Classifications

• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
  • A01N47/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom containing —O—CO—O— groups; Thio analogues thereof
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
  • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
  • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
  • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
  • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
  • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
  • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
  • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
  • A01N47/22—O-Aryl or S-Aryl esters thereof

Definitions

• This invention relates to certain fungicidal quinazolinones, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides.
• This invention is directed to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a compound of Formula I including all geometric and stereoisomers, N-oxides, agriculturally suitable salts thereof, and agricultural compositions containing them:
• R 3 is Cl, Br, I, C r C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 8 haloalkyl, C3-C 8 haloalkenyl, C 3 -C haloalkynyl, C C 8 alkoxy,
• R13; R 4 is hydrogen, Cl, Br, I, C r C 4 alkyl, C r C 4 haloalkyl, C r C 4 alkoxy or
• R 14 is B(OH) 2 ; OH; SH; cyano; CF 3 SO 3 ; C r C 4 haloalkylthio; C r C 4 haloalkylsulfinyl; -C4 haloalkylsulfonyl; thiocyanato; C 3 -C 8 trialkylsilyloxy, Rl 5 OCHR 16 O; (R 15 O) 2 CHO; R 15 SS; R l 5SCH(R !
• each W is independently defined as -O-, -S(O) n -, -NR 5 -, -CH 2 O-, -CH 2 S(O) n -,
• each R 9 is independently methyl, ethyl, methoxy, methylthio, halogen,
• alkyl used in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, «-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
• alkyl used alone includes straight-chain or branched alkyl, such as, methyl, ethyl, w-propyl, /-propyl, or the different butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl isomers.
• Alkenyl includes straight-chain or branched alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl isomers.
• Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
• Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl isomers.
• Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
• Alkoxy includes, for example, methoxy, ethoxy, propyloxy, 1-methylethoxy and the different butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, and decyloxy isomers.
• Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
• Alkenyloxy includes straight-chain or branched alkenyloxy moieties.
• alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 O, CH 3 C----CCH 2 O and CH 3 C ⁇ CCH 2 CH 2 O.
• Alkoxyalkenyl denotes alkoxy substitution of alkenyl.
• alkynyloxyalkyl examples include CH ⁇ CCH 2 OCH 2 and CH 3 C ⁇ CCH 2 OCH 2 CH 2 .
• Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, hexylthio, heptylthio and octylthio isomers.
• Alkylthioalkyl denotes alkylthio substitution on alkyl.
• alkylthioalkyl examples include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
• alkenylthioalkyl denotes alkenyl substitution on sulfur which in turn is substituted on alkyl.
• Alkynylthioalkyl denotes alkynyl substitution on sulfur which in turn is substituted on alkyl.
• alkynylthioalkyl include CIfeCCH 2 SCH 2 and CH 3 C ⁇ CCH 2 SCH 2 CH 2 .
• alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptasulfonyl and octasulfonyl isomers.
• Alkylsulfonylalkyl denotes alkylsulfonyl substitution on alkyl. Examples of “alkylsulfonylalkyl” include
• alkenylthio is defined analogously to the above examples.
• Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepyl and cyclooctyl.
• Cycloalkylalkyl denotes cycloalkyl substituted on alkyl. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
• halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
• haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
• haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
• haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
• haloalkylsulfinyl examples include CF 3 S(O), CCl 3 S(O), CF 3 CH 2 S(O) and CF 3 CF 2 S(O).
• haloalkylsulfonyl examples include CF 3 S(O) 2 , CCl 3 S(O) 2 , CF 3 CH 2 S(O) 2 and CF 3 CF 2 S(O) 2 .
• Trialkylsilylalkyl denotes trialkylsilyl substitution on alkyl.
• Examples of “trialkylsilylalkyl” include (CH 3 ) 3 SiCH 2 , and (CH 3 ) 3 SiCH 2 CH 3 .
• Trialkylsilylalkynyl denotes trialkylsilyl substitution on alkynyl.
• Examples of “trialkylsilylalkynyl” include (CH 3 ) 3 SiC ⁇ C and (CH 3 CH 2 )SiCH 2 C ⁇ C.
• C j -C; The total number of carbon atoms in a substituent group is indicated by the "C j -C;" prefix where i and j are numbers from 1 to 10.
• Cj-C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
• the R 8 , R 9 and R 10 groups may substitute either ring.
• the R 8 , R 9 and/or R 10 groups are shown in the structures Y-l to Y-100, it is noted that they do not need to be present since they are optional substituents.
