound of formula (I) + imazapyr, compound
of formula (I) + imazaquin, compound of formula (I) + imazethapyr, compound of formula (I) +
imazosulfuron, compound of formula (I) + indanofan, compound of formula (I) and indaziflam,
compound of formula (I) + iodomethane, compound of formula (I) + iodosulfuron, compound of
formula (I) + iodosulfuron-methyl-sodium, compound of formula (I) + ioxynil, compound of formula
40 (I) atlo ~pfe~icarua~ou~oll~e~,p o,lldo f formtrla (I) + lsoprotlrron compound of formula (I) +
IsoLron compound of formu a (I) T ~soxabenc ompound of form~la(I ) + lsoxachlortole
compound of formula (I) + isoxaflutole, formula (I) + isoxapyrifop, compound of formula (I) +
karbutilate, compound of formula (I) + lactofen, compound of formula (I) + lenacil, conlpound of
formula (I) + linuror~c, ompound of formula (I) + MAA, compound of forniula (I) + MAMA,
compound of formula (I) + MCPA, compound of formula (I) + MCPAthioethyl, compound of
formula (I) + MCPB, compound of formula (I) + mecoprop, compound of formula (I) + mecoprop-
P, compound of formula (I) + mefenacet, compound of formula (I) + mefluidide, compound of
formula (I) + mesosulfuron, compound of formula (I) + mesosulfuron-methyl, compound of
formula (I) + mesotrione, compound of formula (I) + metam, compound of formula (I) +
metamifop, compound of formula (I) + metamitron, compound of formula (I) + metazachlor,
compound of formula (I) and metazosulfuron, compound of formula (I) + methabenzthiazuron,
formula (I) + methazole, a compound of formula (I) and methiozolin, compound of formula (I) +
methylarsonic acid, compound of formula (I) + methyldymron, compound of formula (I) + methyl
isothiocyanate, compound of formula (I) + metobenzuron, formula (I) + metobromuron, compound
of formula (I) + metolachlor, compound of formula (I) + S-metolachlor, compound of formula (I) +
metosulam, compound of formula (I) + metoxuron, compound of formula (I) + metribuzin,
compound of formula (I) + metsulfuron, compound of formula (I) + metsulfuron-methyl, compound
of formula (I) + MK-616, compound of formula (I) + molinate, compound of formula (I) +
rnonolinuron, a compound of forrnula (I) arid monosulluron, a compound of formula (I) and
monosulfuron-ester compound of formula (I) + MSMA, compound of formula (I) + naproanilide,
compound of formula (I) + napiapamide, compound of fol-mula (I) + naptalani, formula (I) i. NDA-
402989, compound of formula (I) +- neburon, compound of formula (I) + nicosulfuron, formula (I) inipyraclofen,
formula (I) + n-methyl glyphosate, compound of formula (I) + nonanoic acid,
compound of formula (I) + norflurazon, compound of formula (I) + oleic acid (fatty acids),
compound of formula (I) 3. orbencarb, compound of formula (I) + orthosulfamuron, compound of
formula (I) + oryzalin, compound of formula (I) i-ox adiargyl, compound of formula (I) +
oxadiazon, compound of formula (I) + oxasulfuron, compound of formula (I) + oxaziclomefone.
compound of formula (I) + oxyfluorfen, compound of formula (I) + paraquat, compound of formula
(I) + paraquat dichloride, compound of formula (I) + pebulate, compound of formula (I) +
pendimethalin, compound of formula (I) 4- penoxsulam, compound of formula (I) .Ipentaclilorophenol,
compound of formula (I) + pentanochlor, compound of formula (I) +
penioxazone, compound of formula (I) + petlioxatnid, compound of foriiiula (I) 4. petroliurn oils,
compound of formula (I) + phenmedipham, compound of formula (I) + phenmedipham-ethyl,
compoilnd of formula (I) + picloram, compound of formula (I) + picolinafen, compoilnd of formula
(I) + pinoxaden, compound of formula (I) + piperophos, compound of formula (I) + potassium
arsenite, compound of formula (I) + potassium azide, compound of formula (I) 4- pretilachlor,
compound of formula (I) + primisulfuron, compound of formula (I) + primisulfuron-methyl,
compound of formula (I) + prodiamine, compound of formula (I) + profluazol, compound of
formula (I) + profoxydim, formula (I) + prohexadione-calcium, compound of formula (I) +
prometon, compound of formula (I) + prometryn, compound of formula (I) + propachlor,
40 compound of formu a (I) + propanll ConlpO~ndo f forniuta (I) + propaqul~afopc, utrlpo~ndo f
formula (I) + propazine, compound of formula (I) + propham, compound of fornlula (I) 7
propisochlor, compound of formula (I) + propoxycarbazone, compound of formula (I) +
propoxycarbazone-sodiutn, compound of formula (I) + propyzamide, compound of formula (I) +
prosulfocarb, compound of formula (I) + prosulfuron, compound of formula (I) + pyraclonil,
compound of formula (I) + pyraflufen, compound of formula (I) + pyraflufen-ethyl, formula (I) -I~
pyrasulfotole, compound of formula (I) + pyrazolynate, compound of formula (I) + pyrazosulfuron,
compound of formula (I) + pyrazosulfuron-ethyl, compound of formula (I) + pyrazoxyfen,
compound of formula (I) + pyribenzoxim, compound of formula (I) + pyributicarb, compound of
formula (I) + pyridafol, compound of formula (I) + pyridate, compound of formula (I) + pyriftalid,
compound of formula (I) + pyriminobac, compound of formula (I) + pyriminobac-methyl,
compound of formula (I) + pyrimisulfan, compound of formula (I) + pyrithiobac, compound of
forniula (I) + pyrithiobac-sodium, formula (I) + pyroxasulfone, formula (I) + pyroxulam, compound
of formula (I) + quinclorac, compound of formula (I) + quinmerac, compound of formula (I) +
quinoclamine, compound of formula (I) + quizalofop, compound of formula (I) + quizalofop-P,
compound of formula (I) + quizalofop-ethyl, compound of formula (I) + quizalofop-P-ethyl,
compound of formula (I) + rimsulfuron, compound of formula (I) + saflufenacil, compound of
formula (I) + sethoxydim, compound of formula (I) + siduron, compound of formula (I) + simazine,
compound of fornlula (I) + simetryn, conlpound of forniula (I) + SMA, conlpound of fortnula (I) +
sodium arser~itec, ompound of formula (I) + sodium azide, compound of formula (I) + sodium
chlorate, compound of formula (I) + sulcotrione, compound of formula (I) + sulfentrazone,
compound of forrr~ula(I ) + sulforneturori, cotripound of forriiula (I) + sulfot~ieturori-methyl,
compound of formula (I) + sulfosate, compound of formula (I) + st~lfosulfuronc, ompound of
formula (I) .I- sulfuric acid, compound of formula (I) 4- tar oils, compound of formula (I) + 2,3,6-
TEA, compound of formula (I) + TCA, compound of formula (I) + TCA-sodium, formula (I) .ttebutam,
compound of formula (I) + tebuthiuron, formula (I) + tefuryltrione, compound of fornlula
1 + tembotrione, compound of formula (I) + tepraloxydim, coinpound of formula (I) + terbacil,
compound of formula (I) + terbumeton, compound of formula (I) + terbuthylazine, compound of
formula (I) 4- terbutryn, compound of formula (I) + thenylchlor, compound of formula (I) +
thiazafluron, compound offormula (I) + thiazopyr, ~0mp0llndo f formula (I) + thifensulfuron,
compound of formula (I) + tliiencarbazone, compound of formula (I) + thifensulfuron-methyl,
compound of formula (I) + thiobencarb, compound of formula (I) .t- tiocarbazil, compound of
formula (I) + topramezone, compound of formtila (I) + tralkoxydirn, a compound of formula (I) arid
triafamone compound of formula (I) + tri-allate, compound of formula (I) + triasulfuron, compound
of formula (I) + triaziflam, compound of formula (I) + tribenuron, compound of formula (I) +
tribenuron-methyl, compound of formula (I) + tricamba, compound of formula (I) + triclopyr,
compound of formula (I) + trietazine, compound of formula (I) + trifloxysulfuron, compound of
formula (I) + trifloxysulfuron-sodium, compound of formula (I) + trifluralin, compound of formula (I)
+ triflusulfuron, compound of formula (I) + triflusulfuron-methyl, compound of formula (I) + trifop,
compound of formula (I) + trifop-methyl, compound of formula (I) + trihydroxytriazine, compound
of formula (I) + trinexapac-ethyl, compound of formula (I) + tritosulfuron, compound of formula (I)
40 T [3-[2-c~i1oro-4-fI~oro-5.-(I-methyl-6-trii1..orom2e.4r-hU~,Io xo-I 2 3.4-tetrahydropyrinl~ain-3-
yl)phenoxy]-2-pyr1dyloxy]acel1ca cd ethyl ester (CAS RN 353797 -31-6) compound of form..la (I)
+ 2-[[8-chloro-3,4-d1hydro-4-(4-methoxyphenyl)-3-oxo-2-qu1noxalinyl]carbonyl-l.3-
cyclohexaned~one and the compound of formula (I) + VX-573
In particular, the following mixtures are important:
5
mixtures of a compound of formula (I) with an acetanilide (e.g compound of formula (I) +
acetochlor, compound of formula (I) + dimethenamid, compound of formula (I) -+ metolachlor,
compound of formula (I) + S-metolachlor, or compound of formula (I) + pretilachlor) or with other
inhibitors of VLCFAE (e.g compound of formula (I) + pyroxasulfone).
10
mixtures of a compound of formula (I) with an HPPD inhibitor (e.g. compound of formula (I)
+ isoxaflutole, compound of formula (I) + mesotrione, compound of formula (I) + pyrasulfotole,
compound of formula (I) + sulcotrione, compound of formula (I) + tembotrione, compound of
formula (I) + topramezone, compound of formula (I) + bicyclopyrone;
15
mixtures of a compound of formula (I) with a triazine (e.g, compound of formula (I) +
atrazine, or compound of formula (I) + terbuthylazine);
mixtures of a compound of formula (I) with glyphosate;
20
mixtures of a compound of formula (I) with glufosinate-ammonium;
mixtures of a compound of formula (I) with a PPO inhibitor (e.g. compound of formula (I) +
acifluorfen-sodium, compound of formula (I) + butafenacil, compound of formula (I) 3.
25 carfentrazone-ethyl. compound of formula (I) + cinidon-ethyl, compound of formula (I) +
flumioxazin, compound of formula (I) + fomesafen, compound of formula (I) + lactofen, or
compound of formula (I) + SYN 523 ([3-[2-chloro-4-fluoro-5-(l-methyl-6-tritluoromethyl-2,4-dioxo-
1,2,3,4-tetraliydropyrimidin-3-yl)phenoxy-2-pyrdyoxy]acetic acid ethyl ester) (GAS RN 353292-
31-6)).
