EP0874831A1 - Procedes et composes pour preparer des urees cycliques utiles comme fongicides - Google Patents

Procedes et composes pour preparer des urees cycliques utiles comme fongicides

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Publication number
EP0874831A1
EP0874831A1 EP96944218A EP96944218A EP0874831A1 EP 0874831 A1 EP0874831 A1 EP 0874831A1 EP 96944218 A EP96944218 A EP 96944218A EP 96944218 A EP96944218 A EP 96944218A EP 0874831 A1 EP0874831 A1 EP 0874831A1
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EP
European Patent Office
Prior art keywords
alkyl
formula
phenyl
compound
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP96944218A
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German (de)
English (en)
Inventor
Richard James Brown
Dilon J. Daniel
Deborah Ann Frasier
Stephen Lee Hartzell
Gerard Michael Koether
Paul Walter Wojtkowski
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EIDP Inc
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EI Du Pont de Nemours and Co
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Publication of EP0874831A1 publication Critical patent/EP0874831A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
    • C07F9/6518—Five-membered rings

Definitions

  • This invention pertains to compounds and processes which are useful for preparing cyclic urea fungicides.
  • WO 95/14009-A1 discloses cyclic urea fungicides for crop protection. There is a continuing need to develop compounds and processes useful for efficiently preparing these cyclic urea fungicides.
  • This invention provides advantageous processes for preparing compounds of Formula III and compounds of Formula IV which are useful compounds for preparing cyclic urea fungicides.
  • R 3 and R 4 are each independently H; halogen; cyano; nitro; C r C 6 alkyl; C r C (: haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C 2 -C 6 haloalkynyl; C r C 6 alkoxy; C r C 6 haloalkoxy; C 2 -C 6 alkenyloxy; C -C4 alkoxycarbonyl; or C 2 -C 6 alkynyloxy;
  • R 5 is H; or C r C 3 alkyl
  • Lg is halogen; acetoxy; OSO2Q; or OP(OR )2;
  • Q is C ⁇ C 6 alkyl; C]-C 6 haloalkyl; or phenyl optionally substituted with -C3 alkyl;
  • R 16 is C ] -C £ alkyl; C C ⁇ alkenyl; or phenyl.
  • a process for the preparation of a compound of Formula III comprises reacting a compound of Formula IV with a phosgenatmg agent in a suitable solvent.
  • Advantageous processes include those wherein the compounds of Formula IV are reacted with phosgene at a temperature from about 20 to 100°C in a solvent selected from the group consisting of ethyl acetate, toluene, xylenes, tetrahydrofuran, and 1 ,4-dioxane.
  • This invention further provides a process for the preparation of a compound of Formula V.
  • This process uses a compound of Formula V.
  • This process comprises reacting a compound of Formula V with 1 , 1 -dimethylhydrazine in a suitable solvent.
  • Advantageous processes include those wherein the compounds of Formula V are reacted with 1,1 -dimethylhydrazine at a temperature from about 0 to 60°C in a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, toluene, xylenes, and 1 ,4-dioxane.
  • This invention also provides processes for preparing cyclic urea fungicides of Formula I and cyclic urea fungicides of Formula II.
  • R 1 is C r C 6 alkyl; C r C 6 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; 2-C (i haloalkynyl; or C3-C 5 cycloalkyl;
  • R 2 is H; C r C 6 alkyl; C,-C 6 haloalkyl; C r C 6 alkoxy; C r C 6 haloalkoxy; C r C alkylthio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; C 2 -C 6 alkynyl; C -C 6 haloalkynyl, C 3 -C 6 cycloalkyl; C -C 4 alkylcarbonyl, C 2 -C 4 alkoxycarbonyl, cyano; or morphohnyl; Z is C ] -C
  • each nonaromatic or aromatic ring system optionally substituted with one of R 7 , R 8 , or both R 7 and R 8 ; or R 2 and Z are taken together to form CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 ,
  • R 6 is 1-6 halogen; C C 6 alkoxy; C C ⁇ haloalkoxy, C j -C 6 alkylthio; C ⁇ -C 6 haloalkylthio; C r C 6 alkylsulfinyl; C r C 6 alkyisulfonyl; C3-C6 cycloalkyl;
  • R 6 is phenyl, phenoxy, pyridinyl, py ⁇ dinyloxy, thienyl, furanyl, py ⁇ midmyl, or pyrimidinyloxy each optionally substituted with one of R 9 , R 10 , or both R 9 and R 10 ;
  • R 7 is 1-2 halogen; C j -C ⁇ alkyl; C j -C 6 haloalkyl; C j -C ⁇ alkoxy; C j -C 6 haloalkoxy;
  • R 7 is phenyl, benzyl, benzoyl, phenoxy, pyridinyl, pyridmyloxy, thienyl, thienyloxy, furanyl, py ⁇ midinyl, or pyrimidinyloxy each optionally substituted with one of R 9 , R 10 , or both R 9 and R l 0 ;
  • R 8 is halogen, C j -C 4 alkyl; C C 4 haloalkyl, ⁇ -C_> alkoxy, nitro; or cyano; or
  • R 7 and R 8 when attached to adjacent atoms, can be taken together as -OCH 2 O- or
  • a process for the preparation of a compound of Formula II comprises reacting a compound of Formula III in a suitable solvent with an oxime of the formula HONR 2 Z (wherein R 2 and Z are as indicated above) in the presence of a base or with a preformed salt of an oxime of said formula.
