WO2000078712A1 - Substituted arylmalonic acid dinitriles as intermediates for the prepartion of herbicides - Google Patents
Substituted arylmalonic acid dinitriles as intermediates for the prepartion of herbicides Download PDFInfo
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- WO2000078712A1 WO2000078712A1 PCT/EP2000/005477 EP0005477W WO0078712A1 WO 2000078712 A1 WO2000078712 A1 WO 2000078712A1 EP 0005477 W EP0005477 W EP 0005477W WO 0078712 A1 WO0078712 A1 WO 0078712A1
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- 0 CC1(*)C(*)=C(C(C#N)C#N)C(I)=CC(*)=C1 Chemical compound CC1(*)C(*)=C(C(C#N)C#N)C(I)=CC(*)=C1 0.000 description 1
Classifications
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- 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
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/34—Nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/33—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
Abstract
Compounds of formula (I), as intermediates for the preparation of known, herbicidally active 3-hydroxy-4-aryl-5-oxopyrazoline derivatives. A process for their preparation and their use in the preparation of herbicides.
Description
SUBSTITUTED ARYLMALONIC ACID DINITRILES AS INTERMEDIATES FOR THE PREPARATION OF HERBICIDES
The present invention relates to new substituted arylmalonic acid dinitriles as intermediates for a surprisingly advantageous overall process for the preparation of known, herbicidally active 3-hydroxy-4-aryl-5-oxopyrazoline derivatives, to a process for the preparation of those intermediates and to their use in the preparation of 3-hydroxy-4-aryl-5-oxopyrazoline derivatives.
Arylmalonic acid dinitriles and their preparation by means of palladium complexes are described, for example, in Chem. Commun. 1984, 932 and JP-A-60 197 650. Furthermore, J. Am. Chem. Soc. 121 , 1473 (1999) describes the arylation of malonates by means of palladium catalysts.
New substituted arylmalonic acid dinitriles have now been found which are outstandingly suitable as intermediates for an advantageous process for the preparation of herbicidal 3-hydroxy-4-aryl-5-oxopyrazoline derivatives.
The present invention accordingly relates to compounds of formula I
Ro is, each independently of any other, halogen, C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Cι-C6haloalkyl, cyano-C C6alkyl, C2-C6haloalkenyl, cyano-C2-C6alkenyl, C2-C6haloalkynyl, cyano-C2-C6alkynyl, hydroxy, hydroxy-C C6alkyl, CrC-ealkoxy, nitro, amino, Cι- C6alkylamino, di(C C6alkyl)amino, CrCealkylcarbonylamino, CrC6alkylsulfonylamino, C C6alkylaminosulfonyl, C C6alkylcarbonyl, Cι-C6alkylcarbonyl-CrC6alkyl, C C6- alkoxycarbonyl-C C6alkyl, Cι-C6alkylcarbonyl-C2-C6alkenyl, C C6alkoxycarbonyl, C C6alkoxycarbonyl-C2-C6alkenyl, CrC6alkylcarbonyl-C2-C6alkynyl, Cι-C6alkoxycarbonyl-C2- C6alkynyl, cyano, carboxyl, phenyl or an aromatic ring that contains 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the latter two
aromatic rings may be substituted by Cι-C3alkyl, d-C3haloalkyl, Cι-C3alkoxy, d- C3haloalkoxy, halogen, cyano or by nitro; or
