PYRIDAZINONE HERBICIDAL COMPOUNDS
The present invention relates to novel herbicidal compounds, to processes for
their preparation, to herbicidal compositions which comprise the novel derivatives,
and to their use for controlling weeds, in particular in crops of useful plants, or for
inhibiting plant growth.
Herbicidal pyridazinones are known from WO2009/086041. In addition,
herbicidal 5/6 membered heterocyclyl-substituted pyridazinones are known from WO
201 1/045271 . The present invention is based upon the identification of alternative
heterocyclyl-substituted pyridazinones which exhibit improved herbicidal properties.
Thus, according to the present invention there is provided a compound of
Formula (I):
or an agronomically acceptable salt thereof,
wherein: -
X1 is N or CR4;
R1 is selected from the group consisting of Ci-C4 alkyl, Ci-C2 alkoxy-Ci-C2
alkyl, C2-C4 alkenyl, Ci-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 alkynyl and
C2-C4 haloalkynyl;
R is selected from the group consisting of hydrogen, halogen, cyano, C -
C6alkyl, Ci-Cehaloalkyl, Ci-Cehaloalkoxy, Ci-Cshaloalkoxy-Ci-Csalkyl-, C -
C6alkoxy, Ci-Csalkoxy-Ci-Csalkyl, Ci-Csalkoxy-Ci-Csalkoxy-Ci-Csalkyl-,
C3-C6cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C -
Cehydroxyalkyl-, Ci-Cealkylcarbonyl-, -S(0) pCi-C6alkyl, amino, Ci-
Cealkylamino, Ci-Cedialkylamino, -C(C1-C3alkyl)=N-0-C 1-C3alkyl and C2-C6
haloalkynyl;
R is independently selected from the group consisting of hydrogen, halogen,
nitro, cyano, amino, Ci-Cealkyl, Ci-Cehaloalkyl, C3-C6cycloalkyl, Ci-
C6alkoxy, Ci-Cealkoxycarbonyl and -S(0) PC1-C6 alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen,
hydroxyl, halogen, nitro, cyano, amino, Ci-Cealkyl, Ci-Cehaloalkyl, C3-
Cecycloalkyl, Ci-Cealkoxy, Ci-Cealkoxycarbonyl and -S(0) pCi-C6 alkyl;
G is hydrogen or -C(0)-R 6;
R6 is selected from the group consisting of Ci-Cealkyl, Ci-Cealkenyl, Ci-
Cealkynyl, Ci-Cealkyl-S-, Ci-Cealkoxy, -NR7R8 and phenyl optionally
substituted by one or more R9;
R7' and R8 are independently selected from the group consisting of C -C6 alkyl,
C1-C6 alkoxy-;
wherein R7 and R8 can together form a morpholinyl ring;
R9 is selected from the group consisting of halogen, cyano, nitro, Ci-C3alkyl,
Ci-C3haloalkyl, Ci-C3alkoxy and Ci-C3haloalkoxy;
0,1,2,3 or 4; and
0, 1 or 2.
Halogen (or halo) encompasses fluorine, chlorine, bromine or iodine. The
same correspondingly applies to halogen in the context of other definitions, such as
haloalkyl or halophenyl.
Haloalkyl groups having a chain length of from 1 to 6 carbon atoms are, for
example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, 2,2,2-trifiuoroethyl, 2-fluoroethyl, 2-chloroethyl,
pentafluoroethyl, l,l-difluoro-2,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2-
trichloroethyl, heptafluoro-n-propyl and perfluoro-n-hexyl.
Alkoxy groups preferably have a chain length of from 1 to 6 carbon atoms.
Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy or tert-butoxy or a pentyloxy or hexyloxy isomer, preferably methoxy and
ethoxy. It should also be appreciated that two alkoxy substituents present on the same
carbon atom.
Haloalkoxy i s , for examp l e , fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-
chloroethoxy, 2 ,2-difluoroethoxy or 2,2,2-trichloroethoxy, preferably
difluoromethoxy, 2-chloroethoxy or trifluoromethoxy.
Ci-Cealkyl-S- (alkylthio) is, for example, methylthio, ethylthio, propylthio,
isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably
methylthio or ethylthio.
C1-C6alkyl-S(0)- (alkylsulfinyl) is, for example, methylsulfmyl, ethylsulfmyl,
propylsulfinyl, isopropylsulfmyl, n-butylsulfmyl, isobutylsulfmyl, sec-butylsulfinyl or
tert-butylsulfmyl, preferably methylsulfmyl or ethylsulfmyl.
C1-C6alkyl-S(0) 2- (alkylsulfonyl) is, for example, methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.
In a preferred embodiment of the present invention is a compound of Formula
II (Formula I wherein G is hydrogen).
In another preferred embodiment of the present invention R is selected from
the group consisting of hydrogen, -C lkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-
C3alkoxy-Ci-C 3alkyl, C3-C6cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6
alkynyl and C2-C6 haloalkynyl.
Particularly preferred is wherein R is selected from the group consisting of
hydrogen, methyl, ethyl, cyclopropyl and methoxymethyl, most preferably methyl.
In another embodiment of the present invention R is hydrogen.
In another embodiment of the invention n = 0.
In another embodiment of the invention R1 is selected from the group
consisting of methyl, ethyl and n-propyl.
In another embodiment of the present invention X1 is N.
In another embodiment of the present invention X1 is CR4. Especially
preferred is wherein R4 is halogen (most preferably chlorine) and/or R5 is
halogen (most preferably chlorine).
Compounds of Formula I may contain asymmetric centres and may be present
as a single enantiomer, pairs of enantiomers in any proportion or, where more than
one asymmetric centre are present, contain diastereoisomers in all possible ratios.
Typically one of the enantiomers has enhanced biological activity compared to the
other possibilities.
Similarly, where there are disubstituted alkenes, these may be present in E or
Z form or as mixtures of both in any proportion.
Furthermore, compounds of Formula I may be in equilibrium with alternative
tautomeric forms. It should be appreciated that all tautomeric forms (single tautomer
or mixtures thereof), racemic mixtures and single isomers are included within the
scope of the present invention.
The present invention also includes agronomically acceptable salts that the
compounds of Formula I may form with amines (for example ammonia,
dimethylamine and triethylamine), alkali metal and alkaline earth metal bases or
quaternary ammonium bases. Among the alkali metal and alkaline earth metal
hydroxides, oxides, alkoxides and hydrogen carbonates and carbonates used as salt
formers, emphasis is to be given to the hydroxides, alkoxides, oxides and carbonates
of lithium, sodium, potassium, magnesium and calcium, but especially those of
sodium, magnesium and calcium. The corresponding trimethylsulfonium salt may also
be used.
The compounds of Formula (I) according to the invention can be used as
herbicides by themselves, but they are generally formulated into herbicidal
compositions using formulation adjuvants, such as carriers, solvents and surfaceactive
agents (SFAs). Thus, the present invention further provides a herbicidal
composition comprising a herbicidal compound according to any one of the previous
claims and an agriculturally acceptable formulation adjuvant. The composition can be
in the form of concentrates which are diluted prior to use, although ready-to-use
compositions can also be made. The final dilution is usually made with water, but can
be made instead of, or in addition to, water, with, for example, liquid fertilisers,
micronutrients, biological organisms, oil or solvents.
The herbicidal compositions generally comprise from 0.1 to 99 % by weight,
especially 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.
The compositions can be chosen from a number of formulation types, many of
which are known from the Manual on Development and Use of FAO Specifications
for Plant Protection Products, 5th Edition, 1999. These include dustable powders
(DP), soluble powders (SP), water soluble granules (SG), water dispersible granules
(WG), wettable powders (WP), granules (GR) (slow or fast release), soluble
concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL),
emulsifiable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in
water (EW) and water in oil (EO)), micro-emulsions (ME), suspension concentrates
(SC), aerosols, capsule suspensions (CS) and seed treatment formulations. The
formulation type chosen in any instance will depend upon the particular purpose
envisaged and the physical, chemical and biological properties of the compound of
Formula (I).
Dustable powders (DP) may be prepared by mixing a compound of Formula (I)
with one or more solid diluents (for example natural clays, kaolin, pyrophyllite,
bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium
phosphates, calcium and magnesium carbonates, sulphur, lime, flours, talc and other
organic and inorganic solid carriers) and mechanically grinding the mixture to a fine
powder.
Soluble powders (SP) may be prepared by mixing a compound of Formula (I)
with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium
carbonate or magnesium sulphate) or one or more water-soluble organic solids (such
as a polysaccharide) and, optionally, one or more wetting agents, one or more
dispersing agents or a mixture of said agents to improve water dispersibility/solubility.
The mixture is then ground to a fine powder. Similar compositions may also be
granulated to form water soluble granules (SG).
Wettable powders (WP) may be prepared by mixing a compound of Formula
(I) with one or more solid diluents or carriers, one or more wetting agents and,
preferably, one or more dispersing agents and, optionally, one or more suspending
agents to facilitate the dispersion in liquids. The mixture is then ground to a fine
powder. Similar compositions may also be granulated to form water dispersible
granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound
of Formula (I) and one or more powdered solid diluents or carriers, or from preformed
blank granules by absorbing a compound of Formula (I) (or a solution thereof,
in a suitable agent) in a porous granular material (such as pumice, attapulgite clays,
fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a
compound of Formula (I) (or a solution thereof, in a suitable agent) on to a hard core
material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and
drying if necessary. Agents which are commonly used to aid absorption or adsorption
include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers,
ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols,
dextrins, sugars and vegetable oils). One or more other additives may also be
included in granules (for example an emulsifying agent, wetting agent or dispersing
agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of
Formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether.
These solutions may contain a surface active agent (for example to improve water
dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may be
prepared by dissolving a compound of Formula (I) in an organic solvent (optionally
containing one or more wetting agents, one or more emulsifying agents or a mixture
of said agents). Suitable organic solvents for use in ECs include aromatic
hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by
SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered
Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols
(such as benzyl alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as Nmethylpyrrolidone
or N-octylpyrrolidone), dimethyl amides of fatty acids (such as C8-
Cio fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may
spontaneously emulsify on addition to water, to produce an emulsion with sufficient
stability to allow spray application through appropriate equipment.