30
Whilst two-way mixtures of a compound of formula (I) and another herbicide are explicitly
disclosed above, the skilled man will appreciate that the invention extends to three-way, and
further multiple combinations comprising the above two-way mixtures. In particular, the invention
extends to:
35
mixtures of a compound of formula (I) with a triazine and an HPPD inhibitor (e.g.
compound of formula (I) + triazine + isoxaflutole, compound of formula (I) + triazine + mesotrione,
compound of formula (I) + triazine + pyrasulfotole, compound of formula (I) + triazine +
sulcotrione, compound of formula (I) + triazine + tembotrione, compound of formula (I) + triazine
40 + topramezonc, cor~~pounodf forrnu a (I) I trlazine T b cyclopyrone.
mixtures of a compound of formula (I) with glyphosate and an HPPD inhibitor (e.g.
compound of formula (I) + glyphosate + isoxaflutole, compound of formula (I) -I- glyphosate +
mesotrione, compound of formula (I) + glyphosate + pyrasulfotole, compound of formula (I) +
glyphosate + sulcotrione, compound of formula (I) + glyphosate + tembotrione, compound of
5 formula (I) + glyphosate + topramezone, compound of formula (I) + glyphosate + bicyclopyrone;
mixtures of a compound of formula (I) with glufosinate-ammonium and an HPPD inhibitor
(e.g. compound of formula (I) + glufosinate-ammonium + isoxaflutole, compound of formula (I) i
glufosinate-ammonium + mesotrione, compound of formula (I) + glufosinate-ammonium +
10 pyrasulfotole, compound of formula (I) + glufosinate-ammonium + sulcotrione, compound of
formula (I) + glufosinate-ammonium + tetnbotrione, compound of forinula (I) + glufosinateammonium
+ topramezone, compound of formula (I) + glufosinate-ammonium + bicyclopyrone;
mixtures of a compound of formula (I) with a VLCFAE inhibitor and an HPPD inhibitor (eg.
15 compound of formula (I) + S-metolachlor + isoxaflutole, compound of formula (I) + S-metolachlor
+ mesotrione, compound of formula (I) + S-metolachlor + pyrasulfotole, compound of formula (I)
+ S-metolachlor + sulcotrione, compound of formula (I) + S-metolachlor + tembotrione,
compound of formula (I) + S-iiietolachlor + topramezone, cotnpound of formula (I) + Smetolachlor
+ bicyclopyrone, compound of formula (I) + acetochlor + isoxaflutole, compound of
20 formula (I) -1- acetochlor + mesotrione, compound of forinula (I) + acetochlor + pyrasulfolole,
compound of formula (I) + acetochlor + sulcotrione, compound of formula (I) + acetochlor +
tembotrione, compound of formula (I) + acetochlor + topramezone, compound of formula (I) 4.
acetochlor + bicyclopyrone, compound of formula (I) + pyroxasulfone + isoxaflutole, compound of
formula (I) 4. pyroxasulfone + mesotrione, compound of formula (I) + pyroxasulfone +
25 pyrasulfotole, compound of formula (I) + pyroxasulfone 4- sulcotrione, compound of formula (I) ipyroxasulfone
+ tembotrione, compound of formula (I) + pyroxasulfone d- topramezone,
compound of formula (I) + pyroxasulfone + bicyclopyrone.
Particularly preferred are mixtures of the compound of formula (I) with niesotrione,
30 bicyclopyrone, isoxatlutole, tembotrione, topramezone, sulcotrione, pyrasulfotole, metolachlor, Srnetolachlor,
acetochlor, pyroxasulfone, P-dimethenamid, dimethenamid, ilufenacet, petlioxamid,
atrazine, terbuthylazine, bromoxynil, metribuzin, amicarbazone, bentazone, ametryn, hexazinone,
diuron, tebuttiiuron, glyphosate, paraquat, diquat, glufosinate, acifluorfen-sodium, butafenacil,
carfentrazone-ethyl, cinidon-ethyl, flumioxazin, fomesafen, lactofen, [3-[2-chloro-4-fluoro-5-(1-
35 methyl-6-trifluoromethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic
acid ethyl ester.
The mixing partners of the compound of formula (I) may also be in the form of esters or
salts, as mentioned e g in The Pesticide Manual, 14th Edltlon (BCPC), 2006 The reference to
40 ac,fluo~ien-soaluma l>u dpp, es to dcifl~.uifeit~ile iefe~et~cloe U irliettietidi~llua so apples ro
d~metnenamia-Pt,h e reference to glufos nate-ammon om also appl~esto glufoslnare lne
reference to bensulfuron-methyl also applies to bensulfuron, the reference to cloransularn-methyl
also applies to cloransulam, the reference to flamprop-M also applies to flamprop, and the
reference to pyrithiobac-sodium also applies to pyrithiobac, etc.
5 The mixing ratio of the compound of formula (I) to the mixing partner is preferably from 1:
100 to 1000:1.
The mixtures can advantageously be used in the above-mentioned formulations (in which
case "active ingredient" relates to the respective mixture of compound of formula (I) with the
10 mixing partner).
The compounds of formula (I) according to the invention can also be used in combination
with one or more safeners. Likewise, mixtures of a compound of forrnula (I) according to the
invention with one or more further active ingredients, in particular with one or more further
15 herbicides, can also be used in combination with one or more safeners. The term "safener" as
used herein means a chemical that when used in combination with a herbicide reduces the
undesirable effects of the herbicide on non-target organisms, for example, a safener protects
crops from injury by herbicides but does not prevent the herbicide from killing the weeds. Where
a compound of formula (I) is combined with a safener, the following combinations of the
20 compound of formula (I) and the safener are particularly preferred. Compound of formula (I) + AD
67 (MON 4660), compound of formula (I) - 1 benoxacor, compound of formula (I) +- cloqiiintocetmexyl,
compound of formula (I) + cyometrinil and a compound of formula (I) + the corresponding
(2) isomer of cyometrinil, compound of formula (I) + cyprosulfamide (CAS RN 221667.31-8).
compound of formula (I) + dichlormid, compound of formula (I) and dicyclonon, compound of
25 formula (I) and dietholate, compound of formula (I) + fenchlorazole-ethyl, compound of formula (I)
+ fenclorim, compound of formula (I) + flurazole, compound of formula (I) i- fluxofenirn,
compound of formula (I) + furilazole and a compound of formula (I) + the corresponding R isomer
or furilazome, compound of formula (I) .I. isoxadifen-ethyl, compound of formula (I) + mefenpyrdiethyl,
compound of formula (I) and mephenate, compound of forrnula (I) + oxabetrinil,
30 compound of formula (I) 4- naphlhalic anhydride (CAS RN 81-84-5), compound of formula (I) and
TI-35, compound of formula (I) + N-isopropyl-4-(2-methoxy-benzoylsulfa1noyl)-benzamide (CAS
RN 221668-34-4) and a compound of formula (I) + N-(2-methoxybenzoy1)-4..
[(methylaminocarbonyI)amino]benzenesulfonamide. Particularly preferred are mixtures of a
compound of formula (I) with benoxacor, a compound of formula (I) with cloquintocet-mexyl, a
35 compound of formula (I) + cyprosulfamide and a compound of formula (I) with N-(2-
methoxybenzoyI)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.
The safeners of the compound of formula (I) may also be in the form of esters or salts, as
ment~onede g in The Pest~c~dMea nual, 14th Ed~t~o(BnC PC), 2006 The reference to
40 cloquintocet-mcxyl also app cs to cloqu.rirocc1 and to a llln um sodium, potass ,ni, calcium
magnesium, alumtnium, iron, ammonium, quaternary ammonium, sulfontum or phosphonium salt
thereof as disclosed in WOO2134048 and the reference to fenchlorazole-ethyl also applles to
fenchlorazole, etc
5 Preferably the mixing ratio of compound of formula (I) to safener is from 100:l to 1 :lo,
especially from 20:l to I: 1
The mixtures can advantageously be used in the above-mentioned formulations (in which
case "active ingredient" relates to the respective mixture of compound of formula (I) and any
10 further active ingredient, in particular a further herbicide, with the safener).
It is possible that the safener and a compound of formula (I) and one or more additional
herbicide(s), if any, are applied simultaneously. For example, the safener, a compound of formula
(I) atid one or more additional herbicide(s), if any, might be applied to the locus pre-emergence or
15 might be applied to the crop post-emergence. It is also possible that the safener and a compound
of formula (I) and one or more additional herbicide(s), if any, are applied sequentially. For
example, the safener might be applied before sowing the seeds as a seed treatment and a
compound of formula (I) and one or more additional herbictdes, if any, tnight be applied to the
locus pre-emergence or might be applied to the crop post-emergence.
20
Preferred mixtures of a compound of formula (I) witli further herbicides and safeners
include:
Mixtures of a compound of formula (I) with S-metolachlor and a safener, particularly
25 benoxacor.
Mixtures of a compound of formula (I) with isoxaflutole and a safener
Mixtures of a compound of formula (I) witli tnesotrione and a safener
30
Mtxtures of a compound of formula (I) with sulcotrione and a safener.
Mixtures of a compound of formula (I) with tembotrione and a safener
35 Mixtures of a compound of formula (I) with topramezone and a safener
Mixtures of a compound of formula (I) with bicyclopyrone and a safener
Mixtures of a compound of formula (I) with a triazine and a safener.
4 0
Mixtures of a compound of formu a (I) w.th a trazltic and ~soxaflutolea na a safcrier
Mixtures of a compound of formula (I) with a triazine and mesotrione and a safener
Mixtures of a compound of formula (I) with a triazine and sulcotrione and a safener.
5
Mixtures of a compound of formula (I) with a triazine and tembotrione and a safener.
Mixtures of a compound of formula (I) with a triazine and topramezone and a safener.
10 Mixtures of a compound of formula (I) with a triazine and bicyclopyrone and a safener.
Mixtures of a compound of formula (I) with glyphosate and a safener.
15 Mixtures of a compound of formula (I) with glyphosate and isoxaflutole and a safener.
Mixtures of a compound of formula (I) with glyphosate and mesotrione and a safener.
Mixtures of a compound of formula (I) with glyphosate and sulcotrione and a safener.
20
Mixtures of a compound of formula (I) with glyphosate and tembotrione arid a safener.