R0, together with the adjacent substituents R1 ( R2 and R3, forms a saturated or unsaturated C3-C6hydrocarbon bridge that may be interrupted by 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and/or substituted by d-C alkyl; RL R2 and R3 are, each independently of the others, hydrogen, halogen, Cι-C6alkyl, C2-C6- alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, Cι-C6haloaikyl, C2-C6haloalkenyl, Cι-C6aikoxy- carbonyl-C2-C6alkenyl, d-C6alkylcarbonyl-C2-C6alkenyl, cyano-C2-C6alkenyl, nitro-C2-C6- alkenyl, C2-C6haloalkynyl, Cι-C6alkoxycarbonyl-C2-C6alkynyl, d-C6alkylcarbonyl-C2-C6- alkynyl, cyano-C2-C6alkynyl, nitro-C2-C6alkynyl, C3-C6halocycloalkyl, hydroxy-d-C6alkyl, Ci-Cealkoxy-CrCealkyl, d-C-ealkylthio-d-dalkyl, cyano, C C4alkylcarbonyl, d-C6- alkoxycarbonyl, hydroxy, d-C10alkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, d-C6haloalkoxy, C3-C6haloalkenyioxy, d-Cealkoxy-d-Csalkoxy, mercapto, d-C6alkylthio, d-C6haloalkylthio, d-C6alkylsulfinyl, Cι-C6alkylsulfonyl, nitro, amino, Cι-C6alkylamino, di(Cι-C6alkyl)amino or phenoxy in which the phenyl ring may be substituted by d-C3alkyl, d-C3haloalkyl, d-C3- alkoxy, C C3haloalkoxy, halogen, cyano or by nitro;
R2 also may be phenyl, naphthyl or a 5- or 6-membered aromatic ring that may contain 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by halogen, C3-C8cycloalkyl, hydroxy, mercapto, amino, cyano, nitro or by formyl; and/or the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by d-C6alkyl, d-C6alkoxy, hydroxy-d-C6alkyl, d-Cealkoxy-d-Cealkyl, d-C6- alkoxy-d-C6alkoxy, C C6alkylcarbonyl, d-C6alkylthio, C C6alkylsulfinyl, C C6alkylsulfonyl, mono-d-Cealkylamino, di(Cι-C6alkyl)amino, C C6alkylcarbonylamino, d-C6alkylcarbonyl- (Cι-C6alkyl)amino, C2-C6alkenyl, C3-C6alkenyloxy, hydroxy-C3-C6alkenyl, Cι-C6alkoxy-C2-C6- alkenyl, CrC6alkoxy-C3-C6alkenyloxy, C2-C6alkenylcarbonyl, C2-C6alkenylthio, C2-C6alkenyl- sulfinyl, C2-C6alkenylsulfonyl, mono- or di-(C2-C6alkenyl)amino, d-C6alkyl(C3-C6alkenyl)- amino, C2-C6alkenylcarbonylamino, drCealkenylcarbony d-C-ealky amino, C2-C6alkynyl, C3-C6alkynyloxy, hydroxy-C3-C6alkynyl, CrC6alkoxy-C3-C6alkynyl, d-C6alkoxy-C4-C6- alkynyloxy, C2-C6alkynylcarbonyl, C2-C6alkynylthio, C2-C6alkynylsulfinyl, C2- C6alkynylsulfonyl, mono- or di-(C3-C6alkynyi)amino, Cι-C6alkyl(C3-C6alkynyl)amino, C2- C6alkynylcarbonylamino or by d-Cealkynylcarbony d-Cealky amino; and/or
the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by halo-substituted d-C6alkyl, d-C6alkoxy, hydroxy-d-C6alkyl, C C6alkoxy- Cι-C6alkyl, Cι-C6alkoxy-Cι-C6alkoxy, d-C6alkylcarbonyl, d-C6alkylthio, d-C6alkylsulfinyl, CrC6alkylsulfonyl, mono-d-C6alkylamino, di(C C6alkyl)amino, Cι-C6alkyicarbonyiamino, d-Cealkylcarbony CrCβalky amino, C2-C6alkenyl, C3-C6alkenyloxy, hydroxy-C3-C6alkenyl, C C6alkoxy-C2-C6alkenyl, d-C6alkoxy-C3-C6alkenyloxy, C2-C6alkenylcarbonyl, C2-C6- alkenylthio, C2-C6alkenylsulfinyl, C2-C6alkenylsulfonyl, mono- or di-(C2-C6alkenyl)amino, Cι-C6-alkyi(C3-C6alkenyl)amino, C2-C6alkenylcarbonylamino, C2-C6alkenylcarbonyl(CrC6- alkyl)amino, C2-C6alkynyl, C3-C6alkynyloxy, hydroxy-C3-C6alkynyl, d-Cealkoxy-d-Cealkynyl, d-Cealkoxy-dt-Cealkynyloxy, C2-C6alkynylcarbonyl, C2-C6alkynylthio, C2-C6alkynylsulfinyl, C2-C6alkynylsulfonyl, mono- or di-(C3-C6alkynyl)amino, d-C6alkyl(C3-C6alkynyl)aiTiino, C2-C6alkynylcarbonylamino or C2-C6alkynylcarbonyl(Cι-C6all<yl)amino; and/or the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by a radical of formula COOR50, CONR5ι, SO∑NRssRw or SO2OR55, wherein R50, R51, Rδ2, R5-1, R&4 and R55 are, each independently of the others, d-C6alkyl, C2-C6alkenyl or C3-C6alkynyl or halo-, hydroxy-, alkoxy-, mercapto-, amino-, cyano-, nitro-, alkylthio-, alkylsulfinyl- or alkylsulfonyl-substituted d-C6alkyl, C2-C6alkenyl or C3-C6alkynyl; and n is O, 1 or 2.