• N-oxides of compounds of Formula I can be made by oxidizing the corresponding nitrogen compound with a strong oxidizing agent such as wet ⁇ -chloroperoxybenzoic acid.
• Compounds of Formula I can exist as one or more stereoisomers.
• the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
• one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
• the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
• the salts of the compounds of Formula I useful for this invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
• the salts useful for this invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group.
• the present invention comprises the fungicidal use of compounds selected from Formula I, including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof.
• Preferred compounds for use in the method and compositions of this invention for reasons of better activity and/or ease of synthesis are:
• each W is -O-, -S- or - ⁇ R 5 -; each Rl is CJ-CI Q alkyl, C 4 -C 10 cycloalkylalkyl or RU; each R 2 is C j -Cio alkyl, C 4 -C 10 cycloalkylalkyl or Rl 1; and R 3 is R l4 .
• each W is -O-, -S- or - ⁇ R 5 -
• each Rl is CJ-CI Q alkyl, C 4 -C 10 cycloalkylalkyl or RU
• each R 2 is C j -Cio alkyl, C 4 -C 10 cycloalkylalkyl or Rl 1
• R 3 is R l4 .
• each W is -CH 2 O-, -CH 2 S(O) n - or -CH 2 ⁇ R 5 -; each R l is C J-CJQ alkyl, C -C ⁇ 0 cycloalkylalkyl or R l ; and each R 2 is CJ-CJQ alkyl, C 4 -CJO cycloalkylalkyl or R 1 1 .
• Preferred 2a Compounds of Preferred 2 above wherein: R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R 14 ; and
• R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl. Preferred 3.
• each W is a direct bond
• each R 1 is C C j o alkyl, C -C 10 cycloalkylalkyl or R U
• Preferred 3a Compounds of Preferred 3 above wherein:
• R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R ]4 ; and R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl.
• R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl.
• W is a direct bond
• R l is C r C w alkyl, C 4 -C 10 cycloalkylalkyl or RU;
• R 2 is OH or halogen;
• R 3 is halogen, C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl or R 14 ; and R 14 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C haloalkylsulfonyl.
• R 14 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C haloalkylsulfonyl.
• R 1 and or R 2 is substituted C Cjo alkyl (preferably C r C 4 alkyl substituted with OH);
• R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R ⁇ 4 ;
• R 4 is hydrogen, Cl, Br or I;
• R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C 4 haloalkylsulfonyl.
• Most preferred are compounds selected from the group 2-chloro-6-iodo-3- «-propyl-4(3H)-quinazolinone;
• W is a direct bond
• the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-30.
• the definitions of W, Q, X, Y, R R 20 , m, n and p in the compounds of Formulae 1-16 below are as defined above in the Summary of the Invention.
• Compounds of Formulae Ia-Iae are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Iae are as defined above for Formula I.
• the synthesis of compounds of Formula I is described below. First, the synthesis of the quinazolinone ring system is described. In this first section, the groups Rl, WR 2 , R 3 , R 4 and/or (R ]9 ) p are incorporated into the substrates which are used in the syntheses described therein. Alternatively, the quinazolinone ring system can be prepared using a precursor to these groups, and then the R 1 , WR 2 , R 3 , R 4 and/or (R 19 ) p groups can be introduced afterwards. This alternate strategy is outlined in the second section of this synthetic summary.
• the reaction may be run by treating the compounds 1 with excess amine in hydrocarbon, ethereal, alcoholic or polar aprotic solvents at temperatures ranging from ambient to 150 °C for 0.1 to 72 hours. Workup usually involves removal of reaction solvent in vacuo and, if necessary, purification by silica gel chromatography.
• esters of Formula 2 are treated with thiophosgene at temperatures from about -20 to 100 °C for 1 -48 hours in an inert solvent. Often this reaction is performed in a bi-phasic mixture in the presence of an aqueous base (e.g., sodium bicarbonate).
• an aqueous base e.g., sodium bicarbonate.
• the resulting isothiocyanate may be isolated by extraction into a water-immiscible solvent such as methylene chloride, followed by drying of the organic extracts and evaporation under reduced pressure.
• the isothiocyanate can be combined in situ with compounds of formula R 2 OH, R 2 SH or R 2 NHR 5 and stirred at about -20 to 100 °C for 0.1-24 hours.
• the desired product of Formula 1 can be isolated from the reaction mixture by extraction and purified by silica gel chromatography or recrystallization.