Preparation of an EW involves obtaining a compound of Formula (I) either as
a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable
temperature, typically below 70°C) or in solution (by dissolving it in an appropriate
solvent) and then emulsifying the resultant liquid or solution into water containing
one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for
use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes),
aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate
organic solvents which have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one
or more solvents with one or more SFAs, to produce spontaneously a
thermodynamically stable isotropic liquid formulation. A compound of Formula (I) is
present initially in either the water or the solvent/SFA blend. Suitable solvents for use
in MEs include those hereinbefore described for use in in ECs or in EWs. An ME
may be either an oil-in-water or a water-in-oil system (which system is present may
be determined by conductivity measurements) and may be suitable for mixing watersoluble
and oil-soluble pesticides in the same formulation. An ME is suitable for
dilution into water, either remaining as a microemulsion or forming a conventional
oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous
suspensions of finely divided insoluble solid particles of a compound of Formula (I).
SCs may be prepared by ball or bead milling the solid compound of Formula (I) in a
suitable medium, optionally with one or more dispersing agents, to produce a fine
particle suspension of the compound. One or more wetting agents may be included in
the composition and a suspending agent may be included to reduce the rate at which
the particles settle. Alternatively, a compound of Formula (I) may be dry milled and
added to water, containing agents hereinbefore described, to produce the desired end
product.
Aerosol formulations comprise a compound of Formula (I) and a suitable
propellant (for example n-butane). A compound of Formula (I) may also be dissolved
or dispersed in a suitable medium (for example water or a water miscible liquid, such
as n-propanol) to provide compositions for use in non-pressurised, hand-actuated
spray pumps.
Capsule suspensions (CS) may be prepared in a manner similar to the
preparation of EW formulations but with an additional polymerisation stage such that
an aqueous dispersion of oil droplets is obtained, in which each oil droplet is
encapsulated by a polymeric shell and contains a compound of Formula (I) and,
optionally, a carrier or diluent therefor. The polymeric shell may be produced by
either an interfacial polycondensation reaction or by a coacervation procedure. The
compositions may provide for controlled release of the compound of Formula (I) and
they may be used for seed treatment. A compound of Formula (I) may also be
formulated in a biodegradable polymeric matrix to provide a slow, controlled release
of the compound.
The composition may include one or more additives to improve the biological
performance of the composition, for example by improving wetting, retention or
distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of
a compound of Formula (I). Such additives include surface active agents (SFAs),
spray additives based on oils, for example certain mineral oils or natural plant oils
(such as soy bean and rape seed oil), and blends of these with other bio-enhancing
adjuvants (ingredients which may aid or modify the action of a compound of Formula
(I))·
Wetting agents, dispersing agents and emulsifying agents may be SFAs of the
cationic, anionic, amphoteric or non-ionic type.
Suitable SFAs of the cationic type include quaternary ammonium compounds
(for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of
aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of
sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate,
calcium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of
sodium di-z propyl- and tri-zsopropyl-naphthalene sulphonates), ether sulphates,
alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxylates
(for example sodium laureth-3-carboxylate), phosphate esters (products from the
reaction between one or more fatty alcohols and phosphoric acid (predominately
mono-esters) or phosphorus pentoxide (predominately di-esters), for example the
reaction between lauryl alcohol and tetraphosphoric acid; additionally these products
may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates
and lignosulphonates.
Suitable SFAs of the amphoteric type include betaines, propionates and
glycinates.
Suitable SFAs of the non-ionic type include condensation products of alkylene
oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof,
with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such
as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain
fatty acids or hexitol anhydrides; condensation products of said partial esters with
ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide);
alkanolamides; simple esters (for example fatty acid polyethylene glycol esters);
amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as
polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and
swelling clays (such as bentonite or attapulgite).
The composition of the present may further comprise at least one additional
pesticide. For example, the compounds according to the invention can also be used in
combination with other herbicides or plant growth regulators. In a preferred
embodiment the additional pesticide is a herbicide and/or herbicide safener. Examples
of such mixtures are (in which T represents a compound of Formula I). I + acetochlor,
I + acifluorfen, I + acifluorfen-sodium, I + aclonifen, I + acrolein, I + alachlor, I +
alloxydim, I + ametryn, I + amicarbazone, I + amidosulfuron, I + aminopyralid, I +
amitrole, I + anilofos, I + asulam, I + atrazine, I + azafenidin, I + azimsulfuron, I +
BCPC, I + beflubutamid, I + benazolin, I + bencarbazone, I + benfluralin, I +
benfuresate, I + bensulfuron, I + bensulfuron-methyl, I + bensulide, I + bentazone, I +
benzfendizone, I + benzobicyclon, I + benzofenap, I + bicyclopyrone, I + bifenox, I +
bilanafos, I + bispyribac, I + bispyribac-sodium, I + borax, I + bromacil, I +
bromobutide, I + bromoxynil, I + butachlor, I + butamifos, I + butralin, I +
butroxydim, I + butylate, I + cacodylic acid, I + calcium chlorate, I + cafenstrole, I +
carbetamide, I + carfentrazone, I + carfentrazone-ethyl, I + chlorflurenol, I +
chlorflurenol-methyl, I + chloridazon, I + chlorimuron, I + chlorimuron-ethyl, I +
chloroacetic acid, I + chlorotoluron, I + chlorpropham, I + chlorsulfuron, I + chlorthal,
I + chlorthal-dimethyl, I + cinidon-ethyl, I + cinmethylin, I + cinosulfuron, I +
cisanilide, I + clethodim, I + clodinafop, I + clodinafop-propargyl, I + clomazone, I +
clomeprop, I + clopyralid, I + cloransulam, I + cloransulam-methyl, I + cyanazine, I +
cycloate, I + cyclosulfamuron, I + cycloxydim, I + cyhalofop, I + cyhalofop-butyl,, I
+ 2,4-D, I + daimuron, I + dalapon, I + dazomet, I + 2,4-DB, I + I + desmedipham, I +
dicamba, I + dichlobenil, I + dichlorprop, I + dichlorprop-P, I + diclofop, I + diclofopmethyl,
I + diclosulam, I + difenzoquat, I + difenzoquat metilsulfate, I + diflufenican,
I + diflufenzopyr, I + dimefuron, I + dimepiperate, I + dimethachlor, I +
dimethametryn, I + dimethenamid, I + dimethenamid-P, I + dimethipin, I +
dimethylarsinic acid, I + dinitramine, I + dinoterb, I + diphenamid, I + dipropetryn, I
+ diquat, I + diquat dibromide, I + dithiopyr, I + diuron, I + endothal, I + EPTC, I +
esprocarb, I + ethalfluralin, I + ethametsulfuron, I + ethametsulfuron-methyl, I +
ethephon, I + ethofumesate, I + ethoxyfen, I + ethoxysulfuron, I + etobenzanid, I +
fenoxaprop-P, I + fenoxaprop-P-ethyl, I + fentrazamide, I + ferrous sulfate, I +
flamprop-M, I + flazasulfuron, I + florasulam, I + fluazifop, I + fluazifop-butyl, I +
fluazifop-P, I + fluazifop-P-butyl, I + fluazolate, I + flucarbazone, I + flucarbazonesodium,
I + flucetosulfuron, I + fluchloralin, I + flufenacet, I + flufenpyr, I +
flufenpyr-ethyl, I + flumetralin, I + flumetsulam, I + flumiclorac, I + flumicloracpentyl,
I + flumioxazin, I + flumipropin, I + fluometuron, I + fluoraglycofen, I +
fluoroglycofen-ethyl, I + fluoxaprop, I + flupoxam, I + flupropacil, I + flupropanate, I
+ flupyrsulfuron, I + flupyrsulfuron-methyl-sodium, I + flurenol, I + fluridone, I +
flurochloridone, I + fluroxypyr, I + flurtamone, I + fluthiacet, I + fluthiacet-methyl, I
+ fomesafen, I + foramsulfuron, I + fosamine, I + glufosinate, I + glufosinateammonium,
I + glyphosate, I + halauxifen, I + halosulfuron, I + halosulfuron-methyl,
I + haloxyfop, I + haloxyfop-P, I + hexazinone, I + imazamethabenz, I +
imazamethabenz-methyl, I + imazamox, I + imazapic, I + imazapyr, I + imazaquin, I
+ imazethapyr, I + imazosulfuron, I + indanofan, I + indaziflam, I + iodomethane, I +
iodosulfuron, I + iodosulfuron-methyl-sodium, I + ioxynil, I + isoproturon, I +
isouron, I + isoxaben, I + isoxachlortole, I + isoxaflutole, I + isoxapyrifop, I +
karbutilate, I + lactofen, I + lenacil, I + linuron, I + mecoprap, I + mecoprop-P, I +
mefenacet, I + mefluidide, I + mesosulfuron, I + mesosulfuron-methyl, I + mesotrione,
I + metam, I + metamifop, I + metamitron, I + metazachlor, I + methabenzthiazuron, I
+ methazole, I + methylarsonic acid, I + methyldymron, I + methyl isothiocyanate, I +
metolachlor, I + S-metolachlor, I + metosulam, I + metoxuron, I + metribuzin, I +
metsulfuron, I + metsulfuron-methyl, I + molinate, I + monolinuron, I + naproanilide,
I + napropamide, I + naptalam, I + neburon, I + nicosulfuron, I + n-methyl glyphosate,
I + nonanoic acid, I + norflurazon, I + oleic acid (fatty acids), I + orbencarb, I +
orthosulfamuron, I + oryzalin, I + oxadiargyl, I + oxadiazon, I + oxasulfuron, I +
oxaziclomefone, I + oxyfluorfen, I + paraquat, I + paraquat dichloride, I + pebulate, I
+ pendimethalin, I + penoxsulam, I + pentachlorophenol, I + pentanochlor, I +
pentoxazone, I + pethoxamid, I + phenmedipham, I + picloram, I + picolinafen, I +
pinoxaden, I + piperophos, I + pretilachlor, I + primisulfuron, I + primisulfuronmethyl,
I + prodiamine, I + profoxydim, I + prohexadione-calcium, I + prometon, I +
prometryn, I + propachlor, I + propanil, I + propaquizafop, I + propazine, I + propham,
I + propisochlor, I + propoxycarbazone, I + propoxycarbazone-sodium, I +
propyzamide, I + prosulfocarb, I + prosulfuron, I + pyraclonil, I + pyraflufen, I +
pyraflufen-ethyl, I + pyrasulfotole, I + pyrazolynate, I + pyrazosulfuron, I +
pyrazosulfuron-ethyl, I + pyrazoxyfen, I + pyribenzoxim, I + pyributicarb, I +
pyridafol, I + pyridate, I + pyriftalid, I + pyriminobac, I + pyriminobac-methyl, I +
pyrimisulfan, I + pyrithiobac, I + pyrithiobac-sodium, I + pyroxasulfone, I +
pyroxsulam, I + quinclorac, I + quinmerac, I + quinoclamine, I + quizalofop, I +
quizalofop-P, I + rimsulfuron, I + saflufenacil, I + sethoxydim, I + siduron, I +
simazine, I + simetryn, I + sodium chlorate, I + sulcotrione, I + sulfentrazone, I +
sulfometuron, I + sulfometuron-methyl, I + sulfosate, I + sulfosulfuron, I + sulfuric
acid, I + tebuthiuron, I + tefuryltrione, I + tembotrione, I + tepraloxydim, I + terbacil,
I + terbumeton, I + terbuthylazine, I + terbutryn, I + thenylchlor, I + thiazopyr, I +
thifensulfuron, I + thiencarbazone, I + thifensulfuron-methyl, I + thiobencarb, I +
topramezone, I + tralkoxydim, I + tri-allate, I + triasulfuron, I + triaziflam, I +
tribenuron, I + tribenuron-methyl, I + triclopyr, I + trietazine, I + trifloxysulfuron, I +
trifloxysulfuron-sodium, I + trifluralin, I + triflusulfuron, I + triflusulfuron-methyl, I +
trihydroxytriazine, I + trinexapac-ethyl, I + tritosulfuron, I + [3-[2-chloro-4-fluoro-5-
( 1-methyl-6-trifluoromethyl-2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-3-yl)phenoxy]-2-
pyridyloxy] acetic acid ethyl ester (CAS RN 353292-31-6). The compounds of the
present invention may also be combined with herbicidal compounds disclosed in
WO06/024820 and/or WO07/096576.