Mixtures of a compound of formula (I) with glyphosate and topramezone and a safener
25 Mixtures of a compound of formula (I) with glyphosate and bicyclopyrone and a safener
Mixtures of a compound of formula (I) with glufosinate-ammonium and a safener
30 Mlxtures of a compound of forrnula (I) wlth glufos~nate-ammonluln and lsoxallutole and a
salener
Mixtures of a compound of formula (I) with glufosinate-ammonium and mesotrione and a
safener.
35
Mixtures of a compound of formula (I) with glufosinate-ammonium and sulcotrione and a
safener.
Mixtures of a compound of formula (I) with glufosinate-ammonium and tembotrlone and a
34
Mixtures of a compound of formula (I) w~thg lufoslnate-ammonium and toprarnezone and a
safener
Mixtures of a compound of formula (I) with glufosinate~ammonium and bicyclopyrone and a
5 safener.
Mixtures of a compound of formula (I) with S-metolachlor and a safener
Mixtures of a compound of formula (I) with S-metolachlor and isoxaflutole and a safener
10
Mixtures of a compound of formula (I) with S-metolachlor and mesotrione and a safener.
Mixtures of a compound of formula (I) with S-rnetolachlor and sulcotrione and a safener
15 Mixtures of a cotnpound of formula (I) with S-metolachlor and tembotrione and a safener.
Mixtures of a compound of formula (I) with S-metolachlor and topramezone and a safener.
Mixtures of a compound of formula (I) with S-metolachlor and bicyclopyrone and a safener
20
Mixtures of a compound of formula (I) with pyroxasulfone and a safener.
Mixtures of a compound of formula (I) with pyroxasulfone and isoxaflutole and a safener
25 Mixtures of a compound of formula (I) with pyroxasulfone and mesotrione and a safener.
Mixtures of a compound of formula (I) with pyroxasulfone and sulcotrione and a safener
Mixtures of a compound of formula (I) with pyroxasulfone and tembotrione and a safener.
30
Mixtures of a cornpound of forini~la(I ) with pyroxasulfone and toprarnezone and a safener.
Mixtures of a compound of formula (I) with pyroxasulfone and hicyclopyrone and a safener
35 Mixtures of a compound of formula (I) with acetochlor and a safener.
Mixtures of a compound of formula (I) with acetochlor and isoxaflutole and a safener,
Mlxtures of a compound of formula (I) w~tha cetochlor and mesotr~onea nd a safener
40
M xtLres of a conipoJno of fornlula (I) w~tha cetochlor and s~lcotr~onancd a safener
Mixtures of a compound of formula (I) with acetochlor and tembotrione and a safener
Mixtures of a compound of formula (I) with acetochlor and topramezone and a safener.
5
Mixtures of a compound of formula (I) with acetochlor and bicyclopyrone and a safener
Various aspects and embodiments of the present invention will now be illustrated in more
detail by way of example. It will be appreciated that modification of detail may be made without
10 departing from the scope of the invention.
For the avoidance of doubt, where a literary reference, patent application, or patent, is
cited within the text of this application, the entire text of said citation is herein incorporated by
reference.
15 Examples
Preparation Exam&
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 =
20 Septet; m = multiplet; RT = retention time, MH' = molecular mass of the molecular cation.
1H NMR spectra were recorded at 400MIiz either on a Varian Unity lnova instrument
400MHz or on a Bruker AVANCE - II instrument.
The colnpounds may exist in a mixture of diastereoisomers, which may be observed by
25 LC-MS and NMR. The stereochemistry of the chiral centre at the carbon containing the R3 group
was generally found to interconvert at room temperature. Depending on the nature of R,
substitution and the conditions for product synthesis, purification and analysis the ratio of
diastereomers may change.
30 Example 1 - Preparation of 5-hydroxy-l-[5-iodo-4-(trifluorotnothyl)-2-pyridyl]-3,4-dimethylimidazolidin-
2-one (A25)
F I
36
Procedure for synthesis of l-(2,2-dimethoxy-l-methyl-ethyl)-3-[5-iodo-4-(trifluoromethyl)-2-
pyridyll-I-methyl-urea (Step-I)
5-iodo-4-(trifluoromethyl)pyridin-2-amine (for a synthesis see Bioorganic & Medicinal Chemistry
5 Letters, 1994, 4(6), 835-8) (0.500 g, 1.74 mmol) was dissolved in DCM (5 mL) and then carbonyldiimidazole
(1.06g, 80% purity) was added. The reaction mixture was heated at 105'C in a
microwave vial for 15 minutes and then cooled to 10°C. 1.1-dimethoxy-N-methyl-propan-2-amine
(preparation as in example 13) (695 mg, 3 equiv.) was added and the reaction was stirred at
room temperature for 15 mins. The reaction was diluted with DCM (10 mL) and water (5 mL) was
10 added. This mixture was filtered and the aqueous layer extracted with further DCM (2 x10 mL).
The combined organics were dried (Na2S0,), filtered and evaporated and then chromatographed
on silica eluting with 20.30% EtOAc in isohexane. Fractions containing product were evaporated
to give desired product as an amber gum (326 mg, 42%).
LC-MS: (positive ES MH+ 448).
15
Procedure for synthesis of 5-hydroxy~.l-[5-iodo-4-(trifluoromethyl)-2-pyridyrj~~3,4-dimethylimidazolidin-
2-one (Step-2)
'l-(2,2-dimethoxy-l-methyl-ethyl)-3-[5-iodo..4-(trifluoro1nethyl)-2-pyridyl]-~l-methyl-urea (260 rng,
20 0.581 mmol) was dissolved in acetic acid (5.2 rnL) and water (2.6 mL) The reaction ~nixturew as
stirred at room temperature for 2 days. The reaction mixture was then evaporated and dried (100
to ImBar at 20-35%) for 2h to remove traces of acetic acid to give product as a lilac gum which
crystallised to give a solid (230 mg, 98%).
LC-MS: (positive ES MH+ 402).
25 'H NMR (cDc'I~): Major diastereomer: 8.69 (s, IH), 8.64 (s, IH), 5.56 (m, AH), 4.65 (very br s,
IH), 3.53 (m, IH), 2.93 (s, 3H), 1.33 (d, 3H).
Minor diastereomer: 8.70 (s, IH), 8.64 (s, IH), 5.91 (d, IH), 4.65 (very br s, IH), 3.76 (m, 1 H),
2.88 (s, 3H), 1.38 (6, 3H).
Example 2 - Preparation of 5-hydroxy-l-[5-(4-methoxy-3-pyridyl)-4-(trifluoromethyl)-2-
pyridyll-3,4-dimethyl-imidazolidin-2-one (A24)
O i l
I
J+J13.cl,, -- ___f
5-hydroxy-l-[5-iodo-4-(trifluorometliyl)-2-~~yridyl]-3,4-dimetlyl-i1nidazolidin--o(n5e0 liig, 1 equiv.
5 0.125 mmol), (6-methyl-3-pyridy1)boronic acid (22 mg, 1.1 equiv.), tricyclohexylphosphine (4 mg,
0.12 equiv) tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.05 equiv), in 1,4-dioxane (0.5 mL)
was treated with K,CO, (38 mg) in water (0.2 mL) The reaction was heated for 80 minutes at
100°C, then treated with further 6-methyl-3-pyridy1)boronic acid (2.2 equiv.), tricyclohexyl
phosphine (4mg, 0.12 equiv), tris(dibenzylideneacetone)dipalladium(O) (6 mg, 0.05 equiv),
10 K3P04 (45 mg, 1.7 equiv.) and the reaction was then heated for a further 75 minutes at 100°C.
1-he reaction mixture was diluted with EtOAc (6 mL) then filtered through celite, evaporated, then
chromatographed on silica eluting with 20-100% EtOAc in isohexane. Fractions containing
product were evaporated to give desired product as an amber gum (35 mg, 6g0/0).
LC-MS: (positive ES MH+ 367).
15 'H NMK (CDCI,): Major diastereomer: 8.69 (s, IH), 8.46 (s, IH), 8.21 (m, IH). '7.57 (dm, IH),
7.25 (dm. IH), 5.65 (m, IH), 4.91 (br s, It!), 3.56 (m, IH), 2.95 (s, 3H), 2.64 (s, 3H), 1.36 (d, 3H).
Minor diastereomer: 8.69 (s, IH), 8.46 (s, IH), 8.21 (m, IH), 7.57 (dm, IH), 7.25 (dm, IH), 6.00
(d, 1 H), 4.78 (br s, Ili), 3.79 (m, 114). 2.92 (s, 31-1), 2. 64 (s, 314), 1.42 (d, 3H).
20 Example 3 - Preparation of 5-hydroxy-l-[5-methoxy-4-(trifluoromethyl)-2-pyridyl]-3,4-
dimethyl-imidazolidin-2-one (Al2)
25 A mixture of di-fert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphane
(RockPhos) (11 mg, 4.5 mol%), allylpalladium(ll) chloride dimer (3 mg, 1.5mol%) and Cs2C03
(245 mg, 1.5 equiv) in toluene (0.8 mL) was degassed by bubbling NZ through the reaction
mlxture for 5m1ns Th~s mlxture was then heated to 90UC for 3 mlns then methanol (101 ML, 5
equlv ) was added, followeu by 5-hydroxy-l-[5-,odo-4-[~11ro~rfo 1nethyl)-2-pyc1dyl]-3,4-dlmerhylimidazolidin-
2-one (200mg, 0.499 mmol, 1 equiv.). The reaction was then heated in a sealed tube
at 80°C for l h and 25 minutes. Further di-tert-butyl-[G-methoxy-3-methyl-2-(2,4,6-
tl-iisopropylphenyl)phenyl]phosphane (RockPhos) (1 1 mg. 4.5 mol%), allylpalladium(ll) chloride
dimer (3 mg, 1.5mol%) and methanol (40 VL, 2 equiv.) was added. The reaction was then heated
5 in a sealed tube at 80°C for a further 1 h. The reaction mixture was diluted with 4ml EtOAc,
filtered through celite, then evaporated, then chromatographed on silica eluting with 0-100%
EtOAc in isohexane. Fractions containing product were evaporated to give desired product as a
pale yellow solid (80 mg, 53%).
LC-MS: (positive ES MH+ 306).
10 'H NMR (CDCI3): Major diastereomer: 8.45 (s, IH). 8.03 (s. I l i ) , 5.53 (m, IH), 4.90 (br s, IH),
3.95 (s, 3H). 3.50 (m, IH), 2.91 (s, 31i), 1.33 (d, 3H).