  • Advantageous processes include those wherein the compounds of Formula III are reacted with the oxime at a temperature from about 0°C to 100°C in the presence of a base selected from the group consisting of alkali metal alkoxides or inorganic bases in a solvent selected from the group consisting of ethers (e.g., in the presence of NaOH, NaH or potassium t-butoxide in tetrahydrofuran or, preferably, 1 ,4-dioxane).
  • a base selected from the group consisting of alkali metal alkoxides or inorganic bases
  • a solvent selected from the group consisting of ethers (e.g., in the presence of NaOH, NaH or potassium t-butoxide in tetrahydrofuran or, preferably, 1 ,4-dioxane).
  • the compounds of Formula II may be further reacted with a compound of the formula MOR 1 , wherein M is lithium, sodium or potassium and R ⁇ s as defined above, to form compounds of Formula I .
  • M is lithium, sodium or potassium and R ⁇ s as defined above.
  • the processes of this invention as described above may be combined such that fungicidal cyclic urea compounds of Formula II may be prepared from compounds of Formula III, Formula IV, or Formula V; and fungicidal cyclic urea compounds of Formula 1 may be prepared from compounds of Formula II, Formula III, Formula IV or Formula V.
  • This invention also provides novel compounds of Formula III and novel compounds of Formula IV.
  • alkyl used either alone or in compound words such as "haloalkyl” denotes straight-chain or branched alkyl; e.g., methyl, ethyl, / ⁇ -propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkenyl denotes straight-chain or branched alkenes; e.g., 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also denotes polyenes such as 1,3-hexadiene.
  • Alkynyl denotes straight-chain or branched alkynes; e.g., ethynyl, 1-propynyl, 3-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also denote moieties comprised of multiple triple bonds; e.g., 2,4-hexadiync.
  • Alkoxy denotes, for example, methoxy, ethoxy, «-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkynyloxy denotes straight-chain or branched alkynyloxy moieties.
  • halogen either alone or in compound words such as “haloalkyl”, denotes 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 .
  • cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl moieties.
  • nonaromatic heterocyclic ring system includes fully saturated heterocycles and partially aromatic heterocycles.
  • the total number of carbon atoms in a substituent group is indicated by the "C j -Cj" prefix where i and j are numbers from 1 to 10.
  • C ] -C 3 alkyl designates methyl through propyl
  • C 2 alkoxy designates CH 3 CH 2 O
  • C 3 alkoxy designates, for example, CH 3 CH 2 CH 2 O or (CH 3 ) 2 CHO
  • C 2 alkoxycarbonyl designates CH 3 O(O)C.
  • Examples of compounds of Formula III include compounds of Table A below.
  • the compounds of Formula III include compounds where Lg (leaving group) is Cl or Br.
  • Formula III compounds e.g., compounds where R 3 , R 4 and R 5 are all H
  • Lg is neither Cl nor Br.
  • Preferred R 3 groups for Formula III compounds include H, CH 3 , OCH3, Cl and Br.
  • Preferred R 4 groups for Formula III compounds include H, CH3, OCH3, Cl and Br.
  • Preferred R 5 groups for Formula III include H and CH 3 .
  • Preferred Lg groups for Formula III compounds include Cl, Br, acetoxy and OSO 2 CH 3 .
  • Preferred compounds for Formula III include 5-chloro-4-[2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H- l,2,4-triazol-3-one, 4-[2-[(ace.yloxy)methyl]phenyl]-5-chloro-2,4-dihydro-2-methyl-3H- 1,2,4- triazol-3-one, 5-chloro-2,4-dihydro-2-methyl-4-[2- [[(methylsulfonyl)oxy]methyl]phenyl]-3H-l,2,4-triazol-3-one, 4-[2-[(acetyloxy)methyl]- 4-methylphenyl]-5-chloro-2,4-dihydro-2-methyl-3H- 1 ,2,4-triazol-3-one, 5-chloro-2,4- dihydro-2-methyl-4-[4-methyl-2-[[(methylsulfonyl)oxy]methyl]phenyl]-3H-l,2,4-tri
  • Examples of compounds of Formula IV include compounds of Table B below.
  • Preferred R 3 groups for Formula IV compounds include H, CH3, OCH 3 , Cl and Br.
  • R 4 groups for Formula IV compounds include H, CH 3 , OCH 3 , Cl and Br.
  • Preferred R 5 groups for Formula IV compounds include H and CH 3 .
  • Preferred Lg groups for Formula IV compounds include Cl, Br, acetoxy and OSO 2 CH 3 .