In the above definitions, halogen is to be understood as fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The alkyl groups occurring in the substituent definitions are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and the pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl isomers.
Haloalkyl groups preferably have a chain length of from 1 to 6 carbon atoms. Haloalkyl is, for example, fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, dichlorofluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2- fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl or pentafluoroethyl, preferably trichloromethyl, difluorochloromethyl, difluoromethyl, trifluoromethyl or dichlorofluoromethyl.
Alkoxy groups preferably have a chain length of from 1 to 6 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, or a pentyloxy or hexyloxy isomer, preferably methoxy, ethoxy or n-propoxy.
Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoro- ethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy or 2,2,2-trichloroethoxy.
There may be mentioned as examples of alkenyl radicals vinyl, allyl, methallyl, 1 - methylvinyl, but-2-en-1-yl, pentenyl and 2-hexenyl; preferably alkenyl radicals having a chain length of from 3 to 6 carbon atoms.
There may be mentioned as examples of alkynyl radicals ethynyl, propargyl, 1-methyl- propargyl, 3-butynyl, but-2-yn-1-yl, 2-methylbut-3-yn-2-yl, but-3-yn-2-yl, 1 -pentynyl, pent-4- yn-1 -yl and 2-hexynyl; preferably alkynyl radicals having a chain length of from 3 to 6 carbon atoms.
Suitable haloalkenyl radicals include alkenyl groups substituted one or more times by halogen, halogen being in particular bromine or iodine and especially fluorine or chlorine, for example 2- and 3-fluoropropenyl, 2- and 3-chloropropenyl, 2- and 3-bromopropenyl, 2,2- difluoro-1 -methylvinyl, 2,3,3-trifluoropropenyl, 3,3,3-trifluoropropenyl, 2,3,3- trichloropropenyl, 4,4,4-trifluorobut-2-en-1 -yl and 4,4,4-trichlorobut-2-en-1 -yl. Preferred alkenyl radicals substituted once, twice or three times by halogen are those having a chain length of from 3 to 6 carbon atoms. The alkenyl groups may be substituted by halogen at saturated or unsaturated carbon atoms.
Alkoxyalkyl groups have preferably from 1 to 6 carbon atoms. Alkoxyalkyl is, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl or isopropoxyethyl.
Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-tri- fluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy or 2,2,2-trichloroethoxy.
Alkenyloxy is, for example, allyloxy, methallyloxy or but-2-en-1 -yloxy.
Suitable haloalkenyloxy groups include alkenyloxy groups substituted one or more times by halogen, halogen being in particular bromine or iodine and especially fluorine or chlorine, for example 2- and 3-fluoropropenyloxy, 2- and 3-chloropropenyloxy, 2- and 3- bromopropenyloxy, 2,3,3-trifluoropropenyloxy, 2,3,3-trichloropropenyloxy, 4,4,4-trifluorobut- 2-en-1 -yloxy and 4,4,4-trichlorobut-2-en-1-yloxy.
Alkynyloxy is, for example, propargyloxy or 1 -methylpropargyloxy.
Suitable cycloalkyl substituents contain from 3 to 8 carbon atoms and are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. They may be substituted one or more times by halogen, preferably fluorine, chlorine or bromine.
Alkylcarbonyl is especially acetyl or propionyl.
Alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or a butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl isomer, preferably methoxycarbonyl or ethoxycarbonyl.
Alkylthio groups preferably have a chain length of from 1 to 6 carbon atoms. Alkylthio is, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio or hexylthio, or a branched isomer thereof, but is preferably methylthio or ethylthio.
Haloalkylthio is, for example, 2,2,2-trifluoroethylthio or 2,2,2-trichloroethylthio.
Alkylsulfinyl is, for example, methylsulfinyl, ethylsulfinyl, n-propylsuifinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl or ethylsulfinyl.
Alkylsulfonyl is, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.
Alkylamino is, for example, methylamino, ethylamino, n-propylamino, isopropylamino or a butyl-, pentyl- or hexyl-amine isomer.
Dialkylamino is, for example, dimethylamino, methylethylamino, diethylamino, n-propyl- methylamino, dibutylamino or diisopropylamino.
Alkylthioalkyl is, for example, methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthio- ethyl, n-propylthiomethyl, n-propylthioethyl, isopropylthiomethyl or isopropylthioethyl. .