Minor diastereomer: 8.44 (s, IH), 8.05 (s, IH), 5.88 (d, IH), 4.75 (br s. IH), 3.95 (s, 3H), 3.75 (m,
1 H), 2.88 (s, 3H), 1.39 (d, 3H).
15 Example 4 - Preparation of 4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one (A8)
F
Procedure for synthesis of N,1,1-trimethoxypropan-2-imine (Step-I)
20 Metlioxylamine hydrochloride (21.2 g) was suspended in rr~ethanol (65 rnL) then potassium
acetate (50.4 g, quickly ground in pestle and mortar to break up lumps) was added all at once
and the thick white suspension resulting was stirred at room temp for l5mins then cooled to 15OC
and then 1,l-dimethoxypropan-2-one (309) was addded slowly over 25mins. The reaction was
stirred at room temperature for 50 mins and then diluted with 200rn1 DCM, then 100ml sat.
25 NaHC03 (aq) was added cautiously over 15mins. After effervescence subsided, the layers were
separated, extracted with further DCM (2 x 80 mL), dried Na,SO,, filtered and concentrated at
220 mbar and 35% (care as desired product is volatile) to give 379 amber liquid, which was used
wlrnol~tf, .rtner p ~ jfr r al,on
1 H NMR (CDCI,) snowed a 3 1 latlo of E Z Isomers
Procedure for synthesis of N,1,1-trimethoxypropan-2-amin(eS tep-2)
N,1,1-trimethoxypropan-2-imine (20 g) was dissolved in acetic acid (80 niL) then was cooled to
5 13OC NaBH,CN (9.82 g) was added portionwise over 10mins. After 18hrs at room temperature,
the reaction was concentrated to remove bulk of HOAc then residue dissolved in DCM (300 mL)
and satd. NaHCO, (aq) (300 mL) was added slowly with stirring. The mixture was stirred at rt for
90 mins, and then 40% NaOH(aq) was added until the solution reached pli 12. The layers were
separated, extracted with further DCM (3 x 100 mL). The combined DCM layers were dried
10 (Na2S0,), filtered and evaporated to give 16.4 g of crude product as a pale amber oil, which was
further purified by Kugelrohr disliliation (120°C at 70mBar) to give product (12.0 g, 59% yield)
which was approxitnalely 95% pure by NMR arid used without further purificatiori.
Procedure for synthesis of I-(2,2-dimethoxy-I-methyl-ethyl)-I-methoxy-urea (Step-3)
N,1,1-trimethoxypropan-2-amino (7.000 g, 1341 mmol) was dissolved in IPA (5 mL) and the
mixture was cooled to 0°C under N2, then trimethylsilyl isocyanate (commercially available) (4.83
mL, 33.51 mmol) was added and the reaction was allowed to warm to room temperature and was
stirred at room temperature for 24 h. The reaction mixture was worked up by adding DCM (30
20 mL) and water (I5 mL), extracting with further DCM (2 x 15 mL), dried (Na2S0,), filtered and
evaporated then chromatographed on silica eluting with 50-100% EtOAc in isohexane. Fractions
containing product were evaporated to give the desired product as a white solid (2.08 g, 81%
yield).
'H NMR (CDCI1): 5.36 (br s, 2H), 4.47 (d, IH), 4.32 (pentet, IH), 3.75 (s, 3H). 3.37 (d, 6H), 1.24
25 (d, 3H).
Procedure for synthesis of I-(2,2-dimethoxy-I-methyl-ethyl)-I-methoxy-3-[4-
(trifluoromethyl)-2-pyridyllurea (Step-4)
1-(2,2-dimethoxy-1-methyl-ethyl)-I-methoxy-urea (300 mg, 1.56 mmol), 2-chloro-l-
(trifluoromethyl)pyridine (commercially available) (312 mg, 1.1 equiv.), potassiucn carbonate (324
mg), tris(dibenzylideneacetone)dipalladium(O) (30 mg), 4,5-bis(dipheny1phosphino)-9,9-
dimethylxanthene (70 mg) were suspended in I-4-dioxane (4 ml.) and the mixture was then
5 heated at 105'C in a sealed vial for 2h. The mixture was allowed to cool to room temperature,
diluted with EtOAc (6 mL), filtered, then chromatographed on silica eluting with 0-100% EtOAc in
isohexane. Fractions containing product were evaporated to give the desired product as a yellow
gum (170 mg, 32%).
LC-MS: (positive ES MH+ 338).
10
Procedure for synthesis of 4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2.
pyridyllimidazolidin-2-one (Step-5)
1-(2,2~-dimethoxy-l-methyl-ethyl)-l-nietl?oxy-3-[4-(trifluorometliyl)-2-pyridyl]ure(a1 55 I , 0 .459
15 rnmol) was dissolved in acetic acid (1 mL) and water (0.5 mL) and stirred at room temperature for
25 mins and then at 60°C for 2h and 45 mins. The reaction was left at room temperature for 18h
before heating again at 60°C for 2h. Reaction mixture was evaporated and then
chromatographed on silica eluting with 0.24% EtOAc in isohexane. Fractions containing product
were evaporated to give the desired product as a pale beige solid (101 mg, 75%).
20 NMR indicated a ratio of diastereoisomers in approximately a 2:l ratio.
'H NMR (CIICI,): Major diastereomer: 8.55 (s, IH), 8.43 (dd, IH), 7.25 (d, IH), 5.55 (d, IH), 5.04
(very br s, IH), 3.90 (s, 3H), 3.71 (d, IH), 1.45 (d, 31-1).
'H NMR (CDCI,): Minor diastereomer: 8.53 (s, IH), 8.45 (dd. IH), 7.24 (d, IH). 5.87 (d, IH), 4.60
(very br s, 1 I+), 3.93 (s, 3H). 3.80 (m, 1 H). 1.50 (d, 3H).
25 LC-MS: (positive ES MH-I 292).
Example 5 - Preparation of 4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one (AS) -Alternative synthesis
Phenyl N-[4-(trtfluoromethyI)-2-pyr1dyl]carbamate (for a synthes~ss ee WO 2007004749) (9 93 g,
1.05 equiv.) was suspended in 1.4-dioxane.(25 .mL) ..under a Nitrogen atmosphere and treated
with N,1,1-trimetlioxypropan-2-amine (5.00 g, 22.51 mmol, 1 equiv.) and the reaction was heated
to reflux for 2.5h. The reaction was cooled to room temperature, then 2N aqueous I-iCI (30 niL)
5 was added to the reaction mixture and heated to 50°C for 25 minutes. EtOAc (100 mL) and water
(75 mL) was added and the aqueous layer was further extracted EtOAc (2 x 75 mL). The
combined organic fractions were washed with satd NaHC03 (aq), dried (Na2S0,), filtered and
then chromatographed on silica eluting with 0-26% EtOAc in isohexane. Fractions containing
product were evaporated to give the desired product as a crystalline solid (6.865 g).
10 LC-MS: (positive ES MH+ 281).
Example 6 - Preparation of (4R,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolidin-2-one and (4S,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-
(trifluoromethyl)-2-pyridyl]imidazolidin-one (A3)
15 and
Example 7 (4R,5R)4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)9-
pyridyl]imidazolidin-2-one and (4S,5R)-4-hydroxy-l-methoxy-5-methyl-3-[4-
(trifluoromethy1)-2-pyridyl]imidazolidin-one (A4)
20
A sample of compound A8 was separated into two major fractions by preparative chiral SFC (Lux
Cellulose-4 column, eluting with IPA (7%) with other fractions discarded. The analysis could be
perfomed by HPLC on a Lux Amylose-2 or WHELK-01 column eluting with heptane1lPA in a
70130 ratio
25 One fraction eluting from the SFC column was found to equilibrate to (4R,5R)-4-hydroxy-Imethoxy-
5-methyl-3-[4-(trifluoromethyl)-2-pyrdyl]midazolidn-2-one and (4S,5N)-4-hydroxy-Imethoxy-
5-methyl-3-[4-(trifIuoromethyl)-2-pyridyl]imidazolidin-2-one.
The absolute stereochemistry may be proven by synthesis (in an analogous way to example 5-
alternative synthesis below).
30 Another fraction eluting from the SFC colurnn was f o ~ ~ tliod equilibrate to (4R.5.S)-4-hydroxy-Imethoxy-
5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one and (4S,5S)-4-hydroxy-Imethoxy-
5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one.
The absolute stereochemistry could be proven by synthesis (see Example 5 - alternative
synthesis below) and also by X-ray crystallography after recrystallization of a sample from
35 DCMIisoHexane.
Example 8 - Preparation of (4S,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolidin-2-one and (4R,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-
(trifluoromethyl)-2-pyridyllimidazolidin-2-011( A3) - Alternative synthesis.
40
Procedure for synthesis of methyl (2s)-2-(methoxyamino)propanoate (Step-I)
To a stirred solution of methyl (2R)-2-hydroxypropanoate (16.5 g, 158 mmol, 15.1 mL) in DCM
5 (475 mL) at O°C was added trifluoromethanesulfonic anhydride (49.7 g, 174 mmol) followed after
5mins by 2,6-dimethylpyridine (19.5 g, 182 mmol). The resulting mixture was stirred at O°C for 10
minutes to give a solution of methyl (2R)-2-(trifluoro~~ethylsulfonyloxy)propanoatSe.e parately, Omethylhydroxylamine
hydrochloride (65.98 g, 790.0 mmol) was dissolved in water (130 mL) then
sodium hydroxide (50% aqueous) (33.1 mL 632.0 mmol) was added. The solution of O-
10 methylhydroxylamine in water was added to the solution of methyl (2R)-2-
(trifluoromethylsu1fonyloxy)propanoate in DCM, and the mixture was stirred at room temperature
for 30 minutes. The organic layer was separated and chromatographed on silica eluting with O-
45% EtOAc in isohexane. Fractions containing product were evaporated to give the desired
product as a pale yellow oil (23.5 g). The product appears to have some volatility so caution was
15 taken with the evaporation step. The product was used without further purification.
Procedure for synthesis of methyl (2s)-2-[methoxy-[[4-(trifluoromethyl)-2-
pyridyl]carbamoyl]amino]propanoate (Step-2)
Procedure as for example 4 alternative synthesis
Procedure for synthesis of (4S,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-
pyridyI]imidazolidin9-one and (4R,5S)-4-hydroxy-l-methoxy-5-methyl-3-[4-
25 (trifluoromethy1)d-pyridyllimidazolidin-2-one (A3) (Step-3)
To a stirred solution of methyl (2s)-2-[methoxy-[[4-(trifluoromethyl)-2-
pyridyl]carbamoyl]amino]propanoate (18.3 g, 57.0 mmol) in a mixture of tetrahydrofuran (103
mi) and methanol (103 niL) at 5OC under nitrogen was added NaBH4 (5.10 g, 2.25 equiv.)
portionwise over ?Omins, keeping the internal temperature below -65'C. The mixture was then
5 stirred at 65OC for l h before the reaction was quenched with acetone (50 mL) slowly over 45
minutes with external cooling to keep the internal temperature below -65°C Sat. aqueous NH,CI
solution (150 mL) was added followed by water (150 mL). The reaction was stirred at 15OC for
IOmins, then extracted with DCM (4 x 400 mL and then 1 x 100mL). Combined DCM fractions
were washed with water (50 mL) dried (Na2S04), filtered and concentrated to -200 mL volume,
10 then chromatographed on silica eluting with 0.27% EtOAc in isohexane. Fractions containing
product were evaporated to give the desired product as a white solid (5.659, 34%).