  • Preferred compounds for Formula IV include N-[2-(chloromethyl)phenyl]-2,2-dimethylhydrazinecarboxamide, N-[2-[(acetyloxy)methyl]phenyl]-2,2-dimethylhydrazinecarboxamide, 2,2-dimethyl-N-[2- [[(methylsulfonyl)oxy]methyl]phenyl]hydrazinecarboxamide, N-[2-[(acetyloxy)methyl]- 4-methylphenyl]-2,2-dimethylhydrazinecarboxamide, N-[2-[(acetyloxy)methyl]-4- chlorophenyl]-2,2-dimethylhydrazinecarboxamide, N-[4-chloro-2- [[(methylsulfonyl)oxy]methyl]phenyl]-2,2-dimethylhydrazinecarboxamide, N-[2- [(acetyioxy)methyl]-4-bromophenyl]-2,2-dimethylhydrazinecarboxamide
  • R 3 and R 4 are each independently H; halogen; cyano; nitro; C Cg alkyl; C j -C 6 haloalkyl; Co-C 6 alkenyl; C ⁇ - C 6 haloalkenyl; 0 2 -C ⁇ alkynyl; C 2 -Cg haloalkynyl; C j -C 6 alkoxy; C ] -C 6 haloalkoxy; C 2 -C 6 alkenyloxy; or C 2 -C 6 alkynyloxy.
  • reaction steps may be advantageously combined in a series for preparation of the cyclic urea fungicides.
  • one aspect of this invention pertains to a process for preparing compounds of Formula I comprising all four of the following reaction steps: Step 1
  • Step 1 forms compounds of Formula IV by reacting compounds of Formula V with 1 , 1 -dimethylhydrazine in a suitable solvent.
  • Isocyanate compounds of Formula V may be prepared for example, from the reaction of chlorine with otolylisocyanate as described in Synthesis, 376 ( 1978).
  • Other compounds of Formula V can be prepared by the methods of March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, ( 1985). Other methods are also known to the skilled artisan.
  • the reaction temperature is typically from about -20 to 100°C.
  • the temperature is preferably from about 0 to 60°C, and is more preferably from about 0 to 35°C (e.g., 0 to 30°C).
  • the reaction times are typically from about 0.5 to 24 h.
  • the pressure is from about 1 to about 5 atmospheres.
  • suitable solvent for Step 1 a liquid wherein the reactant(s) can be dissolved and the process of Step 1 proceeds.
  • Suitable solvents for Step 1 include polar aprotic solvents such as acetonitrile, dimethylformamide or dimethylsulfoxide; ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether, or 1,4-dioxane; ketones such as acetone or 2-butanone; or acetates such as ethyl acetate; hydrocarbons such as toluene or xylene; or halocarbons such as dichloromethane or chloroform.
  • polar aprotic solvents such as acetonitrile, dimethylformamide or dimethylsulfoxide
  • ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether, or 1,4-dioxane
  • ketones such as acetone or 2-butan
  • the mole ratio of the Formula V compound to dimethylhydrazine is typically from about 1 : 1 to 1 : 10.
  • Preferred Step 1 processes include those using Formula V isocyanate, where the reaction time is from 0.5 to 6 h; the temperature is from 0 to 60°C; the pressure is about 1 atmosphere; the mole ratio of the Formula V isocyanate to 1,1 -dimethylhydrazine is from about 1 : 1 to 1 :5; and the solvent is ethyl acetate, toluene, xylenes, or 1,4-dioxane.
  • Step 1 Particularly preferred for achieving high yields of Formula IV compounds are the processes of Step 1 wherein the reaction time is from about 0.5 to 3 h; the temperature is from about 0 to 35°C (e.g., 0 to 30°C); the pressure is about 1 atmosphere; the mole ratio of isocyanate to 1 , 1 -dimethylhydrazine is about 1 : 1 ; and the solvent is 1 ,4-dioxane or ethyl acetate.
  • the 1,1 -dimethylhydrazine can be added neat, as an aqueous solution or as a salt (e.g., its HC1 salt). Excess 1,1 -dimethylhydrazine can also be used, with the excess discarded or recovered for recycle.
  • the product of Formula IV can be isolated, by for example filtration, or used directly in the next process step without isolation.
  • Examples of the process of Step 1 include the reaction of 2-(chloromethyl)phenyl isocyanate with 1 ,1 -dimethylhydrazine to form N-[2-(chloromethyl)phenyl]-2,2- dimethylhydrazinecarboxamide; the reaction of 2-
  • Step 1 processes for reasons of cost and ease of synthesis include processes for preparing compounds of Formula IV wherein R 3 and R 4 are H, CH 3 , OCH 3 , Br or Cl; R 5 is H or CH 3 ; and Lg is halogen. Particularly preferred are processes for preparing compounds of Formula IV wherein R 3 and R 4 are H; R5 is H; and Lg is chlorine.