• the reaction may be carried out in a variety of solvents in the presence of homo/heterogeneous bases at temperatures from ambient to 150 °C for 0.1 to 24 hours.
• suitable reaction solvents include hexanes, benzene, dioxane, tetrahydrofuran (THF), lower alkanols, NN-dimethylforamide (DMF) and halocarbon solvents.
• Suitable bases include potassium carbonate, sodium hydroxide, triethylamine and pyridine.
• Workup is achieved by removing reaction solvent in vacuo and partitioning the crude residue between dilute aqueous acid and a water-immiscible solvent. The water-immiscible phase is then separated, dried over sodium sulfate ( ⁇ a 2 SO 4 , anhydrous), concentrated, and purified by crystallization or silica gel chromatography to deliver pure I.
• An anthranilic acid of Formula 3 is condensed with an isothiocyanate of Formula Rl-NCS to form the 2-thioquinazolinone of Formula 5.
• the condensation is preferably performed in the presence of a base such as triethylamine.
• S-Methylation of this compound affords the 2-(methylthio)-4(3H)-quinazolinone of Formula Ic.
• Formula Ic is treated with a mixture of a base, for example sodium hydride, in R 2 O ⁇ solvent.
• a base for example sodium hydride
• the reaction mixture is stirred at a temperature from about 0 °C to 120 °C for 1 to
• the desired 2-R 2 O quinazolinone can be isolated from the reaction mixture by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization. Synthetic procedures for the preparation of related 4(3H)-quinazolinones are described in U.S. 3,755,582 and incorporated herein by reference.
• the isothiocyanates of Formula R!-NCS can be prepared from the corresponding amine by treatment with thiophosgene as known in the art. For example, seeJ. Heterocycl. Chem., (1990), 27, 407.
• the reaction is run using either aqueous NaOH or KOH at base concentrations ranging from 0.1 - 3 N.
• the reaction may optionally be conducted in the presence of a co-solvent (e.g., ethanol) at temperatures ranging from ambient to reflux for 0.1 to 24 hours.
• a co-solvent e.g., ethanol
• Workup/purification is achieved by acidifying the crude reaction mixture and isolating the product 5a via suction filtration.
• Compounds of Formula 5b are prepared by reacting the anthranilic acids 3 with suitable acyl isothiocyanates in an aprotic solvent such as acetone (Scheme 6).
• the reaction is optionally conducted in the presence of a soluble base such as triethylamine at reflux temperatures for 0.1-24 hours.
• a soluble base such as triethylamine
• the precipitated product 5b is isolated by suction filtration and utilized without further purification. Analogous procedures are known in the art (Indian J. Chem., (1968), 6, 621 and Ann. Chim. (Rome), (1967), 57, 595).
• OTs 2-R 2 S quinazolinone of Formula Id.
• Bases such as sodium hydroxide and sodium hydride are suitable.
• the 2-thiopyrimidinedione is dissolved or dispersed in an inert solvent such as N,N-dimethylformamide and treated with a base at a temperature from about -20 to 60 °C.
• the reaction mixture may then be heated to just above ambient temperature to the reflux temperature of the solvent for 0.1 to 24 hours to effect deprotonation.
• the reaction mixture is cooled and treated with R 2 -L and stirred for 0.1-24 hours at a temperature from about 20 °C to the reflux temperature of the solvent.
• the quinazolinone of Formula Id can be isolated by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization.
• the reaction may be conducted either neat or in an inert solvent at temperatures ranging from 100 to 250 °C for 1-24 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the crude residue purified by silica gel chromatography to afford Ie. For similar procedures, seeHe v. Chim. Ada, (1968), 69, 1017.
• the amides 7 are accessed from isatoic anhydrides of Formula 8 via treatment with amines of structure R ! N ⁇ 2 (Scheme 10).
• Methods for the preparation of isatoic anhydrides are well-known in the literature, as is their conversion to aminobenzamides (see
• Oxalates of Formula 6 are also well known and are either available commercially, or can be prepared using methods familiar to the skilled practitioner.
• Fused bicyclic quinazolinones of Formula Ig compounds of Formula I wherein Q is O and W is S(O) or S(O) 2 , can be prepared by oxidation of the corresponding -SR 2 compound of Formula If using well-known procedures for oxidation of sulfur (Scheme 11). For example, see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York,
• Fused bicyclic quinazolinones of Formula Ih compounds of Formula I wherein Q is O and W is NR 5 , can be prepared by the method illustrated in Scheme 12. This method is described in detail in U.S. 3,867,384 and incorporated herein by reference.