Examples 9 and 10 - Preparation of 4,5-dihydroxy-I-methyl-3-[4-(triEluoromethyl)-2-
pyridyllimidazolidin-2-one (A7) and 5-ethoxy-4-hydroxy-l-methyI-3-[4-(trifluoromethyl)-2-
15 pyridyllimidazolidin-2-one (A6)
20 Procedure for synthesis of 4 I-methyl-3-[4-(trifluoromethyl)-2-pyridyllurea (Slop-I)
A mixture of tris(dibenzylideneacetone)dipalladium(O) (0.202 g, 0.220 mmol), 4,5-
bis(diphenyiphosphino)-9,9-dimethylxanthene (0.493 g, 0.826 mmol), potassium carbonate (1.93
warmed to 75-80°C with stirring under a Nitrogen atmosphere for 3.5 h. The reaction mixture was
diluted with EtOAc (20 cnL) and water (20 mL) and filtered through a pad of celite, rinsing through
with fuither small portions of EtOAc and water. The organic phase was separated and the
aqt.lnous further extracted with EtOAc (5 mL). The organic extracts were combined, washed with
5 brine (I0 mL), dried over MgSO,, filtered and the filtrate evaporated giving an orange liquid. This
was chromatographed (eluting with an EtOAcIiso-hexane gradient) and fractions containing
product were evaporated and triturated with iso-hexane to give the desired product as a light
yellow powder (0.669 g, 55%).
'H NMR (CDCI,): 9.44 (br.s, IH), 9.04 (brs, IH), 8.32 (d, IH). 7.15 (s, IH), 7.06 (d, IH), 2.99 (6,
10 3H).
LC-MS: (positive ES MH+ 220).
Procedure for synthesis of 4,s-dihydroxy-I-methyl-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolidin-2-one (A7) and S-ethoxy-4-hydroxy-l-methyl-3-[4-(trifluoromethyl)-2-
15 pyridyl]imidazolidin-2-one (A6) (Step-2)
To I-methyl-3-[4-(trifluorornethyl)-2-pyridyl]urea (065 g. 3.0 mmol) in ethanol (20 mL) was added
glyoxal (40% aqueous solution) (2.6 g, 18 mmol, 2.0 mL) via syringe, the mixt~~rthee n being
20 warmed and heated at reflux for 2 hours. The reaction mixture was allowed to cool to room
temperature and conceritrated to give a syrupy residue. This was dissolved in DCM (50 mL) and
washed with brine (2 x 5 mL). The organic phase was dried (MgSO,) filtered and the filtrate
conceritrated giving the crude product as a dark green gum (1.07 g). The crude product was
dissolved in DCM (20 mL) then chromatographed on silica eluting with EtOAc in isohexane
25 Fractions containing product were evaporated to give 4,5-dihydroxy-I-methyl-3-14.,
(trifluoromethyl)-2-pyridyl]imidazolidin20ne (0.562 g, 68%) and 5-ethoxy-4-hydroxy-l-methyl-3-
[4-(trifluoromethyl)-2-pyridyl]imidazolidn-2-one (0.1 1 g. 12%).
4,5-Dihydroxy-l-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one:
30 'H NMR (CDCI,): Major diastereoisomer: 8.35 (brs, IH), 8.32 (d, IH), 7.12 (dd, IH), 5.71 (d, AH);
4.96 (d, IH), 4.82 (d, 1H). 3.54 (6, AH), 3.01 (s, 3H).
Minor diastereoisomer: 8.47 (br.s, IH), 8.38 (d, IH), 7.19 (dd, IH), 5.89 (d, AH), 5.15 (d, AH),
5.12(d,IH),3.82(d,lH),2.97(~,3H).
LC-MS (pos~t~vEeS MH+ 278)
5-Eth0~y-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazo\idin-2-one (existing
predominately in the trans form)
'H NMR (CDCI,): 8.46 (s, IH), 8.38 (d, IH), 7.18 (dd, IH), 5.73 (d, IH), 4.82 (d, IH), 4.71 (s, I l i ) ,
3.66 (m, 2H), 3.00 (s, 3H), 1.28 (t, 3H).
5 LC-MS: (positive ES MH+ 306).
Examples 11 and 12 - Preparation of 5-ethoxy-4-hydroxy-l-methyl-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolldin-2-one (Enantiomer 1, A34) and 5-ethoxy-4-hydroxy-I-methyl-3-[4-
(trifluoromethyl)-2-pyrldyl]imidazolidin-on (Enantiomer 2, A35)
10
5-ethoxy-4-hydroxy-l-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one (A6) was
separated into individual enantiomers E l and E? by preparative chiral HP1.C (CHIRALPAK IC
column, eluting with isoliexane (containing 0.1% TFA) and IPA).
The first eluting enantiomer E l was purified further by chromatography on silica eluting with
15 EtOAc in isohexane. Fractions containing prod~~wcet re evaporated to give pure enantiomer El
(A34). Enantiomer E2 (A35) was sufficiently pure after the chiral HPLC purification.
NMR and LC-MS data was co~isistant wit11 racemic 5-elhoxy-4-hydroxy-1-methyl-3-[4-
(trifluoromethy1)-2-pyridyllimidazolidin-on (A6) - both enantiomers were of predominantly trans
configuration as determined by NMR
20
Example 13 - Preparation of 4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one (A19)
/ Procedure for synthesis of 1,l-dimethoxy-N-methyl-propan-2-amine (Step 1)
Ti(0-iPr), (34.3 g, 2 equiv.) was cooled to 10°C under a nitrogen atmosphere then ethanol (89
mL) was added follovded by 1,l-dimethoxypropati-2-one (7.14 y , 1 eyuiv), i~~eit~ylarnirie
hydrochloride (8.16 g, 2 equiv.) and triethylamine (16.8 mL, 2 equiv.) The reaction was stirred at
5 room temperature for 15h. The reaction was cooled to 10°C and then NaBH, (3.43 g, 1.5 equiv.)
was added and the reaction was stirred at room temperature for 6h. The reaction was cooled to
10°C, then carefully over 10 minutes poured into ice cold aqueous ammonia (180 mL, 2M) The
mixture was filtered, washing through with DCM (300 ml.). The layers were separated and then
the aqueous layer was extracted with further DCM (3 x 100 mL). The combined DCM layers were
10 dried (Na2S0,), filtered and evaporated with care as to not lose any of the volatile product. This
crude material was distilled on a Kugelrohr (70 to 110°C l4mBar) to give product (4.41 g) as a
colourless oil, which was used without further purification.
1H NMR (CDCI3): 4.11 (d, IH), 3.41 (s, 6H), 2.69 (pentet, IH), 2.43 (s, 3H), 1.06 (d, 3H).
15 Procedure for synthesis of 9-(2,2-dimethoxy-I-methyl-ethyl)-I-methyl-urea (Step 2)
1,l-dimethoxy-N-methyl-propan-2-amine (1.0 g, 7.50 mmol) was dissolved in CDC13 (1.5 mL).
Yrimethylsilyl isocyanate (commercially available) (2 equiv.) was added and the reaction was
stirred at room temp for 4 days. The reaction mixture heated to reflux for 160 minutes while
20 incrementally adding a further trimethylsilyl isocyanate (1 5 equiv.) The reaction was evaporated
and treated with water (10 mL), stirred for 90 minutes, then evaporated to give crude product
(1.08 g) which was used without further purification.
1 H NMR: 4.60 (br s, 2H), 4.30 (br s, 1 Ii), 4.24 (d, l t l ) , 3.41 (s, GH), 2.71 (s, 3H), 1.18 (d, 3H).
25 Procedure for synthesis of l-(2,2-dirnethoxy-l-methyl-ethyl)-l-metl~yl-3-[4-
(trifluoromethyl)-2-pyridyllurea (Step 3)
I-(2,2-dlmethoxy-I-methyl-ethyl)-I-methyl-urea (220 mg, 1 249 mmol), 2-chloro-4-
ctrif.~oromethyl)pyr~d~(cnoem merc~al~avya a able) (272 ing, 1 2 eqdv ) putdsslu111c albur~ale( 259
30 mg 1 5 eq.llv ), tris(d~benzyl~deneacetone)d~pallaa~u(n4~7( Om)g ), 4 5-bls(d~pnenylpl~osph1no)-
9,9-dimethylxanthene (1 11 mg) were suspended in I-4-dioxane (6 mL) and the mixture was then
heated at 105°C in a sealed vial .for 1h. The mixture was allowed to cool to rooin temperature,
diluted with EtOAc (6 inL), filtered then chromatographed on silica eluting with 0-100% EtOAc in
isohexane, Fractions containing product were evaporated to give the desired product as a
5 colourless gum (282 mg, 70%).
LC-MS: (positive ES MH+ 322).
Procedure for synthesis of 4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyl]imldazolidin-2-one (A19) (Step 4)
10
l-(2.2-dimethoxy-l-methyl-ethyl)-l-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (240 mg, 0.787
mmol) was dissolved in acetic acid (6 mL), then water (3 mL) was added to give a homogeneous
solution. This was stirred at room temperature for 2 days and then at 60°C for lh. The reaction
was evaporated (100 to ImBar at 20-35°C for 2h) to remove traces of HOAc to give product (204
15 mg, 99%) as an amber gum.
114 NMR (CDCI,): Major diastereomer: 8.54 (s, IH), 8.37 (d, AH), 7.16 (d, IH), 5.61 (m, IH), 4.95
(br s, In), 3.53 (m, I n ) , 2.93 (s, 3H), 1.34 (d, 3H).
Minor diastereomer: 8.54 (s, I l i ) , 8.39 (m, AH), 7.16 (d, IH), 5 95 (d, IH). 4.81 (br s, IH), 3.76
(pentet, 1 H), 2.89 (s, 3H), 1.40 (d, 3H).
20 LC-MS: (positive ES MH+ 276).
Example 14 - Preparation of 4-hydroxy-1,5-dimetliyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one (A19) - alternative synthesis
I:
b "c. + "0 N
I i N ~ O
O/ ''0 O f ?