Phenyl and naphthyl in the definition of R2 and phenoxy in the definition of R1f R and R3 may be in substituted form, in which case the substituents may, as desired, be in the ortho-, meta- and/or para-position and, in the case of the naphthyl ring system, in addition in the 5-, 6-, 7- and/or 8-position.
Examples of suitable 5- or 6-membered aromatic rings that contain 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur in the definition of R0 and R2 are pyrrolidyl, pyridyl, pyrimidyl, triazinyl, thiazolyl, triazolyl, thiadiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, furyl, thienyl, pyrazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, indolyl and quinolyl. These heteroaromatic radicals may, in addition, be substituted.
Meanings corresponding to those given hereinbefore can also be ascribed to substituents in composite definitions, such as, for example, alkoxy-alkoxy, alkyl-sulfonylamino, alkyl- aminosulfonyl, phenyl-alkyl, naphthyl-alkyl and heteroaryl-alkyl.
In the definitions for alkylcarbonyl and alkoxycarbonyl, the carbon atom of the carbonyl is not included in the upper and lower limits given for the number of carbons in each particular case.
Preference is given to compounds of formula I wherein n is as defined for formula I; R0 is, each independently of any other, halogen, d-C6alkyl, C C6haloalkyl, hydroxy, d-C6alkoxy, nitro, amino, d-C6alkylamino, di(C1-C6alkyl)amino, d-C6alkylcarbonylamino, d-C6alkyl- sulfonylamino, CrC6alkylaminosulfonyl, d-C4alkylcarbonyl, C C6alkoxycarbonyl or
carboxyl; and R^ R2 and R3 are, each independently of the others, hydrogen, halogen, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, Cι-C6-haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C3-C6halocycloalkyl, d-C6alkoxy-Cι-C6alkyl, d-Cealkylthio-d-C-ealkyl, cyano, d-C4alkylcarbonyl, d-C6alkoxycarbonyl, hydroxy, C C10alkoxy, C3-C6alkenyloxy, C3-C6all<ynyioxy, d-C6haloalkoxy, C3-C6haloalkenyloxy, d-C6alkoxy-Cι-C6alkoxy, mercapto, d-C6alkylthio, d-C6haloalkylthio, d-C6alkylsulfinyl, d-C6alkylsulfonyl, nitro, amino, C C4alkylamino or di(Cι-C4alkyl)amino.
Preference is given also to compounds of formula I wherein R^ R2 and R3 are, each independently of the others, hydrogen, halogen, d-C4alkyl, d-C4haloalkyl, C2-C alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C3-C6cycloalkyl, d-C4alkylcarbonyl, C C6alkoxycarbonyl, hydroxy, d-C4alkoxy, C3- or C4-alkenyloxy, C3- or C4-alkynyloxy, d-C4haloalkoxy, nitro or amino.
Preference is given also to compounds of formula I wherein R, is C2-C6alkyl.
Likewise preferred are compounds of formula I wherein n is 0.
Of those, special preference is given to compounds of formula I wherein R is C2-C4alkyl, d-dalkoxy, C2-C4alkynyl or C3-C6cycloalkyl and R3 is d-C4alkyl, Cι-C4alkoxy, C2-C4alkynyl or C3-C6cycloalkyl.
Likewise preferred are compounds of formula I wherein Rt is C2-C6alkynyl.
Preference is given to those compounds of formula I wherein Ri and R3 are, each independently of the other, C2-C6alkyl, C2-C6alkynyl, d-C10alkoxy or C3-C6cycloalkyl. Of those, special preference is given to compounds wherein R, is C2-C6alkyl and R3 is C2-C6alkyl, C2-C6alkynyl or Cι-Cιoalkoxy.
Chem. Commun. 1984, 932 and JP-A-60 197 650 describe a palladium-catalysed synthesis of arylmalonic dinitriles, in yields of from 56 to 95 %, by C-C linkage of aryl halides - unsubstituted or mono-substituted in the 2- or 4-position - with the malonic dinitrile anion. Mention is made, by way of example, of (PPh3)2PdCI2 and Pd(PPh3)4 as palladium complexes and of tetrahydrofuran as reaction medium, JP-A-60 197 650, which is drafted with a broader scope, also mentioning bis(trialkylphosphine)- and bis(trialkoxy- and
triphenoxy-phosphine)-palladium(ll) chloride complexes and, as reaction media, ethylene glycol dimethyl ether and dimethylformamide. In both documents, the only aryl halides specifically mentioned are unsubstituted or mono-substituted aryl iodides and a bromo- benzene activated in the 4-position by a cyano group.