  • the reaction conditions e.g., temperature, mole ratio, reaction time and solvent
  • a Step 1 yield based on a Formula V compound reacted to give a Formula IV compound
  • Step 2 a Step 1 yield (based on a Formula V compound reacted to give a Formula IV compound) of at least about 75%, more preferably at least about 85%.
  • Step 2 forms compounds of Formula III by reacting compounds of Formula IV with a phosgenatmg agent (e.g., phosgene) in a suitable solvent
  • a phosgenatmg agent e.g., phosgene
  • phosgenatmg agent a compound having a carbonyl group and chlorine which reacts with the Formula IV compound to undergo cychzation, chlorine addition and demethylation to give Formula III compounds
  • phosgenatmg agents are phosgene, diphosgene, t ⁇ phosgene.
  • the reaction temperature is typically from about 0 to 200°C
  • the temperature is preferably from about 0 to 100°C, and is more preferably from about 20 to 100°C
  • the pressure is from about 1 to 5 atmospheres
  • suitable solvent for Step 2 is meant a liquid wherein the reactant(s) can be dissolved and the process of Step 2 proceeds
  • suitable solvents for Step 2 include polar aprotic solvents such as acetonit ⁇ le, dimethylformamide or dimethylsulfoxide; ethers such as 1 ,4-dioxane, tetrahydrofuran, dimethoxyethane, or diethyl ether; ketones such as acetone or 2-butanone, or acetates such as ethyl acetate, hydrocarbons such as toluene or xylene, or halocarbons such as dichloromethane or chloroform
  • the reaction times are typically from about 0.5
  • the mole ratio of the semicarbazide of Formula IV to the phosgenatmg agent is typically from about 1 :2 to 1 :20.
  • Steps 1 and 2 may be accomplished as separate processes such that the product of Step 1 (I e , the compound of Formula IV) is isolated However, the processes of Step 1 and Step 2 may be combined such that the product of Step 1 is not isolated but reacted with the phosgenatmg agent in a suitable solvent in a second reaction zone (e g , added to a second vessel containing phosgene) to give a product of Formula III
  • Preferred Step 2 processes include those using phosgene as the phosgenatmg agent where the reaction time is from about 1 to 6 h (e g , 2 to 6 h), the temperature is from about 0 to 100°C, the pressure is about 1 atmosphere, the mole ratio of semicarbazide to phosgene is from about 1 1 5 to 1 '5 (e g , 1.2 to 1 5
  • the reaction can be run by simultaneously feeding and maintaining at least two molar equivalents of phosgene and compounds of Formula III into a vessel thereby avoiding the presence of large amounts of hazardous phosgene in the reaction vessel at one time.
  • Compounds of Formula III can be isolated by removing volatiles or used directly in the next process step, preferably after removal of excess unreacted phosgene
  • Preferred Step 2 processes include processes for preparing compounds of Formula III wherein R 3 and R 4 are H, CH 3 , OCH 3 , Br or Cl, R 5 is H or CH 3 , and Lg is Cl, Br, acetoxy or OSO 2 CH 3 .
  • Step 2 includes the reaction of N-[2- (chloromethyl)phenyl]-2,2-d ⁇ methylhydraz ⁇ necarboxam ⁇ de with phosgene to form 5- chloro-4-[2-(chloromethyl)phenyl]-2,4-d ⁇ hydro-2-methyl-3H-l ,2,4-t ⁇ azol-3-one; the reaction of N-[2-[(acetyloxy)methyl]-4-bromophenyl]-2,2- dimethyl hydrazinecarboxamide with phosgene to form 5-chloro-4-[[[2-
  • the reaction conditions e.g , temperature, mole ratio, reaction time and solvent
  • a Step 2 yield based on a Formula IV compound reacted to give a Formula III compound
  • Preferred combined processes include embodiments where the solvent from Step 1 is the same as the solvent from Step 2 (e.g., 1 ,4-dioxane or ethyl acetate)
  • Examples of the combined processes of Step 1 and 2 include the reaction of 2-(chloromethyl)phenyl isocyanate with 1 , 1 -dimethylhydrazine and then the subsequent reaction of the product of that reaction with phosgene to form 5-chloro-4-[2-(chloromethyl)phenyl]-2,4- d ⁇ hydro-2-methyl-3H- l,2,4-t ⁇ azol-3-one; the reaction of
  • Steps 1 and 2 can be combined by reacting 2-(chloromethyl)phenyl isocyanate and 1,1 -dimethylhydrazine in a mole ratio and about 1: 1 to form N-[2- (chloromethyl)phenyl]-2,2-dimethylhydrazinecarboxamide, which is subsequently reacted with at least two molar equivalents of phosgene in the same vessel to form 5-chloro-4- [2-(chloromethyl)phenyl]-2,4-dihydro-2-methyl-3H-l,2,4-triazol-3-one (using a reaction time for combined Steps 1 and 2 within the range from about 0.5 to 5 h; a reaction temperature within the range from about 0 to 100°C; a pressure of about 1 atmosphere; and ethyl acetate or 1,4-dioxane) to achieve a combined Steps 1 and 2 yield of at least about 60% 5-chloro-4-[2-(chloromethyl)phenyl]-2
  • Step 3 forms compounds of Formula II by reacting compounds of Formula III in a suitable solvent with an oxime of the formula HONR 2 Z in the presence of a base, or with a preformed salt of said oxime.