25 Phenyl N-[4-(trifluoromethyl)-2-pyridyllcarbamate (for a synthesis see WO 2007004749) (4.54 g,
1.05 equiv.) was suspended in 1.4-dioxane (12 mL) under a Nitrogen atmosphere and then 1 , I -
dimethoxy-N-methyl-propan-2-amine (3.46 g, 15.3 mmol) was added and the . . reaction was
heated at 105'C for 25 mlns Aq-eo..s 2N HCI (20 mL) was added to tile react~onin x l ~ r ea nd
this was heated to 32°C for 30 mins. EtOAc (5 mL) and water (50 mL) were added and the
aqueous phase was extracted with further EtOAc (2 x 50 mL). The combined EtOAc layers were
washed with sat. aqueous NaHC03 (5 mL), evaporated and then chromatographed on silica
eluting with 0.100% EtOAc in isohexane. Fractions containing product were evaporated to give a
5 colourless gum which slowly crystallised to give product (3.80 g, 90%).
NMR and LC-MS as for first synthesis - Example 11 above.
Example 15 - Preparation of 5-allyl-4-hydroxy-l-methyl-3-[4-(trifluoromethyl)-2-
10 pyridyllimidazolidin-2-one (A32)
Procedure for synthesis of methyl 2-[[4-(trifluoromethyI)-2-pyridyl]carbamoylamino]pent-4-
enoate (Step 1)
15
To phenyl N-[4-(trifluoromethyI)-2-pyridyl]carbamat (for a synthesis see W0 2007004749)
(0.328 g, 1.16 mmol) dissolved in 1.4-dioxane (6 mL), under a Nitrogen atmosphere, was added
methyl 2-aminopent-4-enoate (for a synthesis see W02007137168) (0.150 g. 1.16 mmol). The
20 mixture was then warmed to 80°C for 3h. The reaction temperature was then raised to 100°C.
and heating continued for a further 1.511. The reaction mixture was concentrated to remove the
bulk of solvent, the oily residue being taken up in EtOAc (20 mL) and washed with water (2 x 5
mL) The organic phase was separated and dried over MgS04, filtered and then
chromatographed on silica eluting with EtOAc in isohexane. Fractions containing product were
Procedure for synthesis of 5-allyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-dione
(Step 2 )
5 Methyl 2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoate (0.1 14 g, 0.359 nimol) was
dissolved in 1,4-dioxane (4 rnL) was treated with 2N hydrochloric acid (4 mL) and the mixture
was heated at 60-70°C for 3h. The reaction temp was raised to 85°C and heating continued for a
further lh. The reaction mixture then being allowed to cool to room temperature and then
concentrated. The residue was taker1 into DCM (15 mL) and the orgariic phase separated. The
10 aqueous was further extracted with DCM (2 x 10mL) and the DCM extracts combined, dried over
MgS04, filtered and the filtrate concentrated giving crude intermediate 2-[[4-(trifluoromethyl)-2-
pyridyl]carbamoylamino]pent-4-enoic acid as a white gum (47 mg). The aqueous phase was
evaporated giving further 2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoic acid as a
white foam (73 mg). Both fractions of 2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-
15 enoic acid were combined and used with further purification in the next step. The crude 2-[[4-
(trifluoromethyl)-2-pyridyl]carbarnoylamino]pent-4-enoic acid was taken into DCM (4 mL), then
oxalyl chloride (0.0912 g, 0.719 rnmol) was added to the fine slurry at room temperature. The
reaction mixture was stirred for 2h and then allowed to stand overnight. The reaction mixture was
concentrated and the residue taken into EtOAc (20 mL) and washed with water (5 mL). The
20 organic phase was separated, the aqueous being further extracted with EtOAc (10 mL). The
organic extracts were then combined, washed with water (3 mi.), dried over MgSO,, filtered and
the filtrate concentrated giving crude product as a light brown gum that began to solidify on
standing (141 mg). This was used in the next step without further purification.
LC-MS: (positive ES MHi- 286)
25
Procedure for synthesis of 5-allyl-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-
2,4-dione (Step 3)
A solul~utiu l 5-dlly83 -[4-(trtfluororr1elriyl)-2-pyr~dyljlrii1uaol1d14ri-eu-12o 11e(0 120 g, 0 42 1 nimol)
30 in DMF (1 5 niL) was cooled to 0-5 C in an ice baln was treated dropwise witti LiHMDS (1 OM it1
(0.0717 g, 0.505 mmol) was added and stirring continued for 40 minutes. The reaction mixture
was concentrated and the oily residue being taken up in EtOAc (I5 mL) and washed with brine (3
x 2mL), dried over MgSO,, filtered and the filtrate concentrated giving crude product, which was
5 chromatographed on silica eluting with EtOAc in isohexane. Fractions containing product were
evaporated to give product as a white solid (0060 g, 48%).
LC-MS: (positive ES MH+ 300).
Procedure for synthesis of 5-allyl-4-hydroxy-l-methyl-3-[4-(trifluoromethyl)-2-
10 pyridyl]imidazolidin-2-one (Step 4)
5-allyl-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoldne-2,4-dione (0.057 g, 0.19 mmol) in
methanol (10 ml.) was cooled to around -35°C (acetonelC02 bath). NaBH, (0.0073 g, 0.19 mmol)
15 was added in a single portion and the reaction was stirred for 30 minutes at between -30 and -
40°C. The reaction mixture'was allowed to warm slowly to room temperature. Further NaBH,
(0.0073 g. 0.19 mmol) was added and the mixture stirred at room temp for a further 30 minutes.
The reaction tnixture was quenched by the careful addition of water (2 mL), then concentrated
and the residue being left to stand at room temperature for 72h. The mixture was diluted with
20 EtOAc (20 mL) and the organic phase separated. The aqueous phase was further extracted with
EtOAc (15 mL) and the organic extracts combined, washed with water (5 mL), dried over MgSO,,
filtered and evaporated to give product as a light grey gum (56 mg. 98%).
LC--MS: (positive ES MHc 302).
1H NMR (CDCI,): Major diastereomer: 8.15 (s, IIH), 8.37 (d. IH), 7.15 (dd, IH). Sf5 (m, 1 t i ) ,
25 5.70 (d, 1 IH), 5.23 (dd, 1 H). 5.20 (dd, 1 IH), 4.90 (d, 1 H), 3.54 (ddd, I H), 2.96 (s, 3H), 2.55 (m, 1 IH),
2.53 (m, IH).
114 NMR (CDC13): Minor diastereorner: 8.15 (s, IH), 8.37 (d, IH), 7.15 (dd, IH), 5.98 (m, IH),
5.70 (d, AH), 5.26 (dd, IH), 5.18 (d, IH), 4.79 (br.s, IH), 3.65 (ddd, IH), 2.91 (s, 3H), 2.69 (m,
1 H), 2.55 (m, IH).
30
Example 16 - Preparation of 4-hydroxy-l-methyl-5-(trifluoromethyl)-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolidin-2-one (A33)
Procedure for synthesis of 2,2-dimethoxy-N-methyl-ethanimine (Step 1)
-N O-
5 OMethylamine hydrochloride (4.05 g, 1.05 equiv) in DCM (60 mL) was cooled to O°C, then K2C03
(5.53 g. 1 equiv) was added over 5 minutes. Keaction was stirred at O°C for a further 10 minutes
then 2,2-dimethoxyacetaldehyde (6.04 mL. 40 mmol) was added and the reaction was stirred
vigorously at O°C. After 5 minutes at O°C, the reaction was allowed to warm to room temperature.
10 After 15 minutes at roorn temperalure, DCM was decanted off, solid was extracted with DCM (2 x
15 mL) Combined DCM fractions were dried (Na,SO,), filtered, and evaporated to give product
which was ~ ~ sweidth out further purification (4.10 g, 87%).
Procedure for synthesis of l,l ,l-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (Step 2)
KHF2 (2.01 g, 0.75 equiv.) was suspetided in MeCN (69 mL) and DMF (8.0 mL) under Nitrogen,
and cooled to O°C then 2,2-dimethoxy-N-methyl-ethanimine (4.029, 1 equiv.) was added followed
by dropwise addition of TFA (3.28 mL. 1.25 equiv.) over 2 minutes. Reaction was stirred at OnC
20 for 5 minutes, then trimethyl(trifluoromethyl)silane (7.6 mL, 1.5 equiv) was added over 5 mintues
and the reaction was stirred at O°C for 3h. Reaction was then treated with sat, aqueous NaHC03
(50 mL) over 3 minutes The reaction mixture was then extracted with diethyl ether (3 x 200 mL),
dried (Na2S0,), filtered and evaporated (care as product is volatile) to give product (14.1 g, 44%),
which was used without further purification.
25
Procedure for synthesis of l,l,l-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (Step 3)
Crude 1,1,l-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (3.58 g, 1.2 equiv.) was dissolved
in l,4-dioxane (2.5 mL) and treated with N-[4-(trifluoromethy1)-2-pyridyljcarbamae (for a
synthesis see WO 2007004749) (1.00 g, 3.19 mmol) and heated at llO°C for 2 h 15 minutes.
5 Reaction mixture was then evaporated and the residue chromatographed on silica eluting with
EtOAc in isohexane (0-35%). Fractions containing product were evaporated to give product as a
gum (0.40 g, 33%).
LC-MS: (positive ES MH+ 376).
10 Procedure for synthesis of 4-hydroxy-l-methyld-(trifluoromethyI)-3-[4-(trifluoromethyl)-2-
pyridyllimidaiolidin-2-one (Step 4)
1,1,1-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (0.377 g) was suspended in water (2 mL)
and then treated with TFA (2 mL) and the reaction mixture was then heated to 60°C for 15h. The
15 reaction was evaporated and treated with sat. aqueous NaHC03 (15 mL) and DCM (15 mL) The
aqueous phase was further extracted with DCM (2 x 10 mL) and then the combined DCM phases
were dried (Na2S0,), filtered and evaporated to give product as a white solid (320 mg, 97%).
[LC-MS. (positive ES MH+ 330).
-1H NMR (CDCI,): 8.48 (s, IH), 8.42 (d, I l i ) , 7.25 (d. IH). 6.02 (m, I l i ) , 5.01 (br s, AH), 3.93 (m,
20 IH), 3.10 (s, 3H).
Example 17 - Preparation of (4R,5S)-4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one and (4S,5S)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one (A37)
/ ',
and
5 / ',5
Procedure for synthesis of (4-nitrophenyl) N-14-(trifluoromethy1)-2-pyridyllcarbamate
(Step 1)
5 0'
To a stirred solution of 4-(trifluoromethyl)pyridin-2-amine (5 g, 30.84 mmol) and pyridine (2.56 g,
32.38 niniol) in DCM (75 tiiL) at 0°C (intet-nal temp) was added (4-nitroplienyl) cat-botioctiloridate
(6.22 g. 30.84 mmol,) over 15mins, keeping temp at or below 8"C, and the reaction mixture was
then stirred at PC for 1 h. After 90 mins at O0C, the reaction was allowed to warm to room
10 temperature, and stirred at for I hr. Ice cold water (25 mL) was added. The biphasic mixture was
filtered and the precipitate washed with ice cold water (10 mL) and DCM (2 x 10 mL). The
precipitate was dried under vacuum to give product as a white solid (7.60 g, 75%)
LC-MS: (positive ES MH+ 328).