• 2-methylthio quinazolinone of Formula 9 (Z SMe) with an excess of an amine of Formula HNR 5 R 2 at about 150 to 175 °C.
• Phosgene, phosphorous trichloride, phosphorous oxybromide, phosphorous tribromide and diethylamino sulfur trifluoride (DAST), may also be used to access compounds of Formula 9, wherein Z is halogen from 2-thio-quinazolinones of Formula 5.
• Amines of Formula HNR 5 R 2 are commercially available or can be prepared by well-known methods (March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), p 1153).
• compounds of Formula lb and Id can be prepared by displacement of the 2-chlorine in the appropriate fused quinazolinone, rather than by displacement of the 2-SCH 3 group (Scheme 4) or S-alkylation of the thiocarbonyl (Scheme 8).
• 2-chlorine in the appropriate fused quinazolinone
• 2-SCH 3 group Scheme 4
• S-alkylation of the thiocarbonyl Scheme 8
• WR 2 , R 3 , R 4 and/or (R !9 ) p substituents may be more conveniently introduced after cyclization to form the quinazolinone system.
• R 5 H precursor of Formula Ii as illustrated in Scheme 13.
• DMSO/oxalyl chloride/Et 3 N Tetrahedron, (1990), 46, 1295.
• the oxidations may be conducted in halocarbon solvents at temperatures ranging from -78 °C to 100 °C and the desired product isolated by filtration from the reaction mixture.
• the precursors of Formula II may be synthesized from compounds of Formula 10 through contact with aqueous base (Scheme 15) as demonstrated in the art (Tetrahedron, (1990), 46, 1295).
• the reaction may be conducted using aqueous K 2 CO 3 , NaCO 3 , or NaOH at temperatures of ambient to 50 °C for 0.5-72 hours.
• the product II can be isolated by extraction of the aqueous reaction mixture with a water-immiscible solvent, followed by drying and concentration of the organic phase in vacuo.
• Acid halides of Formula 11 can be prepared from the corresponding -acetoxy acids by treatment with oxalyl chloride as described in Tetrahedron, (1990), 46, 1295.
• the requisite ⁇ -acetoxy acids are well known and accessible via methods known in the art (e.g., Ber., (1904), 37, 3971 ; J. Org. Chem., (1990), 55, (1928); Tetrahedron Asymmetrie, (1990), 9, 87).
• the reaction may be run in solvents such as DMF, THF, benzene, acetonitrile, or neat at temperatures ranging from ambient to 150 °C.
• Bases such as potassium carbonate (K 2 CO 3 ), sodium hydroxide (NaOH), or sodium hydride (NaH) may be employed to facilitate the reaction.
• Workup is achieved by concentrating the crude reaction mixture in vacuo and partitioning the residue between a water-immiscible solvent and water. Drying and concentration of the water-immiscible phase delivers Io, which may be further purified by recrystallization or column chromatography.
• Halides of Formula In can be prepared from aminobenzamides 7 in a manner analogous to that described inJ. Med. Chem., (1979), 22, 95. Reaction of acid halides 12 with the aminobenzamides 7 in acetic acid (HOAc) at temperatures ranging from ambient to reflux for 0.1-24 hours affords the halides In after cooling, concentrating in vacuo, and optional purification via column chromatography and/or recrystallization (Scheme 18).
• HOAc acetic acid
• the acid halides 12 are either commercially available or preparable using established methods.
• Aminobenzamides 7 may be accessed as described previously in this document.
• carbenoid species such as 13 and subsequent reaction with Ip to deliver compounds of Formula Ir can be accomplished by the analogous application of known methods (e.g. J. Het. Chem., (1990), 27, 807). Likewise, established methods can be applied in preparing the acylated/thioacylated materials Ir and Is (see, for example,J Med. Chem., (1985), 28, $16).
• Salts of compounds of Formula I can be formed by treating the free base of the corresponding compound with strong acids such as hydrochloric or sulfuric acid. Salts can also be prepared by alkylation of a tertiary amine group in the molecule to form, for example, the trialkylammonium salt. N-Oxides of compounds of Formula I can be made by oxidizing the corresponding reduced nitrogen compound with a strong oxidizing agent such as et ⁇ -chloroperoxybenzoic acid. Synthesis of RU Groups
• R l 1 group can be prepared by incorporation of the R l 1 group after the synthesis of the quinazolinone ring system.