  • Step 3 starting material is prepared using the Step 2 process described above, it is typically separated from other Step 2 material which might adversely influence the Step 3 reaction (e.g., solvents which substantially inhibit the effect of the base).
  • Step 3 reaction e.g., solvents which substantially inhibit the effect of the base.
  • the reaction temperature is typically from about 0 to 200°C.
  • the temperature is preferably from about 0 to 100°C and is more preferably from about 20 to 100°C.
  • the pressure is from about 1 to 5 atmospheres.
  • suitable solvent for Step 3 is meant a liquid wherein the reactant(s) can be dissolved and the process of Step 3 proceeds.
  • suitable solvents for Step 3 include polar aprotic solvents such as acetonitrile, dimethylformamide or dimethylsulfoxide; ethers such as tetrahydrofuran, 1 ,2-dimethoxyethane, diethoxymethane, or dioxane (e.g.
  • 1,4-dioxane 1,4-dioxane
  • diethyl ether ketones such as acetone or 2-butanone
  • acetates such as ethyl acetate
  • hydrocarbons such as toluene or xylene
  • halocarbons such as dichloromethane or chloroform or protic solvents such as methanol, ethanol and water.
  • Suitable bases include alkali metal alkoxides such as potassium tert-butoxide, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, or tertiary amines such as triethylamine, pyridine, 1 ,8-diazabicyclo- [5.4.0]undec-7-ene (DBU), or triethylenedia ine.
  • the reaction times are typically from about 0.5 to 48 h.
  • the mole ratio of the cyclic urea of Formula III to the oxime is typically from about 1: 1 to 1 :3 and the mole ratio of the oxime to the base is typically from about 1 :0.75 to 1 : 10 (e.g., 1 : 1 to 1: 10).
  • Oximes of the formula HONR Z may be prepared from ketones, (e.g., acetophenone and hydroxylamine) using conventional chemistry known to one skilled in the art.
  • Preferred Step 3 processes include those wherein the reaction time is from about 1 to 6 h (e.g., 2 to 6 h); the temperature is from about 0 to 100°C; the pressure is about 1 atmosphere; the mole ratio of cyclic urea to oxime is from about 1 : 1 to 1 :2; the mole ratio of the oxime to base is from about 1 :0.75 to 1:5 (e.g., 1 : 1 to 1:5); the solvent is tetrahydrofuran, dimethylformamide, diethoxymethane, 1 ,2-dimethoxy ethane, acetonitrile, dimethylsulfoxide, dioxane (e.g., 1,4-dioxane), methanol, toluene, water, or a mixture thereof (optionally in the presence of a phase transfer catalyst), and the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or potassium t-butoxide
  • Step 3 Particularly preferred for achieving high yields of Formula II compounds are processes of Step 3 wherein the reaction time is from about 2 to 6 h; the temperature is from about 20 to 100°C; the pressure is about 1 atmosphere; the mole ratio of cyclic urea to oxime is about 1 : 1 ; the mole ratio of the oxime to base is about 1 :0.75 to 1 :5 (e.g., 1: 1 or, more preferably, 1 :0.75); the solvent is tetrahydrofuran or 1,4-dioxane; and the base is sodium hydroxide, potassium hydroxide or sodium hydride.
  • compounds of Formula II can be reacted with a preformed salt of the oxime.
  • Preferred oximes of Formula VI for use in this process include l-[3- (trifluoromethyl)phenyl]ethanone oxime, l-[3,5-(bistrifluoromethyl)phenyl]ethanone oxime, and l -[3,5-dichlorophenyl]ethanone oxime.
  • Examples of the process of Step 3 include the reaction of 5-chloro-4-[2-(chloromethyl)phenyl]-2,4- dihydro-2-methyl-3H-l,2,4-triazol-3-one with -l-[3,5-
  • Step 3 processes for reasons of cost, ease of synthesis, and fungicidal activity are processes for preparing compounds of Formula II wherein R 2 is C ] -C 6 alkyl; Z is an aromatic ring system optionally substituted with one of R 7 , R 8 , or both R 7 and R 8 ; R 5 is H or C r C 3 alkyl; R 7 is 1-2 halogen, C,-C 6 alkyl, C r C 6 haloalkyl, C ⁇ -C 6 alkoxy or C j -Cg haloalkoxy; R 8 is halogen, C ] -C 4 alkyl or C r C 4 haloalkyl; C ] -C 4 alkoxy; R 13 , R 14 , and R 15 are each independently C r C 6 alkyl, C r C 6 alkenyl, C j -C 4 alkoxy or phenyl; and R 3 , and R 4 are as indicated above.
  • R 2 is CH 3 ;
  • Z is aromatic ring system substituted with R 7 , R 8 or both R 7 and R 8 ;
  • R 5 is H; and
  • R 7 is 1-2 halogen or CF 3 ; and
  • R 8 is CF 3 .