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, Fourteenth Edition, British
Crop Protection Council, 2006.
The compound of Formula I can also be used in mixtures with other
agrochemicals such as fungicides, nematicides or insecticides, examples of which are
given in The Pesticide Manual.
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 b e used in the above-mentioned
formulations (in which case "active ingredient" relates to the respective mixture of
compound of Formula I with the 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
Formula I according to the invention with one or more further herbicides can also be
used in combination with one or more safeners. The safeners can be AD 67 (MON
4660), benoxacor, cloquintocet-mexyl, cyprosulfamide (CAS RN 2 1667-31-8),
dichlormid, fenchlorazole-ethyl, fenclorim, fluxofenim, furilazole and the
corresponding R isomer, isoxadifen-ethyl, mefenpyr-diethyl, oxabetrinil, N-isopropyl-
4-(2-methoxy-benzoylsulfamoyl)-benzamide (CAS RN 221668-34-4). Other
possibilities include safener compounds disclosed in, for example, EP0365484 e.g N-
(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.
Particularly preferred are mixtures of a compound of Formula I with cyprosulfamide,
isoxadifen-ethyl, cloquintocet-mexyl and/or N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)
amino]benzenesulfonamide.
The safeners 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 Edition (BCPC), 2006. The
reference to cloquintocet-mexyl also applies to a lithium, sodium, potassium, calcium,
magnesium, aluminium, iron, ammonium, quaternary ammonium, sulfonium or phosphonium
salt thereof as disclosed in WO 02/34048, and the reference to
fenchlorazole-ethyl also applies to fenchlorazole, etc.
Preferably the mixing ratio of compound of Formula I to safener is from 100:1
to 1:10, especially from 20: 1 to 1:1.
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 safener).
The present invention still further provides a method of selectively controlling
weeds at a locus comprising crop plants and weeds, wherein the method comprises
application to the locus of a weed controlling amount of a composition according to
the present invention. 'Controlling' means killing, reducing or retarding growth or
preventing or reducing germination. Generally the plants to be controlled are
unwanted plants (weeds). 'Locus' means the area in which the plants are growing or
will grow.
The rates of application of compounds of Formula I may vary within wide
limits and depend on the nature of the soil, the method of application (pre- or postemergence;
seed dressing; application to the seed furrow; no tillage application etc.),
the crop plant, the weed(s) 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 g/ha, especially from 50 to 1000 g/ha.
The application is generally made by spraying the composition, typically by
tractor mounted sprayer for large areas, but other methods such as dusting (for
powders), drip or drench can also be used.
Useful plants in which the composition according to the invention can be used
include crops such as cereals, for example barley and wheat, cotton, oilseed rape,
sunflower, maize, rice, soybeans, sugar beet, sugar cane and turf.
Crop plants can also include trees, such as fruit trees, palm trees, coconut trees
or other nuts. Also included are vines such as grapes, fruit bushes, fruit plants and
vegetables.
Crops are to be understood as also including those crops which have been
rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-,
PPO-, ACCase- and HPPD-inhibitors) by conventional methods of breeding or by
genetic engineering. An example of a crop that has been rendered tolerant to
imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield®
summer rape (canola). Examples of crops that have been rendered tolerant to
herbicides by genetic engineering methods include e.g. glyphosate- and glufosinateresistant
maize varieties commercially available under the trade names
RoundupReady® and LibertyLink®. In a particularly preferred aspect, the crop plant
has been engineered to over-express homogentisate solanesyltransferase as taught in,
for example, WO2010/0293 11.
Crops are also to be understood as being those which have been rendered
resistant to harmful insects by genetic engineering methods, for example Bt maize
(resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also
Bt potatoes (resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize
hybrids of NK® (Syngenta Seeds). The Bt toxin is a protein that is formed naturally
by Bacillus thuringiensis soil bacteria. Examples of toxins, or transgenic plants able to
synthesise such toxins, are described in EP-A-451 878, EP-A-374 753, WO 93/07278,
WO 95/34656, WO 03/052073 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 KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B®
(cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®.
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 to include those which are obtained by
conventional methods of breeding or genetic engineering and contain so-called output
traits (e.g. improved storage stability, higher nutritional value and improved flavour).
Other useful plants include turf grass for example in golf-courses, lawns, parks
and roadsides, or grown commercially for sod, and ornamental plants such as flowers
or bushes.
The compositions can be used to control unwanted plants (collectively,
'weeds'). The weeds to be controlled may be both monocotyledonous species, for
example Agrostis, Alopecurus, Avena, Brachiaria, Bromus, Cenchrus, Cyperus,
Digitaria, Echinochloa, Eleusine, Lolium, Monochoria, Rottboellia, Sagittaria, Scirpus,
Setaria and Sorghum, and dicotyledonous species, for example Abutilon, Amaranthus,
Ambrosia, Chenopodium, Chrysanthemum, Conyza, Galium, Ipomoea, Nasturtium,
Sida, Sinapis, Solanum, Stellaria, Veronica, Viola and Xanthium. Weeds can also
include plants which may be considered crop plants but which are growing outside a
crop area ('escapes'), or which grow from seed left over from a previous planting of a
different crop ('volunteers'). Such volunteers or escapes may be tolerant to certain
other herbicides.
The compounds of the present invention can be prepared according to the following
scheme(s).
Certain compounds of the present invention may be prepared from compounds of
formula (la), by heating with morpholine (Nagashima, Hiromu et al. Heterocycles,
26(1), 1-4; 1987) as shown in Reaction scheme 1.
Reaction scheme 1
Compounds of formula (la) may be prepared from compounds of formula (2) as
shown in Reaction scheme 2.
Compounds of formula (la) may be prepared by reacting pyridazinones (2) with the
requisite fused-bicyclic heteroaromatic building block, in the presence of a strong
base such as NaH or NaHMDS. Suitable solvents are THF or DMF.
The compound (2) where R1= Me and R2 = H may be prepared by reaction of
commercially available 4,5-Dichloro-2-methyl-3(2H)-pyridazinone with NaOMe in
1,4-dioxane, according to Tetrahedron2001, 57, 1323-1330.
The compound (2) where R1 = Me and R2 = Me may be prepared as shown in reaction
scheme 3.
Reaction scheme 3
145 C
70%
Alternatively, certain compounds of the present invention may be prepared according
to Reaction scheme 4.
Reaction scheme 4
Compounds of the present invention may be prepared from compounds of formula (3)
by heating with concentrated aqueous NaOH in a suitable solvent.
Compounds of formula (3) may be prepared as shown in Reaction scheme 5.
Reaction scheme 5
(4) (3)
Compounds of formula (3) may be prepared by reacting compounds (4) with 2 or
more equivalents of the requisite fused-bicyclic heteroaromatic building block, in the
presence of a strong base and a suitable solvent. Examples of suitable bases are NaH,
NaHMDS and CS2CO3. Examples of suitable solvents are THF and DMF. An example
of compounds (4) i s commercially available 4,5-Dichloro-2-methyl-3(2H)-
pyridazinone.
A variation used to access certain compounds of the present invention involves the
mono- or bis-chlorination of Compounds (lb) as shown in Reaction scheme 6.
Reaction sche
Certain compounds of formula (la) may be prepared by mono-bromination of
chloro compounds as shown in Reaction scheme 7.
Reaction scheme 7
Certain compounds of formula (la) may be prepared by tri-chlorination of compounds
(lb) as shown in Reaction scheme 8.
Reaction scheme 8
( 1b)
Certain compounds of formula (la) may be prepared by the mono-bromination of
compounds (lb) as shown in Reaction scheme 9.