• the aziridines of Formula Iw can be prepared from the alkenes of Formula 14 by condensation with a nitrene as illustrated in Scheme 23 and described in Abramovitch, R. J. Chem. Soc, Chem. Commun., (1972), 1160.
• the NH aziridine compound of Formula Ix can be prepared from the corresponding epoxide by contact with sodium azide and triphenylphosphine as illustrated below in Scheme 24 and described by Ittah, Y. in J. Org. Chem. , ( 1978), 43, 4271.
• the episulfide of Formula Iy can also be prepared from the epoxide using triphenylphosphine sulfide using techniques taught by Chan, T. inJ Am. Chem. Soc, (1972), 94, 2880.
• oxetanes of Formula Iz may be achieved by ring expansion of the corresponding epoxide using dimethyloxosulfonium methylide as illustrated in Scheme 25 and described by J. Okuma inJ Org. Chem., (1983), 48, 5133. In some cases, a mixture of regioisomers will be obtained. Additional methods for preparing oxetanes, as well as other 4-membered ring heterocycles, from an alkene precursor are well-known in the art. For example, see: Buchi, G., J. Am. Chem. Soc, (1954), 76, 4327; and Pifferi, G., J Heterocyclic Chem., (1967), 4, 619.
• dioxolane compounds can be prepared from the glycol using known methods.
• a method exemplifying the preparation of the dimethyl - dioxolane is illustrated in Scheme 26 and described by A. Hampton inJ Am. Chem. Soc, (1961), 83, 3640.
• Scheme 26 A method exemplifying the preparation of the dimethyl - dioxolane is illustrated in Scheme 26 and described by A. Hampton inJ Am. Chem. Soc, (1961), 83, 3640.
• the glycol of Formula 15 can be prepared from the alkene of Formula 14 using vicinal bis-hydroxylation reagents such as osmium tetroxide (see Wade, P., Tetrahedron Lett., (1989), 5969).
• 5-membered ring compounds can be prepared from the alkene of Formula 14 using a 1,3-dipole cyclization.
• reaction of 14 with bromonitrile oxide produces the dihydroisoxazole of Formula lab as illustrated in Scheme 27 (see Wade, P., in J. Org. Chem., (1990), 55, 3045).
• 1,3-dipoles are known to react with alkenes and alkynes of Formulae 14 and 16, respectively, in cycloaddition reactions. Dipoles and methods for generating them are described in 1,3-Dipolar Cycloaddition Reactions, A. Padwa, Ed., Wiley Interscience, NY, 1984, Vols. 1 and 2; and Comprehensive Heterocyclic Chemistry, Katritzky, A., Ed., Pergamon, NY, 1984, Vol. 5, p 143). Examples of known 1,3 dipoles are nitrile ylides, nitrile imines, nitrile sulfides, diazoalkanes, azides, azomethine ylides and nitrones.
• Compounds of Formula I wherein R 11 comprises a 6-membered ring heterocycle can be prepared from the alkene of Formula 14 by [4+2] cycloaddition with a suitable heterodiene. For example, conditions similar to those described by Krespan, C, inJ Am.
• alkynes can also engage in reactions with heterodiene systems to afford unsaturated ring compounds such as those of
• heterodienes known to undergo cycloaddition reactions are thiophene, furan, ⁇ , ⁇ -unsaturated aldehydes and ketones, ⁇ , ⁇ -unsaturated thiocarbonyl compounds, ⁇ , ⁇ -unsaturated imines, vinyl nitroso species, azoalkenes, acyldiimides, acyl sulfenes, ⁇ -quinones, and thioamide-N-methylium salts.
• the regiochemical course of the [4+2] condensation depends on the structure of the alkene or alkyne and the heterodiene. Both regioisomers are often obtained in which case the desired regioisomer can be isolated by chromatography or recrystallization.
• Iaf Acids of Formula 3 are optimally reacted with isocyanates of Formula 17 at temperatures from ambient to about 150 °C in the presence of an inert solvent and base, followed by solvent distillation and heating of the subsequent residue to 200-250 °C for about 0.5 to 1 hour.
• Suitable solvents for this transformation include acetonitrile, DMF, or dioxane.
• Suitable bases include triethylamine or pyridine.
• Phosphonates of Formula Iah are accessible by reacting halides of Formula lag with phosphites of Formula 18 (Scheme 32).