  • the reaction conditions e.g., temperature, mole ratio, reaction time, base and solvent
  • a Step 3 yield based on a Formula III compound reacted to give a Formula II compound
  • the product of process Step 3 may be further reacted with a compound of MOR 1 in a suitable solvent. This is illustrated in the process of Step 4.
  • Step 4 forms compounds of Formula I by reacting compounds of Formula II with an alkoxy lating agent of the formula MOR 1 in a suitable solvent.
  • Alkoxylating compounds of the formula MOR 1 are defined above.
  • the reaction temperature is typically from about 0 to 200°C.
  • the temperature is preferably from about 0 to 100°C.
  • the pressure is from about 1 to about 5 atmospheres.
  • suitable solvent for Step 4 is meant, a liquid wherein the reactant(s) can be dissolved and the process of Step 4 proceeds.
  • suitable solvents for Step 4 include ethers such as tetrahydrofuran, dimethoxyethane, diethoxymethane, diethyl ether, or 1,4-dioxane, and alcohols such as methanol, and ethanol.
  • the reaction times are typically from about 0.5 to 48 h.
  • the mole ratio of the coupled product of Formula II to alkoxylating agent is typically from about 1 : 1 to 1 :20.
  • Preferred Step 4 processes include those wherein the reaction time is from about 1 to 6 h (e.g., 2 to 6 h); the temperature is from about 0 to 100°C; the pressure is about 1 atmosphere; the mole ratio of coupled product to alkoxylating agent is from about 1 : 1 to 1:5; the solvent is tetrahydrofuran, methanol, diethoxymethane or 1,4-dioxane; and the alkoxylating agent is sodium methoxide or potassium methoxide.
  • the reaction time is from about 1 to 6 h (e.g., 2 to 6 h); the temperature is from about 0 to 100°C; the pressure is about 1 atmosphere; the mole ratio of coupled product to alkoxylating agent is from about 1 : 1 to 1:5; the solvent is tetrahydrofuran, methanol, diethoxymethane or 1,4-dioxane; and the alkoxylating agent is sodium methoxide or potassium methoxide
  • Step 4 Particularly preferred for achieving high yields of Formula I compounds are processes of Step 4 wherein the reaction time of Step 4 is from about 1 to 6 h (e.g., 2 to 6 h); the temperature is from about 0 to 100°C; the pressure is about 1 atmosphere; the mole ratio of coupled product to alkoxylating agent is about 1 :2, the solvent is tetrahydrofuran or 1 ,4-dioxane; and the alkoxylating agent is sodium methoxide.
  • the methoxide can be preformed or formed in situ, by for example reaction of sodium hydride or sodium hydroxide with methanol.
  • Preferred alkoxylating agents of Formula MOR 1 for use in this process include sodium methoxide and potassium methoxide.
  • Examples of the process of Step 4 include the reaction of sodium methoxide with 5-chloro-2, 4-dihydro-2-methyl-4-[2-[[[[[ l- [3(trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]- 3H- 1 ,2,4-triazol-3-one to form 2,4-dihydro-5-methoxy-2-methyl-4-[2-[[[[[l-[3-trifluoromethyl)phenyl]- ethylidene]amino]oxy]methyl]phenyl]- 3H-l,2,4-tr ⁇ azol-3-one; the reaction of potassium methoxide with 5-chloro-2, 4-dihydro-2-methyl-4-[2-[[[[[l-[3(trifluoromethyl)phenyl]- ethylidene]amino]oxy]methyl]phenyl]- 3H-l,2,4-triazol-3-
  • Step 4 processes for reasons of cost, ease of synthesis, and fungicidal activity are processes for preparing compounds of Formula I wherein R 1 is C j -C 6 alkyl, C r C 6 haloalkyl, C 2 -C 6 alkenyl, C -C 6 haloalkenyl, C -C 6 alkynyl, C 2 -C 6 haloalkynyl or C3-C6 cycloalkyl; R 2 is C1-C alkyl; Z is an aromatic ring system containing 1 to 6 heteroatoms independently selected from the group 1-4 nitrogen, 1-2 oxygen, and 1 -2 sulfur, each nonaromatic or aromatic ring system optionally substituted with one of R 7 , R 8 , or both R 7 and R 8 ; R 5 is H or C r C 3 alkyl; R 7 is 1-2 halogen, C,-C 6 alkyl, C,-C 6 haloalkyl, C C 6 alkoxy or C ]
  • the reaction conditions e g , temperature, mole ratio, reaction time, base and solvent
  • a Step 4 yield based on a Formula II compound reacted to give a Formula I compound
  • Step 3 and Step 4 may be accomplished as separate processes such that the product of Step 3 (I e , the compound of Formula II) is isolated
  • the processes of Step 3 and Step 4 may be combined such that the product of Step 3 is not isolated but is reacted with an alkoxylating agent without isolation (e g , in the same vessel) to give a product of Formula I
  • Steps 3 and 4 can typically be carried out sequentially in the same vessel without isolation of compounds of Formula II by adding alkoxylating agent (e.g , methoxide) to the product of Step 3 in situ, as described in Example 5