Reaction s heme 9
( 1b)
Certain compounds of formula (la) may be prepared by mono-chlorination of
bromo compounds as shown in Reaction scheme 10.
Reaction heme 10
Certain compounds of formula (la) may be prepared by bis- and tri-bromination of
compounds (lb) as shown in Reaction scheme 11.
Reaction scheme 11
Certain compounds of formula (la) may be prepared by reacting a bromide compound
with a suitable coupling partner using a suitable catalyst/ligand, base and solvent as
shown in Reaction scheme 12. Examples of suitable catalyst/ligands are
Pd2dba 3/XantPhos, [Pd(allyl)Cl]2/RockPhos or tBuXPhos precatalyst. Examples of
suitable bases are DIPEA, LiHMDS, or Cs2C0 3. Examples of suitable solvents are
1,4-dioxane, THF, DMF or toluene.
Reaction scheme 12
(1a)
Certain compounds of formula (la) may be prepared by reacting a bromide compound
with a suitable organoboron coupling partner using a suitable catalyst/ligand, base and
solvent as shown in Reaction scheme 13. Examples of suitable organoboron coupling
partners are boronic acids, boronic esters and potassium trifluoroborate salts.
Examples of suitable catalyst/ligands are Pd(OAc)2/RuPhos or Pd-dppf. An example
of a suitable base is CsF. Examples of suitable solvents are 1,4-dioxane, water, or
DME.
Reaction scheme 13
( 1a )
Suitable potassium trifluoroborate salts are commercially available or may be
prepared by reacting trifluoroethanol with potassium (bromomethyl)trifluoroborate,
both commercially available, as shown in Reaction scheme 14.
Reaction scheme 14
NaH
Certain methylsulfide compounds may be prepared by cross coupling of NaSMe with
a bromide compound as shown in Reaction scheme 15.
Certain compounds of formula (la) may be prepared by sulphur oxidation as shown in
Reaction scheme 16, (n = 1 or 2).
Reaction heme 16
Certain compounds of formula (la) may be prepared by reduction of an zso-propenyl
compound as shown in Reaction scheme 17.
Reaction scheme 17
Certain compounds of formula (la) may be prepared by nitrile formation as shown in
Reaction scheme 18. (The required aldehyde starting material is prepared according to
Reaction scheme 21)
Reaction scheme 18
Certain compounds of the present invention may be prepared as shown in Reaction
scheme 19.
Reaction scheme 19
With reference to Reaction scheme 19, certain compounds of the present invention
may be prepared by a final dione derivatisation step. The dione substrate is reacted
with 1 or more equivalents of the requisite electrophilic species R-X, in the presence
of NEt3 and a suitable solvent at a temperature between 0 °C to reflux. Examples of
suitable solvents are DCM and THF. Examples of suitable commercially available
electrophilic species R-X are acyl chlorides, chloroformates, sulfonyl chlorides, amine
carbonyl chlorides, alkyl halides and S-alkyl chlorothioformates.
Certain compounds of formula (la) may be prepared by the mono-chlorination or
mono-bromination of indole intermediates already substituted at the indole 2-position,
as shown in Reaction scheme 20.
Reaction scheme 20
Certain compounds of formula (la) may be prepared by ozonolysis of alkenes, as
shown in Reaction scheme 2 1.
R action scheme 21
Certain compounds of formula (la) may be prepared by the difluorination of carbonyl
compounds, as shown in Reaction scheme 22. The carbonyl compound is reacted with
2 or more equivalents of diethylaminosulfur trifluoride (DAST), in a suitable solvent,
at -78 °C to 25 °C. Examples of suitable solvents are dichloromethane and chloroform.
(The carbonyl compound starting material is typically prepared according to Reaction
scheme 21).
Reaction scheme 22
Certain compounds of formula (la) may be prepared by the reduction of carbonyl
compounds, as shown in Reaction scheme 23. The carbonyl compound substrate is
reacted with 0.5 or more equivalents of sodium borohydride, in a suitable solvent, at -
78 °C to 25 °C. Examples of suitable solvents are methanol and ethanol.
R action scheme 23
Certain compounds of formula (la) may be prepared by the methylation of alcohols,
as shown in Reaction scheme 24. The alcohol starting material is reacted with 1 or
more equivalents of iodomethane, in the presence of a suitable base, in a suitable
solvent, at -78 °C to 25 °C. An example of a suitable base is sodium hydride.
Examples of suitable solvents are N N-dimethylformamide and tetrahydrofuran. (The
alcohol substrate is typically prepared according to Reaction scheme 23)
Reaction scheme 24
Certain compounds of formula (la) may be prepared by the fluorination of alcohols,
as shown in Reaction scheme 25. The alcohol starting material is reacted with 1 or
more equivalents of diethylaminosulfur trifluoride (DAST), in a suitable solvent, at -
78 °C to 25 °C. Examples of suitable solvents are dichloromethane and chloroform.
Reaction scheme 25
Examples
Example 1. 4-f3-Chloro-indol-l-yl)-2-methyl-2H-pyridazine-3.,5-(iione.
A mixture of 4-(3-Chloro-indol-l-yl)-5-methoxy-2-methyl-2H-pyridazin-3-one (1.70
g, 5.87 mmol) and morpholine (8 ml) is heated to 140 °C under microwave irradiation
for 10 min. The mixture is allowed to cool then evaporated under reduced pressure to
remove most of the morpholine. The residue is stirred with 1: 1 v/v glacial AcOH :
DCM (100 ml) to give a free-flowing semi-solid. Volatiles are removed in-vacuo and
the solid obtained slurried with water. The solid is recovered by filtration under
reduced pressure and dried at 1 mBar and 60 °C to give the title compound as a beige
solid, 1.54 g, 95 % yield. 1H nmr (DMSO-d6) d (ppm) 7.89 (1H, s), 7.57-7.50 (2H, m),
7.24-7.17 (2H, m), 7.12-7.06 (1H, m), 3.66 (3H, s)
(Certain other compounds of the present invention also prepared according to
Reaction scheme 1, may variously require modified purification procedures such as
the use of column chromatography on silica, prep-HPLC or crystallisation).
4-f3-Chloro-indol-l-yl)-5-methoxy-2-methyl-2H-pyridazin-3-one
Sodium hydride (60% mass in mineral oil, 874 mg, 21.9 mmol) is suspended in dry
DMF (10 ml) under N . With stirring, a solution of 3-chloroindole (3.01 g, 19.9 mmol)
in DMF (30 ml) is added over 20 min. During the addition, cooling is employed by
means of a water bath at ambient temperature. Gas evolution is observed and the
mixture stirred for 30 min.
The reaction mixture is then diluted with further DMF (20 ml). A solution of 5-
Chloro-4-methoxy-2-methyl-2H-pyridazin-3-one (3.47 g, 19.9 mmol) in DMF (30 ml)
is added over 5 min. The mixture is then stirred for a further 3 h at ambient
temperature before being cooled in an ice bath and quenched with saturated aqueous
KH2PO4 (100 ml). The mixture is extracted into EtOAc (3 x 150 ml) and the
combined organic extracts dried over MgS0 4. Evaporated in vacuo to afford a crude
residue which is purified by flash chromatography (silica gel, eluant a 0 - 100 %
EtOAc in Isohexane gradient). The title compound was obtained as a beige coloured
solid, 3.41 g, 59 % yield. 1H nmr (CDC13) d (ppm) 7.92 (1H, s), 7.62-7.67 (1H, m),
7.20-7.28 (3H, m), 6.96-7.01 (1H, m), 3.86 (3H, s), 3.85 (3H, s).
Example 2. 4-(3-chloroindazol-l-yl)-2-methyl-pyridazine-3.,5-dione.
A 1:1 w/w 32% NaOH : water mixture (8 g total) is added to 4,5-bis(3-chloroindazoll-
yl)-2-methyl-pyridazin-3-one (768 mg, 1.87 mmol) in methanol (30 mL) and then
the mixture heated at 80 °C for 20 minutes. The mixture is allowed to cool to room
temperature then concentrated in vacuo. Dichloromethane (50 mL) and water (50 mL)
are added to the residue and the organic layer removed. The aqueous layer is acidified
to pH 1 with cone. HC1. then extracted with dichloromethane (40 mL x 2). The
combined organic extracts are passed through a phase separator cartridge and
concentrated in vacuo to give the title compound as a white solid (490 mg). 1H nmr
(DMSO-d6) d (ppm) 7.93 ( 1 H, s) 7.71 - 7.79 ( 1 H, m) 7.45 - 7.54 ( 1 H, m) 7.26 -
7.38 (2 H, m) 3.66 (3 H, s). Some other dione products prepared analogously were
triturated with ethyl acetate or ether.
4,5-bis(3-chloroindazol-l-yl)-2-methyl-pyridazin-3-one.
A mixture of 4,5-dichloro-2-methyl-pyridazin-3-one (551 mg, 3.08 mmol), 3-chlorolH-
indazole (1.17 g, 7.70 mmol), and caesium carbonate (1.48 g, 7.70 mmol) in DMF
(15 ml) is heated to 110 °C for 1 h. The reaction mixture is cooled then concentrated
in vacuo. The reaction mixture is diluted with ethyl acetate (50 ml) and washed with
water (50 mL) and brine (50 mL x 2). The organic extract is dried over magnesium
sulphate, filtered and concentrated in vacuo. The crude product is purified by
chromatography on silica eluting with 0-95% ethyl acetate in isohexane to give the
product as a light orange oil (940 mg). 1H NMR (CDC13) d (ppm) 8.36 ( 1 H, s) 7.45 -
7.62 (2 H, m) 7.34 ( 1 H, ddd) 7.08 - 7.20 (3 H, m) 7.04 ( 1 H, ddd) 6.68 ( 1 H, d) 3.97
(3 H, s).
Example procedure according to Reaction scheme 6 - dichlorination.