• Step B Preparation of methyl 5-iodo-2-isothiocyanatobenzoate
• 2-amino-5-iodobenzoate hydrochloride 20.0 g, 0.063 mol
• Toluene 720 mL
• water 180 mL
• sodium bicarbonate 49 g, 0.583 mol
• thiophosgene 13.2 mL, 0.172 mol
• the biphasic mixture was stirred at room temperature for 24 h, diluted with water (400 mL), and the phases separated.
• the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 21.43 g of the title compound, ]
• H NMR 300 MHz, CDC1 3
• Step D Preparation of 6-iodo-2-propoxy-4(3H)-quinazolinone Methyl 5-iodo-2-[(propoxythioxomethyl)amino]benzoate (1.0 g, 2.64 mmol) was combined with ammonia-saturated 1-propanol (20 mL) in a lightly-capped nalgene® vessel and stirred at room temperature for 24 hours.
• Step B Preparation of S-[3,4-dihvdro-4-oxo-3-propyl-2-rpropylthio)-6-quinazolinyl] dimethylcarbamothioate O-[3,4-dihydro-4-oxo-3-propyl-2-(propylthio)-6-quinazolinyl]dimethylcarbamo-thioate
• Step C Preparation of 6-[(difluoromethyl)thio]-3-propyl-2-(propylthio -4(3H)- quinazolinone
• Step B Preparation of 6.6'-dithiobis[3-propyl-2-(propylthio)-4(3H)-quinazolinone]
• 6-Iodo-3 «-propyl-2-thio-4(3H)-quinazolinedione (5 g, 0.014 moles, prepared from propyl isothiocyanate in a manner similar to that described in Example 4, Step A using 2-amino-5-iodo benzoic acid in place of 2-amino-5-hydroxybenzoic acid) was slurried in n-propyl acetate and treated with phosgene (2.1 mL, 0.029 mol). The slurry was heated at reflux for 1 hour. The excess phosgene was removed by co-distillation with r ⁇ -propyl acetate at atmospheric pressure. The pot residue was then evaporated to dryness under vacuum.
• phosgene 2.1 mL, 0.029 mol
• R 3 6-C1
• R 4 H
• R 1 CH 2 CH 2 CH 3)
• R 3 6-C1
• R 4 H
• Compounds of Formula I used in this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
• the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
• Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels.
• Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible (“wettable”) or water-soluble.
• Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient.
• Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation.
• the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
• Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsi ⁇ ers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
• Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers.
• Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
• Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
• Solutions can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wetmilling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 141-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714.
• Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
• Compound 25 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
• Granule Compound 25 10.0% attapulgite granules (low volatile matter
• Example C Extruded Pellet Compound 25 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
• Example D Emulsifiable Concentrate
• Compound 25 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
• the compounds of Formula I are useful as plant disease control agents.
• the present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound.
• the compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops.
• pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides, Cercospora beticola, Botrytis cinerea, Monilinia fructicola, Pyricularia oryzae, Podosphaera leucotricha, Venturia inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia recondita, Puccinia graminis, Hemileia vastatrix, Puccinia striiformis, Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuligine
• Compounds of Formula I can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
• insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene
• insecticides such as abamectin, acep
• Preferred for better control of plant diseases caused by fungal plant pathogens e.g., lower use rate or broader spectrum of plant pathogens controlled
• resistance management are mixtures of a compound of this invention with a fungicide selected from the group: flusilazole, epoxiconazole, fenpropimorph, fenpropidin, azoxystrobin, kresoxim methyl, benomyl, mancozeb and cymoxanil.
• Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
• the compounds can also be applied to the seed to protect the seed and seedling.
• Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
• BIOLOGICAL EXAMPLES OF THE INVENTION Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha.
• TEST A The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
• TEST B The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
• TEST C The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
• test suspension was sprayed to the point of run-off on rice seedlings.
• seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made.
• test suspension was sprayed to the point of run-off on tomato seedlings.
• seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
• Phytophthora infestans the causal agent of potato and tomato late blight
• TEST E The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made. TEST F The test suspension was sprayed to the point of run-off on cucumber seedlings.
• Plasmopara viticola the causal agent of grape downy mildew
• Results for Tests A-F are given in Table A.
• a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls).
• a dash (-) indicates no test results.
• ND indicates disease control not determined due to phytotoxicity.
• Test A 48 98 0 0 0 28 0 Cmpd No. Test B Test C Test D Test E Test F

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