  • the reaction conditions e g , temperature, mole ratio, reaction time, base and solvent
  • a combined Step 3 and 4 yield based on a Formula III compound reacted to give a Formula I compound of at least about 60%. more preferably at least about 70%
  • Steps 3 and 4 examples include the reaction of 5- chloro-2, 4-d ⁇ hydro-2-methyl-4-[2-[[[[[l-[3(t ⁇ fluoromethyl)phenyl]- ethyhdene]am ⁇ no]oxy]methyl]phenyl]- 3H-l,2,4-t ⁇ azol-3-one with l -[3-
  • the compounds of Formula II can be provided from the compounds of Formula III in accordance with Step 3, the compounds of Formula III can be provided from the compounds of Formula IV in accordance with Step 2, and the compounds of Formula IV can be provided from the compounds of Formula V in accordance with Step 1. Accordingly, Step 3 can be combined (a) with Step 2 or (b) with both Step 1 and Step 2, as necessary to provide cyclic urea fungicides of Formula II from compounds of Formula III, Formula IV or Formula V; and Step 4 can be combined (a) with Step 3, (b) with both Step 2 and Step 5, or (c) with Step 1 , Step 2, and Step 3, as necessary to provide cyclic urea fungicides of Formula I from compounds of Formula II, Formula III, Formula IV or Formula V.
  • this invention provides a process for the preparation of cyclic urea fungicides of Formula I comprising reacting an isocyanate of Formula V with 1 , 1 -dimethylhydrazine in the presence of a suitable solvent at a temperature of from about -20 to 100°C and a pressure of from about 1 to 5 atmospheres to give a semicarbazide of Formula IV, which is then reacted with an excess of phosgene in a suitable solvent at from about 0 to 200°C and a pressure of from about 1 to 5 atmospheres to give a cyclic urea of Formula III, which is then coupled with an oxime of the formula HONR 2 Z in the presence of a suitable base which has sufficient basicity to form an oxime salt, or with the preformed salt of the oxime of the formula HONR 2 Z and in a suitable solvent at a temperature of from about 0 to 200°C and a pressure of from about 1 to 5 atmospheres to give a compound of Formula II, and then treating a process for
  • the reaction conditions e.g. temperature, mole ratio, reaction time and solvent
  • a combined Step 1, 2 , 3 and 4 yield based on a Formula V compound reacted to give a Formula I compound of at least about 50%, more preferably at least about 60%.
  • 2,4-dihydro-5-methoxy-2-methyl-4-[2-[[[[l-[3- trifluoromethyl)phenyl]-ethylidene]amino]oxy]methyl]phenyl]- 3H- 1 ,2,4-triazol-3-one can be advantageously prepared by reacting 2-(chloromethyl)phenyl isocyanate with 1,1- dimethylhydrazine in a mole ratio of from about 1 : 1 to 1 :5 in a solvent selected from the group consisting of ethyl acetate, toluene, xylenes, and 1 ,4-dioxane at a temperature of from about 0 to 60°C, and the desired product (i.e., N-[2-(chloromethyl)phenyl]-2,2- dimethylhydrazinecarboxamide) can be reacted (with or without isolation) with from about 2 to 5 molar equivalents of phosgene in a solvent
  • the 5-chloro-4-[2- (chloromethyl)phenyl]-2,4-dihydro-2-methyI-3H-l,2,4-triazol-3-one can be recovered and reacted with l-[3-(trifluoromethyl)phenyl] ethanone oxime in the presence of a base selected from the group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and potassium t-butoxide (where the mole ratio of the oxime to base is from about 1.0.75 to 1:5 (e g , 1 1 to 1 5) and the mole ratio of the cyclic urea to oxime is from about 1 : 1 to 1 2) in a solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, diethyoxymethane, 1,2- dimethoxyethane, acetonitrile, dimethylsulfoxide, dioxane (e.g.
  • Step 1 A 250 mL 3-necked round bottom flask is fitted with thermometer, nitrogen by-pass, dropping funnel and magnetic stirrer. The flask is charged with 40 mL of ethyl acetate and 17 83 g of 94% pure 2-(chloromethyl)phenyl isocyanate (0 10 mol) The resultant solution is cooled to approximately 0°C and to this is added dropwise with stirring over approximately 45 min, 6 61 g of 1,1 -dimethylhydrazine (0 1 1 mol) keeping the mixture at approximately 0°C After addition is complete, the resultant slurry is allowed to stir for one hour at approximately 0°C The mixture is suction-filtered through sintered glass and the collected solid is washed one time with cold ethyl acetate (approximately 10 mL) and allowed to dry at room temperature yielding 22 4 g of white solid, m.p 132 5- 134°C (dec), H !