4-f2,3-dichloroindol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one
To a stirred solution of 4-indol-l-yl-5-methoxy-2,6-dimethyl-pyridazin-3-one (175
mg, 0.650 mmol) in dichloromethane (4 mL) at RT is added sulfuryl chloride ( 116 ,
1.43 mmol). The reaction mixture changed to pale brown. After stirring for 1 h, the
reaction is cooled to 0 °C and then saturated aqueous NaHC0 3 (5 mL) is added
dropwise. The colour changed to a pale yellow and it is stirred for 10 min. The
mixture was then poured into dichloromethane (20 mL) and water (20 mL) and the
layers are separated. The aqueous layer is re-extracted with dichloromethane (20 mL x
2) and the combined organics were dried (MgS0 4) and concentrated under reduced
pressure onto silica. Flash chromatography (combiflash, 10% EtOAc / isohexane on a
GOLD column) afforded the desired product 4-(2,3-dichloroindol-l-yl)-5-methoxy-
2,6-dimethyl-pyridazin-3-one (150 mg, 0.444 mmol, 68%) as a pale yellow solid.
1H NMR (CDC13) d (ppm) 7.60 (1H, m), 7.27 - 7.24 (2H, m), 6.98 (1H, m), 3.74 (3H,
s), 3.46 (3H, s), 2.35 (3H, s).
Preparation of 5-chloro-4-methoxy-2,6-dimethyl-pyridazin-3-one according to
Reaction scheme 3.
5-chloro-4-methoxy-2,6-dimethyl-pyridazin-3-one
4,5-dichloro-lH-pyridazin-6-one (1.95 g, 11.8 mmol) and bromine (0.73 ml, 14.2
mmol) aer suspended in water (10 ml) and the mixture heated under microwave
irradiation to 180 °C for 30 min. The resulting reaction mixture is filtered and the
crude solid obtained washed thoroughly with water, then DCM, to yield 3-bromo-4,5-
dichloro-lH-pyridazin-6-one, 2.06g, as a white solid (71.5% yield).
1H NMR (DMSO-d6) d ppm = 13.88 (1H, br. s)
To a stirred solution of 3-bromo-4,5-dichloro-lH-pyridazin-6-one (12.5 g, 51.3 mmol)
in DMF (75.0 ml) is added K2C0 3 (10.7 g, 76.9 mmol) and iodomethane (10.9 g, 76.9
mmol, 4.79 ml). The resulting mixture is stirred at ambient temperature for 18 h.
The reaction mixture is then poured onto ice-water (300 ml) and the mixture stirred
for 2 h. The resulting precipitate is collected by filtration then dried to give 6-bromo-
4,5-dichloro-2-methyl-pyridazin-3-one (10.7g) as a beige solid (77% yield).
1H NMR (CDCI3) d ppm = 3.83 (3H, s)
6-bromo-4,5-dichloro-2-methyl-pyridazin-3-one (1.5 g, 5.8 mmol) is dissolved in 1,4-
dioxane (150 ml). Sodium methoxide (1.5 ml, 25 mass% methanolic solution, 6.4
mmol) is added dropwise and the reaction stirred for 2 h . The mixture is concentrated
to a volume of 50 ml then diluted with 50 ml EtOAc. It i s washed with 2 x 35 m l
aqueous saturated brine. The organic layer is dried thoroughly over sodium sulfate,
filtered and concentrated in vacuo. The crude residue so obtained was purified by
flash chromatography (silica gel, eluant a 0-10 % EtOAc in Isohexane gradient) to
afford 6-bromo-5-chloro-4-methoxy-2-methyl-pyridazin-3-one (960 mg) as a white
solid (65% yield).
1H NMR (CDC1 3) d ppm = 3.75 (3 H, s) 4.32 (3 H, s)
6-bromo-5-chloro-4-methoxy-2-methyl-pyridazin-3-one (500 mg, 1.68 mmol, 85
mass% purity), CsF (509 mg, 3.353 mmol), trimethylboroxine (242 mg, 1.93 mmol)
and [ l ,r-Bis(Diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane
adduct (140 mg, 0.168 mmol) are dissolved in 1,2-Dimethoxyethane (5 ml) under N .
The mixture is heated to 145 °C under microwave irradiation for 30 min.
The resulting mixture is filtered through celite, washing with EtOAc. The solution is
washed with 2 x 25.0 ml aqueous saturated brine. The organic layer is separated, dried
over Na2S0 4, filtered and concentrated in vacuo. The crude residue is purified by
flash chromatography (silica gel, eluant a 0-20 % EtOAc in Isohexane gradient). The
title compound 5-chloro-4-methoxy-2,6-dimethyl-pyridazin-3-one was obtained as a
pale yellow solid (212 mg, 67 % yield).
1H NMR (CDCI 3) d ppm = 2.37 (3 H, s) 3.72 (3 H, s) 4.26 (3 H, s).
Example procedure according to Reaction scheme 7 - bromination of chlorocompound.
5-methoxy-2,6-dimethyl-4-f2-bromo-3-chloroindol-l-yl)pyridazin-3-one
Part of a solution of bromine (200 mg, 1.25 mmol) in DCM (4 mL) is added dropwise,
slowly, to a solution o f 4-(3-chloroindol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-
one (184 mg, 0.606 mmol) in DCM (2 mL) at 0 °C. The bromine decolourised as it
was added and addition was continued cautiously until an orange colour just persisted.
NaHCC"3 (0.5 g saturated solution in water) is added cautiously, followed by sufficient
sodium metabisulphite to decolorise the excess bromine. The resulting reaction
mixture was extracted with DCM (3 x 60 mL) and the combined DCM layers were
filtered through MgS0 4 and concentrated in vacuo. The resulting yellow gum was
purified by flash chromatography (combiflash, 0 to 30% DCM / EtOAc) to yield the
desired product 5-methoxy-2,6-dimethyl-4-(2-bromo-3-chloroindol- 1-yl)pyridazin-3-
one ( 115 mg, 0.301 mmol, 50%> Yield) as a white solid.
1H NMR (CDC13) d ppm = 7.64 - 7.58 (1H, m), 7.28 - 7.20 (2H, m), 7.02 - 6.96 (1H,
m), 3.74 (3H, s), 3.44 (3H, s), 2.35 (3H, s).
Example procedure according to Reaction scheme 8 - trichlorination.
5-methoxy-2,6-dimeth l-4- 2,3 6-trichloroindol-l -yl)pyridazin-3-one
A solution of S0 2C 12 (185 mg, 1.365 mmol) in DCM (2 mL + 0.5 mL wash) is added
dropwise to a solution of 4-(indol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (145
mg, 85% purity, 0.455 mmol) in DCM (1.5 mL) at 0 °C. The solution went yellow
and then orange. After stirring for 30 min the solution went yellow and the reaction
mixture is allowed to warm over 1 h to ambient temperature and stirred for a further
2 1 h . The reaction mixture is concentrated in vacuo and the resulting gum was
purified by flash chromatography (combiflash, 0 to 10% DCM / EtOAc) to yield the
desired product 5-methoxy-2,6-dimethyl-4-(2,3,6-trichloroindol-l-yl)pyridazin-3-one
(128 mg, 0.344 mmol, 75% Yield) as a white solid.
1H NMR (CDCI3) d ppm = 7.52 (1H, d), 7.22 (1H, dd), 6.99 (1H, d), 3.74 (3H, s),
3.49 (3H, s), 2.35 (3H, s).
Example procedure according to Reaction scheme 9 - mono-bromination.
5-methoxy-2,6-dimethyl-4-f3-bromoindol-l-yl)pyridazin-3-one
A solution of NBS ( 110 mg, 0.619 mmol) in DCM (3 mL) is added dropwise to a
solution of 4-(indol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (197 mg, 85%
purity, 0.619 mmol) in DCM (2 mL) at 0 °C. The resulting reaction mixture is
allowed to warm to ambient temperature, stirred for 2 h and then concentrated in
vacuo. Purification by flash chromatography (combiflash, 0 to 10% DCM / EtOAc)
afforded the first desired product 4-(3-bromoindol-l-yl)-5,6-dimethoxy-2-methylpyridazin-
3-one (195 mg, 0.560 mmol, 90%> yield) as a white solid.
1H NMR (CDC13) d ppm = 7.63 - 7.59 (1H, m), 7.34 (1H, s), 7.32 - 7.23 (2H, m),
7.07 - 7.03 (1H, m), 3.76 (3H, s), 3.25 (3H, s), 2.34 (3H, s).
Example procedure according to Reaction scheme 10 - chlorination of bromocompound.
5-methoxy-2,6-dimethyl-4-f2-chloro-3-bromoindol-l-yl)pyridazin-3-one
A solution of SO2CI2 (47 m , 0.583 mmol) in DCM (2 mL) is added dropwise to a
solution of 4-(3-bromoindol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (203 mg,
0.583 mmol) in DCM (6 mL) at 0 °C. The solution went pale yellow. After stirring for
5 min the cooling bath is removed and the resulting reaction mixture stirred at
ambient temperature for 2 h. The reaction mixture is shaken well with a solution of
NaHC0 3. The layers are separated and the aqueous layer extracted with DCM (3 x 20
mL). The combined DCM layers were filtered through MgS0 4 and concentrated in
vacuo. The resulting solid was purified by flash chromatography (combiflash, 0 to
10% DCM / EtOAc) to yield the desired product 5-methoxy-2,6-dimethyl-4-(2-
chloro-3-bromoindol-l-yl)pyridazin-3-one (194 mg, 0.507 mmol, 87% Yield).
1H NMR (CDCI3) d ppm = 7.57 - 7.52 (1H, m), 7.30 - 7.22 (2H, m), 7.00 - 6.95 (1H,
m), 3.74 (3H, s), 3.45 (3H, s), 2.35 (3H, s).
Example procedure according to Reaction scheme 11 - bis- and tribromination.