15
Procedure for synthesis of (5S)-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoliditlc.
2,4-dione (Step 2)
A mixture of (4-nitrophenyl) N-[4.(trifluoromethyI)-2-pyridyllcarbamate (1.20 g, 3.67 mmol) and
1,4-dioxane (12 mL), under a nitrogen atmosphere, was treated with (2s)-2-
(methylarnino)propanoic acid (0.416 g, 4.03 mmol, and the mixture was stirred at room
temperature for 5h then at 60°C for 15h, left at room temperature overnight, then heated at 80°C
5 for 1.5h and then left over the weekend at rt. The reaction mixture was filtered rinsing through
with small portions of EtOAc, then the filtrate and washings were combined and concentrated to
give a deep yellow oily residue. The oily residue was taken into EtOAc (25 mL) and washed with
saturated NaHC03 solution (3 x 15 mL) and brine (10 mL) The organic phase was dried over
MgS04, filtered, evaporated and the residue chromatographed on silica eluting with EtOAc in
10 isohexane. Fractions containing product were evaporated to give product (0.675 g, 67%).
LC-MS: (positive ES MH+ 274).
Procedure for synthesis of (4R,5S)-4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one and (4S,5S)-4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
15 pyridyllimidazolidin-2-one (A37) (Step 3)
(5S)-1,5-dimethyl-3-[4-(trifluorometliyl)-2-pyridyl]imidazolidine-2,4-dione (0.660 g, 2.42 mmol)
20 was stirred in methanol (20 mL) and the solution was cooled to around -15°C (ice-salt bath).
Sodium borohydride (0.0933 g, 2.42 mmol) was added in a single portion and the reaction was
allowed to warm to 15°C over l h , and was then quenched by the careful addition of water (0.5
mL). After 5 minutes stirring the tnixture was diluted ful-ther with water (40 ml.). A white
precipitate formed, which was filtered off, washed with water and dried under suction giving a
25 white powder. The combined filtrate and washings were extracted with DCM (3 x 20mL). 7-he
organic extracts were then combined, washed with brine (2 x 20mL), dried over MgS04, filtered
and the filtrate concentrated giving a light grey gum, (0.367 g, 55%).
NMR and LC-MS as for example 11 (A19)
Example 18 - Preparation of (4R,5R)-4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyllimidazolidin-2-one and (4S,5R)-4-hydroxy-l,5-dimethyl-3-[4-(trifluoromethyl)-2-
pyridyl]imidazolidin-2-one (A38)
I and
Method as for example 17 but using (2R)-2-(methylamino)propanoic acid
5 Table 1 lists examples of compounds of the general formula (I)
wherein Ra, R" Rc, R" R', R ~R,~ and X are as defined above.
10 These compounds were made by the general methods described
DCI, unless otherwise
.

~. ~ ~ ~.~ ~ . . . ~ .,.. .~ ~~. .~~
/entry [STRUCTUKE /IHNM R (measured in LC-MS
I I / CDClj unless otlierw~se 1 I
I I i / indicated) 6 I 1
5 (br.s, IH), 8.32 (d,
) 7.12 (dd, IH), 5.71
IH); 4.96 (d, IH), 4.82
It+), 3.54 (d, IH), 3.01
nor diastereoisorner:
~~~~~~~ ....... ~
positive ES MH-I- 1
i I 1 CDCI, unless otherwise / I
(d, I I i ) , 5.15 (d, 11-1). 5.12
(d. IH). 3.82 (d, IH), 2.97
~~~~~~~~ ~~. ,,.~,,,
ajor diastereomer: 8.55 positive ES MH+
(s, 1 H), 8.43 (dd, 1 H),
7.25 (d, IH), 5.55 (d, IH),
5.04 (very br s, 1 H), 3.90
(s, 3H), 3.71 (d. IH). 1.45
(d, 3H).
Minor diastereomer: 8.53
(s, 1 H), 8.45 (dd, 1 H),
7.24 (d, 1 H), 5.87 (d. 1 H).
4.60 (very br s. 1 H). 3.93
(s, 3H). 3.80 (m, IH), 1.50
(d, 3H).
.
Major diastereomer: 8.72
(m. IH). 8.67 (s, IH), 8.42
(S, IH), 7.78 (t, IH), 7.45
(d. I 7.35 (dd, IH),
5.65 (s, IH), 4.94 (s, IH),
3.56 (m, IH), 2.94 (s, 3H),
1.36 (d. 3H).
Minor diastereomer: 8.72
(m, IH), 8.67 (s. IH), 8.44
(s, IH), 7.78 (t, IH), 7.45
(d, I I ) 7.35 (dd, 1 ti),
5.99 (d, IH), 4.77 (s, IH),
3.79 (pentet. IH), 2.95 (s,
3H), 1.41 (d. 3H).
--
. ~. ~ ~. ~~~~~.~
positive t S MH+
353
...
entry
CDCI:% unless otherwise
.
0.36 (s, 11-i), 0.03 (s, IH),
5.66 (s. I n ) , 4.80 (br s,
1 H), 4.69 (s, IH), 3.95 (s,
3H), 3.65 (m, 2H), 2.97 (s,
3H), 1.26 (t, 3H).
. --
Major diastereomer: 9.30
(s, IH), 8.75 (s, 1H) 8.72
(s, 2H), 8.24 (s. In). 5.65
(m. 1 4.80 (m, IH),
3.55 (m, IH). 2.96 (s, 3H),
1.35 (d. 3H).
Minor diastereomer: 9.30
(S, IH), 8.75 (s, I n ) 8.72
(s, 2H). 8.24 (s, In), 6.00
(d, 1 IH), 4.65 (s, 1 H), 3.85
(m, I n ) , 2.92 (s, 3H), 1.42
(d, 3H).
....... ........
Major diastereomer: 8.45
(s, i n ) , 8.03 (s. i n ) , 5.53
(rn, IH), 4.90 (br s, IH),
3 95 (s. 3H). 3.50 (m, In),
2.91 (s. 3H), 1.33 (d, 3H).
Minor diastereomer: 8.44
(s, 1 H), 8.05 (s, 1 H), 5.88
(d, In), 4.75 (br s, AH),
3.95 (s, 3H), 3.75 (m. In),
. ...........
positive ES MH+
336
...
positive ES MH+
........
positive ES MH+
306 1
2.88 (s, 3H), 1.39 (d, 3H).
..

.
..
.70 (d, 1 H), 3.46. (s, 3H),
4.54 (d, 11-I), 3.66 (m, ZIH),
3.00 (s, 3H), 1.27 (t, 3H).
.81 (d, IH), 2.91 (s, 3H).
DCI, unless otherwise
.70 (s, IH), 8.57 (s, 11-i),
.71 (d, IH). 4.66 (s, IH),
.58 (d, 1 H). 3.43 (s, 3H).
ajor diastereomer: 8.54
s, IH). 8.37 (d, IH). 7.16
d, IH), 5.61 (m. IH), 4.95
brs, AH), 3.53 (m, AH),
inor diastereomer: 8.54
s, 11-I), 8.39 (m, 1 ti), 7.16
d, AH), 5.95 (d. IH), 4.81
br s, IH). 3.76 (pentet,
ajor diastereorner: 8.70
m. IH), 8.48 (s, AH), 8.25
s, IH), 8.20 (s, AH), 7.18
s, IH), 5.62 (s, lt-i), 4.92
s, IH), 3.90 (s, 3H), 3.55
m, 11-I), 2.94 (s, 31-I), 1.36
.~ ~ ~. ~ LC-MS 1 . ~~~~~~~~~ ...., .~
positive ES MH+
~ ....
positive ES MH+
383
STRUCTURE
CDCI, unless otherwise
Major diasleseoii~es. 8. sitive ES MH+
(m, IH), 8.20 (s, In), 8.
(s, IH), 7.55 (s, IH), 6.
(s, AH), 5.62 (s, IH), 4.
(s, IH), 3.90 (s, 3H), 3.
(rn, AH), 2.95 (s, 3H). 1
s, IH), 5.62 (s, AH), 4.
s, IH), 1.08 (s, 3H), 3.
m, IH), 2.94 (s, 3H), 1
STRUCTURE
CDCI3 unless otherwis
Major diaskreonle~8. . sitive ES MH+
(s, 1H): 8.46 (s, IH): 8
(m, I n ) , 7.57 (dm, 1H)
7.25 (dm, I n ) , 5.65 (m
(m, In), 2.95 (s, 3H),
(s, 3H). 1.36 (d, 3H).
...... ..
s, 1 ti), 8.64 (s, 1 Id), 5
m, AH), 4.65 (very br
H), 3.53 (m, IH), 2.9
H), 3.76 (m. 111). 2.8
.
ositive ES Midi-
(d, IH), 6.43 (d, In),
(d, IH). 3.37 (m, IIH),
(s, 3n), 1.18 (d, 3 ~ ) .
Minor diastereomer
5.91 (d, IH), 3.39 (m,
2.72 (s, 3H), 1.18 (d,
CDCi3 unless otherwise
inor diastereomer 8.58
.55(s. 3H), 1.45 (d, 3H).
.25 (d, IH), 5.55 (d, I n ) ,
.04 (very br s, IH), 3.90
inor diastereomer 8.53
.24 (d. IH), 5.87(d, IH),
60 (very br s, IH). 3.93
.46 (s, IH), 8.38 (d, IH), positive ES MH+
. I 8 (dd, IH), 5.74 (d,
H), 4.80 (d, IH), 4.79 (s,
H), 3.51-3.73 (m, 31H),
33 (m, IH), 1.27 (t, 3H),
DC13 unless otherwise
.91 (d, AH), 5.50 (d, IH),
.41 (m, IH), 2.84 (s. 3H).
.31 (4, 3H), 1.24 (s, 9H).
inor diastereomers
1 7 (d, IH), 8.05 (d, IH),
.92 (d, IH), 5.85 (d, IH),
.63 (m, AH), 2.80 (s, 3H),
m, IH), 5.75 (ddd, AH),
70 (d. IH), 5.44 (m, IH),
43 (m. IH), 5.01 (br s,
H), 3.89 (rn, IH), 2.89 (s,
inor diastereomer: 8.54
s, AH), 8.39 (m, IH), 7.17
m, I t l ) , 6.02 (m, 2H).