  • a 3-liter 4-necked round-bottomed flask is fitted with overhead stirrer, thermometer, inlet tube and air-cooled reflux condenser capped with a dry ice condenser
  • the dry ice condenser is fitted with a nitrogen bypass
  • the flask is charged with 450 mL of ethyl acetate followed by 74.16 g phosgene (0.75 mol).
  • the mixture is heated to reflux and stirred.
  • 34.17 g of N-[2-(chloromethyl)phenyl]-2,2- dimethylhydrazinecarboxamide (0.15 mol) in 1350 mL ethyl acetate is added over three hours via the inlet tube.
  • the reflux temperature increased from 56 to 72°C during the addition.
  • the mixture is allowed to reflux for one hour, then cooled to room temperature and allowed to stand overnight.
  • the condensers are replaced with a dry ice-cooled distillation head.
  • the mixture is heated to reflux and 1300 mL of a mixture of excess phosgene and ethyl acetate is removed by distillation.
  • the resultant mixture is allowed to cool to room temperature and one liter of hexane is added with stirring. This is filtered through a 2 inch bed of silica gel twice and the silica gel is rinsed with one liter of 30% ethyl acetate in hexanes. These organic filtrates are combined and solvents are removed on the rotary flash evaporator. The residue is triturated with 500 mL of hexanes.
  • Step 3 A 100-mL 2-necked round bottom flask is fitted with thermometer, reflux condenser capped with nitrogen bypass and magnetic stirrer. The flask is charged with 30 mL tetrahydrofuran and 0.22 g 60% sodium hydride in mineral oil (5.5 mmol). To this is added with stirring, 1.02 g l-[3-(trifluoromethyl)phenyl]ethanone oxime (5 mmol) resulting in a vigorous reaction with off-gassing.
  • Steps 3 and 4 A 200 mL 2-necked round bottom flask is fitted with thermometer, reflux condenser capped with nitrogen bypass and magnetic stirrer. The flask is charged with 100 mL of tetrahydrofuran, 1.28 g of 60% sodium hydride in mineral oil (32 mmol). To this is added with stirring 2.03 g of l-[3-(trifluoromethyl)phenyl]ethanone oxime
  • Methyl-3H-1.2.4-Triazol-3-one (Steps 1 and 2) 1 ,1 -Dimethylhydrazine (0.263 mol) was added to a solution of 0.276 moles of 2-(chloromethyl)phenyl isocyanate in 350 mL of 1 ,4-dioxane. The addition required about 10 min and the temperature was kept belwo 35°C by external cooling. The hydrazine addition funnel was rinsed with another 50 mL of 1 ,4-dioxane after the charge. The resulting slurry was then transferred to a second flask which contained 0.934 mol of phosgene dissolved in 600 mL of 1,4-dioxane.

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Abstract

L'invention concerne la préparation de composés de la formule (I), servant à préparer les composés de la formule (II), servant à préparer les composés de la formule (III), servant à préparer les composés de la formule (IV). Dans ces formules, R3 et R4 sont d'une manière indépendante H, halogène, cyano, nitro, C¿1?-C6 alkyle, C1-C6 haloalkyle, C2-C6 alcényle, C2-C6 haloalcényle, C2-C6 alcynyle, C2 C6 haloalcynyle, C1-C6 alcoxy, C1-C6 haloalcoxy, C2-C6 alcényloxy, C2-C4 alcoxycarbonyle ou C2-C6 alcynyloxy; R?5¿ est H ou C¿1?-C3 alkyle, Lg est un halogène, acétoxy, OSO2Q ou (a); Q est C1-C6 alkyle, C1-C6 alcényle ou phényle éventuellement subtitué par C1-C3 alkyle; R?16¿ est C¿1?-C6 alkyle, C1-C6 alcényle ou phényle; et Z, R?1 et R2¿ ont la signification donnée dans la description. L'invention concerne également des voies de synthèse et des conditions opératoires avantageuses, ainsi que les nouveaux composés de la formule (III) et les nouveaux composés de la formule (IV).
EP96944218A 1995-12-01 1996-12-02 Procedes et composes pour preparer des urees cycliques utiles comme fongicides Withdrawn EP0874831A1 (fr)

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US783895P 1995-12-01 1995-12-01
US7838P 1995-12-01
PCT/US1996/019207 WO1997019935A1 (fr) 1995-12-01 1996-12-02 Procedes et composes pour preparer des urees cycliques utiles comme fongicides

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AU677448B2 (en) * 1993-11-19 1997-04-24 E.I. Du Pont De Nemours And Company Fungicidal cyclic amides
AU4869596A (en) * 1995-02-24 1996-09-11 E.I. Du Pont De Nemours And Company Fungicidal cyclic amides
JP2771334B2 (ja) * 1995-05-16 1998-07-02 イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー 殺菌・殺カビ性環状アミド類
WO1996036229A1 (fr) * 1995-05-17 1996-11-21 E.I. Du Pont De Nemours And Company Amides cycliques fongicides
MX9708807A (es) * 1995-05-17 1998-02-28 Du Pont Amidas ciclicas fungicidas.

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