5-methoxy-2,6-dimethyl-4-f2,3-dibromoindol-l-yl)pyridazin-3-one and 5-
methoxy-2,6-dimeth l-4- 2,3 6-tribromoindol-l -yl)pyridazin-3-one
A solution of NBS (360 mg, 2.02 mmol) in DCM (8 mL) is added dropwise to a
solution of 4-(indol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (201 mg, 85%
purity, 0.631 mmol) in DCM (2 mL) at 0 °C. The resulting reaction mixture is
allowed to warm to ambient temperature, stirred for 2 h and then concentrated in
vacuo. Purification by flash chromatography (combiflash, 0 to 10% DCM / EtOAc)
afforded the first desired product 4-(2,3-dibromoindol-l-yl)-5,6-dimethoxy-2-methylpyridazin-
3-one (40 mg, 0.094 mmol, 15% yield) as a yellow solid.
1H NMR (CDC13) d ppm =7.58 - 7.53 (1H, m), 7.28 - 7.21 (2H, m), 7.01 - 6.95 (1H,
m), 3.74 (3H, s), 3.43 (3H, s), 2.35 (3H, s).
Repeated purification of isolated impure product by flash chromatography
(combiflash, 0 to 40% EtOAc / isohexane) yielded 4-(2,3,6-tribromoindol-l-yl)-5,6-
dimethoxy-2-methyl-pyridazin-3-one (104 mg, 0.206 mmol, 33% yield) as a white
solid.
1H NMR (CDCI3) d ppm = 7.42 (1H, d), 7.35 (1H, dd), 7.14 (1H, d), 3.75 (3H, s),
3.47 (3H, s), 2.36 (3H, s).
Example procedure according to Reaction scheme 12 - cross coupling with
bromide compound.
4-f2,3-dichloroindol-l-yl)-5,6-dimethoxy-2-methyl-pyridazin-3-one
6-bromo-4-(2,3 -dichloroindol- 1-yl)-5-methoxy-2-methyl-pyridazin-3 -one (0.200 g ,
0.496 mmol), Pd2C12(allyl)2 (2.7 mg, 0.00744 mmol), ditert-butyl-[6-methoxy-3-
methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphane ( 11.6 mg, 0.0248 mmol) and
dicesium carbonate (0.243 g, 0.744 mmol) are suspended in toluene (3 mL) and
methanol (60 m ) . The resulting reaction mixture is heated under microwave
irradiation to 110 °C for 20 min. The resulting reaction mixture is filtered, washing
with EtOAc and concentrated under reduced pressure onto silica. Purification by flash
chromatography (combiflash, 0 to 30% EtOAc / isohexane) afforded the desired
product 4-(2,3-dichloroindol-l-yl)-5,6-dimethoxy-2-methyl-pyridazin-3-one (0.1 16 g,
0.3275 mmol, 66%> yield) as a brown oil.
1H NMR (CDCI3) d ppm = 7.62 - 7.58 (1H, m), 7.28 - 7.22 (2H, m), 7.02 - 6.97 (1H,
m), 3.98 (3H, s), 3.68 (3H, s), 3.60 (3H, s).
Example procedure according to Reaction schemes 17 and 13 - reduction of isopropenyl
group and cross-coupling of bromide compound & organoboron.
4-indol-l-yl-6-isopropyl-5-methoxy-2-methyl-pyridazin-3-one
To a stirred solution o f 4-(2,3-dichloroindol-l-yl)-6-isopropenyl-5-methoxy-2-
methyl-pyridazin-3-one (355 mg, 0.975 mmol) in ethanol (5.0 mL) is added
ammonium formate (1.24 g) and 20% palladium hydroxide on carbon, (50% water by
weight, 273 mg, 0194 mmol). The resulting reaction mixture is stirred at ambient
temperature for 1 h and then heated to 60 °C for 30 min. The resulting reaction
mixture is allowed to cool and then filtered through celite, washing with ethanol and
concentrated in vacuo. The resulting crude yellow solid was 4-indol-l-yl-6-isopropyl-
5-methoxy-2-methyl-pyridazin-3-one (253 mg, 0.851 mmol, 87%), which was used
without further purification.
1H NMR (CDC13) d ppm = 7.66 - 7.63 (1H, m), 7.30 (1H, d), 7.24 - 7.15 (2H, m), 7.05
- 7.02 (1H, m), 6.73 (1H, dd), 3.78 (3H, s), 3.24 (1H, m), 3.14 (3H, s), 1.28 (6H, m).
4-f2,3-dichloroindol-l-yl)-6-isopropenyl-5-methoxy-2-methyl-pyridazin-3-one
6-bromo-4-(2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-pyridazin-3-one (0.600 g ,
1.49 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.0608 g, 0.0744 mmol) and cesium fluoride (0.476 g,
2.98 mmol) are suspending in DME (3 mL) and 2-isopropenyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (330 m , 1.79 mmol) is added. The resulting reaction mixture is
heated under microwave irradiation to 150 °C for 20 min. The resulting reaction
mixture is diluted with EtOAc (50 mL) and then washed with brine (50 mL). The
organic layer was dried (MgS0 4) and then concentrated under reduced pressure onto
silica. Purification by flash chromatography (combifiash, 0 to 20% EtOAc / isohexane)
afforded the desired product 4-(2,3-dichloroindol-l-yl)-6-isopropenyl-5-methoxy-2-
methyl-pyridazin-3-one (503 mg, 1.38 mmol, 93%) as a pale brown oil.
1H NMR (CDCI3) d ppm = 7.62 - 7.59 (1H, m), 7.28 - 7.25 (2H, m), 7.01 - 6.98 (1H,
m), 5.62 (1H, m), 5.47 (1H, m), 3.81 (3H, s), 3.42 (3H, m), 2.15 (3H, m).
Example procedure according to Reaction scheme 14 - formation of boron
tetrafluoride potassium salt,
Potassium trifluoro(2,2,2-trifluoroethoxymethyl)boranuide
To a suspension of sodium hydride (0.5377 g, 60 mass%, 13.44 mmol) in anhydrous
THF (45 mL) at 0 °C is added dropwise 2,2,2-trifluoroethanol (1.345 g, 13.44 mmol).
The resulting reaction mixture is slowly warmed to ambient temperature over 1 hour
and then re-cooled to 0 °C. Further potassium bromomethyl(trifluoro)boranuide
(1.000 g, 4.481 mmol) is added in one portion and the resulting reaction mixture is
stirred at ambient temperature for a further 22 h. The reaction is quenched with
potassium hydrogen fluoride (2 mL, 4.5 M, 9.1 mmol) and stirred for 30 min. The
suspension was concentrated in vacuo and diethyl ether was added to the solid residue.
The resulting suspension is filtered, washing with more diethyl ether and the washed
solid was re-dissolved in acetonitrile and filtered. The filtrate was concentrated in
vacuo and triturated with diethyl ether to yield potassium trifluoro(2,2,2-
trifluoroethoxymethyl)boranuide (0.950 g, 4.32 mmol, 96.4% Yield).
1H NMR (DMSO-d6) d ppm = 3.72-3.65 (m, 2 H), 2.67-2.63 (m, 2 H).
1 F NMR (DMSO-d6) d ppm = -72.7, -141.5.
Example procedure according to Reaction schemes 16 and 15 - Oxidation of
sulfur and cross coupling of bromide compound with thiolate salt.
4-f2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-6-methylsulfinyl-pyridazin-3-one
T o a stirr e d s o luti o n o f 4-(2,3-dichloroindol- 1-yl)-5-methoxy-2-methyl-6-
methylsulfanyl-pyridazin-3-one (60 mg, 0.16 mmol) in DCM (2 mL) at -20 °C is
added mCPBA (36 mg, 0.17 mmol). After stirring for 10 min at this temperature, a
yellow precipitate had appeared. The reaction was poured into a mixture of DCM (20
mL), sodium bicarbonate saturated solution (10 mL) and sodium thiosulphate
saturated solution (10 mL), then stirred for 10 min. The resulting mixture was then
passed through a phase separator and the DCM layer was concentrated under reduced
pressure to afford the desired product 4-(2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-
6-methylsulfinyl-pyridazin-3-one (59 mg, 0.12 mmol, 95%) as a yellow solid, which
was used without further purification.
1H NMR (CDC13) d ppm = 7.59 - 7.66 ( 1 H, m) 7.27 - 7.35 (2 H, m) 6.98 - 7.05 (0.6 H,
m) 6.91 - 6.97 (0.4 H, m) 3.90 (3 H, m) 3.55 (3 H, m) 3.01 (3 H, m)
4-f2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-6-methylsulfanyl-pyridazin-3-one
and 4-f2,3-dichloroindol-l-yl)-2-methyl-6-methylsulfanyl-pyridazine-3.,5-dione
6-bromo-4-(2,3 -dichloroindol- 1-yl)-5-methoxy-2-methyl-pyridazin-3 -one (600 mg,
1.49 mmol), XantPhos (36 mg, 0.060 mmol), Pd2dba3 (28 mg, 0.030 mmol) and
NaSMe ( 115 mg, 1.64 mmol) are suspended in dioxane (8 mL) and DIPEA (0.773 mL,
4.47 mmol) is added. The resulting reaction mixture was heated to 60 °C and within 2
minutes it became black. After stirring at this temperature for 1 h, the reaction mixture
is warmed to 80 °C and stirred overnight. The reaction was allowed to cool and
poured into DCM (100 mL) and 10% NaOH solution (100 mL). The layers were
separated and the DCM layer was dried (MgS04) and concentrated under reduced
pressure onto silica and then purified by flash chromatography (20% EtOAc /
isohexane) to give desired product 4-(2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-6-
methylsulfanyl-pyridazin-3-one (125 mg, 0.338 mmol, 23%) as a yellow crystalline
solid.
1H NMR (CDC13) d ppm = 7.62 - 7.58 (1H, m), 7.27 - 7.24 (2H, m), 7.01 - 6.97 (1H,
m), 3.78 (3H, s), 3.49 (3H, s), 2.48 (3H, s).
The NaOH aqueous layer was acidified with cone. HC1 to cause a yellow precipitate
to crash out. This precipitate was then extracted with DCM (100 mL x 3) and the
DCM layers were dried (MgS0 4) and concentrated in vacuo. The resulting crude
residue was purified by preparatory HPLC( reverse phase fraction lynx) to yield the
demethylated 4-(2,3-dichloroindol-l-yl)-2-methyl-6-methylsulfanyl-pyridazine-3,5-
dione (34 mg, 0.064 mmol, 6%>) as a pale brown solid.