.51 (m, 2H), 4.06 (m.
dd, IH), 5.75 (m, IH),
70 (d, IH), 5.23 (dd,
i)5,.2 0 (dd, IH), 4.90
, IH), 3.54 (ddd, IH),
96 (s, 3H), 2.55 (m, 114).
inor diastereomer: 8.15
, IH), 8.37 (d, 1 H). 7.15
d, IH), 5.98 (m, IH),

Exam~le19 - Herbicidal action
Example 19a: Pre-emerqence herbicidal activity
5
Seeds of a variety of test species were sown in standard soil in pots. After cultivation for one day
(pre-emergence) under controlled conditions in a glasshouse (at 24116'C, daylnight; 14 hours
light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the
formula1 on of the techntcal act ve lngreolenl tn acetone, water (50 50) sol-t 011 cuntaln ng 0 5O/.
10 Tween 20 (polyoxyethelyene sorbttan monoladrate, CAS RN 9005-64-5) Tne test plants were
then grown in a glasshouse under controlled cond~tions( at 24/16'C, dayln~ght,1 4 hours l~ght,
G5% humidlty) and watered twlce dally After 13 days, the test was evaluated (5= total damage to
plant; 0 = iio damage to plant). Results are shown in Table 2
Example Rate ABUTH AMARE
numbel (g/Ha)
A1 1000 5 5
SE TFA ECHCG ALOMY ZEAMX
Example 19b: Post-emerqence herbicidal activiti
Seeds of a variety of test species were sown in standard soil in pots. After 8 days cultivation
5 (post-emergence) under controlled conditions in a glasshouse (at 24/16"C, daylnight; 14 hours
light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the
formulation of the technical active ingredient in acetone 1 water (50:50) solution containing 0.5%
Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). The test plants were
then grown in a glasshouse under controlled conditions (at 24/16OC, daylnight; 14 hours light;
10 65% humidity) and watered twice daily. After 13 days, the test was evaluated (5 = total damage
to plant; 0 = no damage to plant). Results are shown in Table 3.
Table 3: Application post-emerqence
ABUTH = Abutilon theophrasti;; AMARE = Amaranthus retroflexus; SETFA = Setaria faberi;
ALOMY = Alopecurus myosuroides; ECHCG = Echinochloa crus-galli; ZEAMX = Zea mays.
1. A herbicidal compound of formula (I)
wherein
X is selected from S and 0 ;
10
R" is selected from hydrogen and halogen;
R ~seSlec ted from hydrogen, halogen, C,-C, alkyl, C,-C, haloalkyl, C,-C, alkoxy, C,-C3
alkoxy-C,-C3 alkoxy, a group Rk6N-, a group R~(o)N(R~)a-, g roup R%(o,)N(R"-, a
15 group R?~~Nso,-, a group R??~Nc(o)-, aryl optionally substituted by one or more groups
independently selected from halogen, nitro, cyano, C,-C3 alkyl, C1-C3 alkoxy, C1-C3
haloalkyl and CI-C3 haloalkoxy, and heteroaryl optionally substituted substituted by one or
Inore groups independently selected from halogen, nitro, cyano, Ct'.C3 alkyl, C,-C3 alkoxy,
C,-C3 haloalkyl and C,-C3 haloalkoxy;
20
R" is selected from hydrogen, halo, CI-C, alkyl, Cl-C6 haloalkyl, C,-C, alkenyl. Cl-C,
cyanoalkyl, C,-Cti alkoxy, c1-C~hy droxyalkyl, CZ-C, alkenyloxy C,-CG alkyl, C3-CB
cycloalkyl optionally substituted by from 1 to 3 groups independently selected from cyano,
C1-C3 alkyl and Ct-C, alkoxy;
25
Rd is selected from hydrogen, halogen, cyano, C1'C6 alkyl and C,-C, haloalkyl;
R' IS selected from hydrogen, C,-C, alkyl, Cl-C, alkoxy and Cl-C, haloalkyl and R7 IS
selected from hydrogen, hydroxyl, C,-C4 alkyl, C,-C, alkoxy, C1-C4 alkoxy-Cl-C4 alkyl, C,
30 Cq haloalkyl, C,-C, haloalkoxy and C1-C, cyanoalkyl, with the provlso that when R' 1s
or R' and R2 together with the nitrogen and carbon atoms to which they are attached form
a 3-7 membered saturated or partially unsaturated ring optionally coinprising from 1 to 3
heteroatoms independently selected from S, 0 and N and optionally substituted with from
1 to 3 yroups irideperiderilly selected frorir iiydroxyl. -0, C1-CG alkyl or C,-C, lhaloalkyl.
5
R3 is selected from halogen, hydroxyl, or any one of the following groups
R5 and RG are independently selected from hydrogen, C,-C, alkyl, Cl-C6 haloalkyl, C2CG
10 alkenyl, C2-Cs alkynyl, or R%nd R"ogether with the carbon atoms to which they are
attached form a 3-6 meinbered saturated or partially unsaturated ring optionally comprising
frorn 1 to 3 tieteroatonis independenlly selected liorrr S, O and N and optioiially substituted
with from 1 to 3 groups independently selected from halogen and Cl-C, alkyl;
15 R7 and R' are independently selected from hydrogen, C,-C6 alkyl, Cl-C, haloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, a C5-Clo heteroaryl group which can be mono- or bicyclic
comprising from 1 to 4 heteroatoms independently selected from N. O and S and optionally
substituted with 1 to 3 groups independently selected from halogen, Cl-C3 alkyl, C,-C3
haloalkyl and C,-C, alkoxy, a Cs-CIo aryl group optionally substituted with 1 to 3 groups
20 independently selected from halogen, nitro, cynno, C,-C3 alkyl, C1-C3 alkoxy, C1-C3
haloalkyl and C,-C, haloalkoxy, or R7 and R' together with the atoms to which they are
attached form a 3-6 membered saturated or partially unsaturated ring optionally comprising
from 1 lo 3 heteroatotns independently selected froin S, 0 and N and optionally substiluted
with from 1 to 3 groups independently selected from halogen or Cl-Cs alkyl;
25
R' is selected from C,-C6 alkyl or benzyl optionally substituted with 1 to 3 groups
independently selected from halogen, nitro, cyano, C,-C3 alkyl, C1-C3 alkoxy, C1-C3
haloalkyl and C1-C3 haloalkoxy;
30 or an N-oxide or salt form thereof
2 The compound of c1a.m 1 where111X 1s O
3 The compound of cla~m1 or cla~tn2 , wheretn Ra IS hydrogen
The compound of any one of claims 1 to 3, wherein R' is hydrogen
The compound of any one of claims 1 to 4, wherein R' is C,-C4 alkyl, C1.-C4 alkoxy or C1-C,
haloalkyl.
The compound of claim 5, wherein R' is Cl-C, alkyl or Cl-C, alkoxy
The compound of claim 6, wherein R' is methyl or methoxy
Tlie cornpound of any one of claims 1 lo 7, wherein R2 is alkyl. C,-C3 alkoxy or C,-C,
alkoxy-Cl-C, alkyl.
The compound of claim 8, wherein R2 is methyl, methoxy, ethoxy or methoxymethyl
The compound of any one of claims 1 to 9, wherein R3 is hydroxyl, halogen, Cl-CG
alkylcarbonyloxy, c1-C~al koxycarbonyloxy or aryloxycarbonyloxy wherein the aryl group
may be substituted with 1 to 3 groups independently selected from halogen, nitro, cyano,
C1-C3 alkyl, C,-C3 alkoxy, C1-C, haloalkyl and Cl-C3 haloalkoxy.
The compound of claim 10, wherein R3 is hydroxyl or halogen
The compound of claim 11, wherein R3 is hydroxyl.
The compound of any one of claims 1 to 12, wherein R1' is hydrogen, halogen, methoxy,
heteroaryl substituted by halogen or methoxy or aryl substituted by halogen or methoxy
groups.
The compound of claim 13, wherein R%S hydrogen
The compound of any one of claims 1 to 14, wherein RC is C1-CI, alkyl. C1-CG haloalkyl, C2-
C8 alkenyl and C,-CG cyanoalkyl or C,-CG cycloalkyl optionally substituted by from 1 to 3
groups independently selected from cyano and C,-C, alkyl.
The compound of claim 15, wherein RC is CI-CG alkyl, C1-C3 haloalkyl, Cl-CG cyanoalkyl or
C3-Ce cycloalkyl optionally substituted by from 1 to 3 groups independently selected from
cyano and Cl-C3 alkyl.
The compound of claim 16, wherein RC is methyl, ethyl, ;so-propyl, (2-methyl)-prop-I-yl. (1-
methyl)-prop-I-yl, tea-butyl, (1,l-dimethyl)-prop-I-y(l1,.1 -dimethyl)-but-I-yl, (l-methyl-lethyl)-
prop-I-yl, cyclobutyl, cyclopropyl, (1-methy1)cycloprop-I-yl, (I-methyl-I-cyano)-eth-
I-yl, (I-methyl-I-ethyl-2-cyano)-prop-1-yl. (1,l-dimethyl-2-cyano)-prop-I-yl, I-fluoroethyl,
18 The compound of clarm 17, where~n RC I S t e ~btu tyl, (1 methyl-I cyano)-eth-I-yl, I , ? -
difluoroethyl, I-fluoro-I-methylethyl or trifluoromethyl
19. The compound of claim 18. wherein RC is trifluoromethyl
5
20. The compound of any one of claims 1 to 12 wherein R" is R%'Nc(o).- or R~(O)N(R').
and RC is hydrogen, halo, C1-C4 alkyl or C,-C, haloalkyl.
21. The compound of claim 20, wherein R ~RS~R ~Nc(o)-.
10
22. The compound of any one of claims 1 to 12, wherein Rb is halo or C,-C, alkyl and RC is Cl-
C, haloalkyl
23. The compound of claim 22, wherein RC is trifluoromethyl.
15
24. A herbicidal composition comprising a compound of formula I as defined in any one of
claims 1 to 23 together with at least one agriculturally acceptable adjuvant or diluent
25. A composition according to claim 24 which comprises a further herbicide in addition to the
20 compound of formula I.
26. A composition according to claim 23 or 24 which comprises a safener.
27. LJse of a compound of formula I as defined in any one of claims 1 to 23 or a composition as
25 defined in any one of claims 24 to 26 as a herbicide.
28. A method of controlling weeds in crops of useful plants, comprising applying to said weeds
or to the locus of said weeds, or to said useful plants or to the locus of said useful plants, a
compound of formula I as defined in any one of claims 1 to 23 or a composition as claimed
30 in any one of claims 24 to 26.