1H NMR (CDCI3) d ppm = 7.61 - 7.57 (1H, m), 7.27 - 7.21 (2H, m), 6.95 - 6.91 (1H,
m), 3.73 (3H, s), 2.53 (3H, s).
Example procedure according to Reaction schemes 18 & 21 - Nitrile formation
and ozonolysis.
5-f2,3-dichloroindol-l-yl)-4-methoxy-l-methyl-6-oxo-pyridazine-3-carbonitrile
To a stirred solution o f 5-(2,3-dichloroindol-l-yl)-4-methoxy-l-methyl-6-oxopyridazine-
3-carbaldehyde (98 mg, 0.278 mmol) in THF (1.5 mL) is added
ammonium hydroxide (30%> aq. solution, 1.5 mL), followed by iodine (92 mg, 0.362
mmol), which caused a dark brown colour to appear. The resulting reaction mixture
was stirred for 1 h and then quenched with NaHC03 solution (5 mL) and Na2S203
solution (5 mL). This caused the reaction to change from dark brown to a clear pale
yellow mixture. After stirring for 10 min the reaction was extracted with DCM (20
mL x 2), dried (MgS04) and concentrated under reduced pressure to afford the
desired product 5-(2,3-dichloroindol- 1-yl)-4-methoxy- 1-methyl-6-oxo-pyridazine-3-
carbonitrile (82 mg, 0.235 mmol, 85%) as a yellow foam that crushed into a yellow
solid.
1H NMR (CDC13) d ppm = 7.65 - 7.61 (1H, m), 7.34 - 7.28 (2H, m), 7.00 - 6.95 (1H,
m), 3.86 (3H, s), 3.61 (3H, s).
5-f2,3-dichloroindol-l-yl)-4-methoxy-l-methyl-6-oxo-pyridazine-3-carbaldehyde
A 3-necked flask is charged with 4-(2,3-dichloroindol-l-yl)-5-methoxy-2-methyl-6-
vinyl-pyridazin-3-one (418 mg, 1.19 mmol) and dichlormethane (10 mL). The flask
was fitted with a thermometer, an inlet tube and an outlet tube connected to two
Dreschel bottles, the latter of which contained a 10% aq. K solution. The inlet tube
was connected to the ozone generator (turned off). The airflow was turned on to give
a steady bubbling through the reaction flask and out through the KI solution. The flask
was cooled to -78°C and once at this temperature, the ozone generator was turned on
and bubbled for 10 min. The KI solution became darker over the course of the
reaction. The ozone generator was turned off and the reaction purged with air for 2
min. It was then disconnected from the inlet and outlet tubes and triphenylphosphine
(939 mg, 3.58 mmol) was added. The reaction was allowed to stir and gradually warm
to RT over 1 h, then stirred at RT for a further 3 h and left to stand overnight. The
resulting reaction mixture was concentrated onto silica and the purified by
chromatography (combiflash, 0 to 50%> EtOAc / ihexane) to give the desired product
5-(2,3-dichloroindol-l-yl)-4-methoxy-l-methyl-6-oxo-pyridazine-3-carbaldehyde
(262 mg, 0.744 mmol, 63%>) as a yellow solid.
1H NMR (CDCI3) d ppm = 9.92 (1H, s), 7.64 - 7.60 (1H, m), 7.3 1 - 7.26 (2H, m), 7.00
- 6.96 (1H, m), 3.93 (3H, s), 3.57 (3H, s).
Example procedure according to Reaction scheme 19 - dione derivatisation
[5- 2,3- ichloroin ol-l -yl)-l .,3- imethyl-6-oxo-pyri iazin-4-yll
isopropylsulfanylformate
To a stirred suspension of 4-(2,3-dichloroindol-l-yl)-2,6-dimethyl-pyridazine-3,5-
dione (120 mg, 0.370 mmol) in dichloromethane (8 mL) at RT is added triethylamine
(129 m , 0.925 mmol). The reaction mixture turned homogeneous. S-Isopropyl
chlorothioformate (69 m , 0.555 mmol) is added and the reaction mixture is stirred for
15 min. The mixture is then quenched with water (10 mL) and the layers are separated.
The aqueous layer i s re-extracted with dichloromethane (10 mL x 3) and the
combined organics were dried (phase separator cartridge) and concentrated under
reduced pressure onto silica. Flash chromatography (combiflash, 0-20% EtOAc /
isohexane) afforded the desired product [5-(2,3-dichloroindol-l-yl)-l,3-dimethyl-6-
oxo-pyridazin-4-yl] isopropylsulfanylformate (140 mg, 0.328 mmol, 89%>) as yellow
solid.
l NMR (CDCl ) d (ppm) 7.52 - 7.57 (1H, m), 7.21 - 7.27 (2H, m), 6.94 - 6.98 (1H, m), 3.86
(3H, s), 3.22 (1H, sept), 2.38 (3H, s), 1.11 (3H, d), 1.04 (3H, d).
Example procedure according to Reaction scheme 20 - halogenation of 2-
substituted indole.
4-f3-chloro-2-methyl-indol-l-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one
To a stirred solution of 5-methoxy-2,6-dimethyl-4-(2-methylindol-l-yl)pyridazin-3-
one (147 mg, 0.52 mmol) in DCM (3 ml) at 0 °C, was added dropwise a solution of
sulfuryl chloride (70 mg, 0.52 mmol) in DCM ( 1 ml). Further DCM ( 1 ml) was added.
After a reaction time of 1 h, the mixture was quenched by addition of sat. aqueous
NaHC0 3 (2 ml). The resulting mixture was filtered through solid MgS0 4, washing
with DCM. The filtration liquors were concentrated in vacuo to afford the title
compound as a pale brown solid (158 mg, 96 %). The material was used for
subsequent reactions without further purification.
H NMR (CDCy d (ppm) 7.60-7.54 (1H, m), 7.22-7.16 (2H, m), 6.96-6.90 (1H, m),
3.75 (3H, s), 3.27 (3H, s), 2.34 (3H, s), 2.32 (3H, s).
Example procedure according to Reaction scheme 22 - difluorination of
carbonyl compound.
4-f2,3-dichloroindol-l-yl)-6-fdifluoromethyl)-5-methoxy-2-methyl-pyridazin-3-
one
T o a stirred solution of 5-(2,3-dichloroindol-l-yl)-4-methoxy-l-methyl-6-oxopyridazine-
3-carbaldehyde (100 mg, 0.284 mmol) in DCM (3 mL) at 0 °C is added
(diethylamino)sulfurtrifluoride (94 , 0.710 mmol). The reaction is allowed to warm
to RT over 1 h. The reaction is quenched cautiously at 0 °C with water (5 mL) and
then the dropwise addition of NaHC0 3 solution (5 mL). After stirring for 10 min it is
extracted with DCM (20 mL), dried (MgS0 4) and concentrated under reduced
pressure to give 4-(2,3-dichloroindol-l-yl)-6-(difluoromethyl)-5-methoxy-2-methylpyridazin-
3-one (102 mg, 0.273 mmol, 96%) as a brown solid.
1H NMR (400 MHz, CDC13) : 7.64 - 7.59 (1H, m), 7.32 - 7.27 (2H, m), 7.01 - 6.97
(1H, m), 6.61 (1H, t), 3.82 (3H, s), 3.52 (3H, s).
Example procedure according to Reaction scheme 23 - reduction of carbonyl
compound.
4-f2,3-dichloroindol-l-yl)-6-fl-hydroxyethyl)-5-methoxy-2-methyl-pyridazin-3-
one
To a stirred solution o f 6-acetyl-4-(2,3-dichloroindol-l-yl)-5-methoxy-2-methylpyridazin-
3-one (500 mg, 1.37 mmol) in ethanol ( 1 mL) at 0 °C is added sodium
borohydride (79 mg, 2.05 mmol). After stirring for 20 min, the reaction is quenched
with water (10 mL), then concentrated under reduced pressure to remove most of the
ethanol. The aqueous solution is then extracted with Et20 (20 mL x 2), then
concentrated under reduced pressure to give the desired product 4-(2,3-dichloroindoll-
yl)-6-(l-hydroxyethyl)-5-methoxy-2-methyl-pyridazin-3-one (379 mg, 1.03 mmol,
75%) as a white solid.
1H NMR (400 MHz, CDC13), 7.63 - 7.59 (1H, m), 7.31 - 7.22 (2H, m), 7.00 - 6.93
(1H, m), 5.05 - 4.97 (1H, m), 3.79 (3H, s), 3.47 (3H, s), 3.03 - 3.00 (1H, m), 1.56 -
1.53 (3H, m).
Example procedure according to Reaction scheme 24 - methylation of alcohol
compound.
4-f2,3-dichloroindol-l-yl)-5-methoxy-6-fl-methoxyethyl)-2-methyl-pyridazin-3-
one
To a stirred solution of 4-(2,3-dichloroindol-l-yl)-6-(l-hydroxyethyl)-5-methoxy-2-
methyl-pyridazin-3-one (98 mg, 0.27 mmol) in DMF ( 1 mL) at 0 °C is added sodium
hydride (60% dispersion in mineral oil, 32 mg, 0.80 mmol). After stirring for 5 min,
Mel (50 , 0.80 mmol) is added. After 30 min, the reaction is cautiously quenched
with ammonium chloride solution (10 mL) and allowed to stand overnight. The
following day, the reaction mixture is extracted with DCM (10 mL x 3), then dried
(MgS0 4) and concentrated under reduced pressure. The residue is resubmitted to the
reaction conditions with the same procedure and reagent/solvent quantities as above.
After stirring for 30 min, it is warmed to RT and allowed to stir for a further 1.5 h. It
is then cooled to 0 °C and then quenched cautiously with ammonium chloride solution
(20 mL). Et20 is then added and the layers were separated. The organic layer is
washed with water (20 mL x 3), then dried (MgS0 4) and concentrated under reduced
pressure onto silica. Chromatography (0 to 30% EtOAc / isohexane) affords the
desired product 4-(2,3-dichloroindol-l-yl)-5-methoxy-6-(l-methoxyethyl)-2-methylpyridazin-
3-one (64 mg, 0.168 mmol, 63%>) as a colourless oil.
1H NMR (400 MHz, CDC13) : 7.63 - 7.58 (1H, m), 7.30 - 7.24 (2H, m), 7.01 - 6.94
(1H, m), 4.66 - 4.62 (1H, m), 3.80 (3H, s), 3.45 - 3.43 (6H, m), 1.56 - 1.54 (3H, m).
Example procedure according to Reaction scheme 25 - fluorination of alcohol
compound.
4-f2,3-dichloroindol-l-yl)-6-fl-fluoroethyl)-5-methoxy-2-methyl-pyridazin-3-one
To a stirred solution of 4-(2,3-dichloroindol-l-yl)-6-(l-hydroxyethyl)-5-methoxy-2-
methyl-pyridazin-3-one (185 mg, 0.502 mmol) in DCM (4 mL) at 0 °C is added
(diethylamino)sulfurtrifluoride (86 L , 0.65 mmol). After stirring for 30 min, the
reaction is quenched cautiously at 0 °C with the dropwise addition of NaHC0 3
solution (10 mL). After stirring for 10 min it is extracted with DCM (20 mL), dried
(MgS0 4) and concentrated under reduced pressure. Chromatography (0 to 20%
EtOAc / isohexane) gives the desired product 4-(2,3-dichloroindol-l-yl)-6-(lfluoroethyl)-
5-methoxy-2-methyl-pyridazin-3-one (194 mg, 0.524 mmol, 104%). 1H
NMR analysis showed a ~10%> impurity, which was separated after the subsequent
step.
1H NMR (400 MHz, CDC13) : 7.63 - 7.59 (1H, m), 7.30 - 7.24 (2H, m), 7.01 - 6.94
(1H, m), 5.91 - 5.73 (1H, m), 3.81 (3H, s), 3.48 (3H, s), 1.75 (3H, dd).
TABLE 1 - Examples of herbicidal compounds of the present invention.

TABLE 2 - Examples of herbicidal compounds of the present invention.

TABLE 3 - Examples of herbicidal compounds of the present invention.
TABLE 4 - Examples of herbicidal compounds of the present invention.
Biological Examples
Seeds of a variety of test species are sown in standard soil in pots:- Solanum nigrum
(SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Alopecurus
myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Ipomoea hederacea
(IPOHE). After 8 days cultivation (post-emergence) under controlled conditions in a
glasshouse (at 24/16°C, day/night; 14 hours light; 65 % humidity), the plants are
sprayed with an aqueous spray solution derived from the formulation of the technical
active ingredient in acetone / water (50:50) solution containing 0.5% Tween 20
(polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are
applied at 1000 g/ha. The test plants are then grown in a glasshouse under controlled
conditions in a glasshouse (at 24/16°C, day/night; 14 hours light; 65 % humidity) and
watered twice daily. After 13 days, the test is evaluated for the percentage damage
caused to the plant. The biological activities are shown in the following table on a
five point scale (5 = 80-100%; 4 = 60-79%; 5=40-59%; 2=20-39%; 7=0-19%).
Compound POST Application
SOLNI AMARE SETFA ALOMY ECHCG IPOHE
1.001 5 5 2 1 4 5
1.002 5 4 1 1 1 4
1.003 5 5 1 1 2 5
1.004 4 1 1 1 1 1
1.005 5 2 1 1 2
1.006 4 1 1 1 1 1
1.007 5 2 1 1 1 1
1.008 4 1 1 1 1 2
1.009 4 4 1 1 1 1
1.010 3 1 1 1 1 1
1.012 5 5 1 2 5
1.013 5 5 1 1 5
1.014 5 3 1 1 4 4
1.016 5 2 1 1 1 4
1.017 5 3 1 1 1 4
1.020 5 5 1 1 4 5
1.021 5 5 1 2 5
1.022 5 3 1 1 2 5
1.023 5 5 1 3 5
1.024 5 5 1 2 5
1.025 5 4 1 1 1 3
1.026 5 5 4 5
1.027 5 4 1 1 3 4
2.001 5 3 1 2 5
2.002 5 5 1 1 1 5
2.003 2 2 1 1 1 4
2.004 2 2 1 1 1 2
2.005 5 2 1 1 1 5
Compound POST Application
SOLNI AMA E SETFA ALOMY ECHCG IPOHE
2.006 4 1 1 1 1 4
2.008 5 3 1 1 1 5
2.009 4 1 1 1 1 2
2.010 4 3 1 1 1 3
2.01 1 4 2 1 1 1 5
2.012 4 1 1 1 1 4
2.013 4 3 1 1 1 2
2.014 4 2 1 1 1 5
2.015 4 2 1 1 1 5
2.016 4 4 1 1 1 2
2.017 3 4 1 1 1
2.01 8 4 3 1 1 1 4
2.019 4 4 1 1 1 2
2.020 4 4 1 1 1 3
2.021 4 3 1 1 3
2.022 5 4 1 1 1 5
2.023 4 2 1 1 1 4
2.024 2 2 1 1 1 1
2.025 5 2 1 5
2.026 5 4 1 1 5
2.027 5 4 1 1 1 5
2.028 5 5 1 1 1 5
3.001 5 5 1 1 1 5
3.002 5 2 1 1 1 5
3.003 5 5 1 1 4 5
3.004 5 5 4 5
3.005 5 4 1 1 3 5
3.006 5 4 1 4 5
3.007 5 5 1 1 1 5
3.008 5 5 1 3 5
3.009 5 5 1 1 1 5
3.010 5 5 1 1 3 5
3.01 1 5 5 2 1 4 5
4.026 5 4 3 2 2 5
4.027 5 5 4 3 5 5
Comparative Experiment
A comparative experiment is conducted to compare the biological efficacy of a
compound of the present invention with those of WO 201 1/045271. The test is
performed as outlined above using the following compounds. Three different
application rates are employed (250g/ha, 500g/ha and lOOOg/ha).
The results observed are summarised in the Table below.
These results show that compounds of the present invention exhibit an increased
efficacy vis-a-vis those disclosed in WO201 1/045271, which is particularly apparent
at lower application rates.
Claims
1. A compound of Formula (I) :
or an agronomically acceptable salt thereof,
wherein: -
X1 is N or CR4;
R1 is selected from the group consisting of C1-C4alkyl, C1-C2alkoxy-C1-C2
alkyl, C2-C4alkenyl, C1-C4haloalkyl, C2-C4haloalkenyl, C2-C4alkynyl and C -
C4haloalkynyl;
R is selected from the group consisting of hydrogen, halogen, cyano, C -
C6alkyl, Ci-Cehaloalkyl, Ci-Cehaloalkoxy, Ci-Cshaloalkoxy-Ci-Csalkyl-, Ci-
C6alkoxy, Ci-Csalkoxy-Ci-Csalkyl, Ci-Csalkoxy-Ci-Csalkoxy-Ci-Csalkyl-,
C3-C6cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C -
C6hydroxyalkyl-, Ci-Cealkylcarbonyl-, -S(0 )pC1-C6alkyl, amino, C -
Cealkylamino, Ci-Cedialkylamino, -C(C1-C3alkyl)=N-0 -C1-C3alkyl and C2-C6
haloalkynyl;
R is independently selected from the group consisting of hydrogen, halogen,
nitro, cyano, amino, Ci-Cealkyl, Ci-Cehaloalkyl, C3-C6cycloalkyl, Ci-
C6alkoxy, Ci-Cealkoxycarbonyl and -S(0 )pCi-C6 alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen,
hydroxyl, halogen, nitro, cyano, amino, Ci-Cealkyl, Ci-Cehaloalkyl, C3-
Cecycloalkyl, Ci-Cealkoxy, Ci-Cealkoxycarbonyl and -S(0) pCi-C6 alkyl;
G is hydrogen or -C(0)-R 6;
R6 is selected from the group consisting of Ci-Cealkyl, Ci-Cealkenyl, Ci-
Cealkynyl, Ci-Cealkyl-S-, Ci-Cealkoxy, -NR7R8 and phenyl optionally
substituted by one or more R9;
R7' and R8 are independently selected from the group consisting of C - C6 alkyl,
C -C alkoxy-;
wherein R7 and R8 can together form a morpholinyl ring;
R9 is selected from the group consisting of halogen, cyano, nitro, Ci-C3alkyl,
Ci-C3haloalkyl, Ci-C3alkoxy and Ci-C3haloalkoxy;
n = 0,1,2,3 or 4; and
p = 0, 1 or 2.
2. A compound according to claim 1, wherein G is hydrogen.
3. A compound of claim 1 or claim 2, wherein R is selected from the group
consisting of hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-
C3alkoxy-Ci-C3alkyl, C3-Cecycloalkyl, C2-C6alkenyl, C2-Cehaloalkenyl, C2-C6
alkynyl and C2-C6haloalkynyl;
4. A compound according to claim 3, wherein R is selected from the group
consisting of hydrogen, methyl, ethyl, cyclopropyl and methoxymethyl.
5. A compound according to any one of the previous claims, wherein R is
methyl.
6. A compound according to any one of the previous claims, wherein n = 0.
7. A compound according to any one of the previous claims, wherein R1 is
selected from the group consisting of methyl, ethyl and n-propyl.
8. A compound according to any one of the previous claims, wherein X1 is N.
9. A compound according to any one of the previous claims, wherein X1 is CR4.
10. A compound according to claim 9, wherein R4 is halogen and/or R5 is halogen.
11. A herbicidal composition comprising a herbicidal compound according to any
one of the previous claims and an agriculturally acceptable formulation
adjuvant.
12. A herbicidal composition according to claim 11, further comprising at least
one additional pesticide.
13. A herbicidal composition according to claim 12, wherein the additional
pesticide is a herbicide or herbicide safener.
14. A method of controlling weeds at a locus comprising application to the locus
of a weed controlling amount of a composition according to any one of claims
11 to 13.
15. Use of a compound of Formula (I) as defined in claim 1 as a herbicide.