It has now been found, surprisingly, that the C-C linkage of malonic acid dinitrile with a large group of mono- or poly-substituted aryl derivatives additionally containing a leaving group is feasible in various reaction media in the presence of a wide variety of palladium(ll) or palladium(O) complexes in high product yields and purities.
The present process is distinguished by: a) wide variability of reaction media and reaction conditions, b) high volume concentrations of the reactants (up to 10%), c) a large number of suitable palladium catalysts, d) widely - especially in the 2- and 6-positions - substituted phenyl derivatives as starting compounds, having various leaving groups, including sterically hindered (low-reactivity) leaving groups, e) easy accessibility of the starting compounds, f) the use of catalysts that are either commercially available or easily prepared 'in situ' from commercially available palladium salts, such as, for example, palladium(ll) chloride solution (20 %) in concentrated hydrochloric acid with the addition of dimethyl acetamide (DMA) as solubility promoter, and corresponding ligands, g) a simple reaction procedure, such as, for example, reaction of the 'in situ'-generated malonic acid dinitrile anion and palladium catalyst with an aryl halide or arylsulfonate, h) simple and effective working-up methods that yield the C-C linkage products of formula I in a high degree of purity (Example P17), i) generally very high product yields, and j) economic and ecological advantages derived from the fact that the process can be used as a partial step in a continuous reaction procedure for the preparation of 3-hydroxy-4-aryl-
5-oxopyrazoline derivatives of formula III (Reaction Scheme 3).
The present preparation process is therefore suitable especially for the large-scale preparation of arylmalonic acid dinitrile derivatives of formula I.
The process according to the invention for the preparation of compounds of formula I comprises reacting a compound of formula II
The preparation of compounds of formula I is illustrated in the following Reaction Scheme 1.
Reaction Scheme 1
" (Ro) n
Ra
According to Reaction Scheme 1 , the compounds of formula I are obtained from the compounds of formula II by adding the latter, in a first reaction step, at a temperature of from 0° to 100°C, to a prepared solution of malonic acid dinitrile in a suitable solvent, for example an aromatic hydrocarbon, an ether or dimethyl sulfoxide, e.g. xylene or tetrahydrofuran, and in the presence of a base, for example an alkali metal alcoholate, e.g. sodium tert-butanolate, together with a palladium catalyst, for example a separately prepared palladium catalyst, for example, bis(tricyclohexylphosphine)palladium(ll) dichloride (Pd(PCy3)2CI ). The coupling reaction is started by heating the resulting reaction solution to a temperature of from 30° to 250°C, depending on the solvent used.
Suitable leaving groups X for the C-C linkage reaction of the compound of formula II with the malonic acid dinitrile anion in the presence of palladium catalysts are halogen, R10S(O)2O- (wherein R10 is d-C alkyl, preferably methyl, d-C4haloalkyl, preferably halomethyl or n-C4F9, aryl, preferably phenyl, or phenyl mono- to tri-substituted by halogen, methyl or by halomethyl) and mono-, di- or tri-arylmethoxy.
The aryl radicals of the mono-, di- and tri-arylmethoxy groups are preferably phenyl radicals, which may be substituted for example by methyl from once to three times, the substituents preferably being in the 2-, 4- and/or 6-position of the phenyl ring.
Examples of such leaving groups are methylsulfonyloxy (mesylate), trifluoromethylsulfonyl- oxy (triflate), p-tolylsulfonyloxy (tosylate), CF3(CF2)3S(O)2O- (nonaflate), diphenylmethoxy, di(methylphenyl)methoxy, triphenylmethoxy (trityl) and tri(methylphenyl)methoxy.
Special preference is given to those leaving groups wherein X is chlorine, bromine, iodine, CF3S(O)2O- (triflate), CF3(CF2)3S(O)2O- (nonaflate), p-tolyl-S(O)2O- (tosylate), (C6H5)2CHO-, (CH3-C6H4)2CHO-, (C6H5)3CO- (trityl) or (CH3-C6H4)3CO-. Of those, preference is given more especially to leaving groups wherein X is chlorine, bromine or iodine.
The palladium catalysts suitable for the C-C linkage reaction of the compound of formula II with the malonic acid dinitrile anion are generally palladium(ll) or palladium(O) complexes, such as, for example, palladium(ll) dihalides, palladium(ll) acetate, palladium(ll) sulfate, bis(triphenylphosphine)palladium(ll) dichloride, bis(tricyclopentylphosphine)palladium(ll) dichloride, bis(tricyclohexylphosphine)palladium(ll) dichloride, bis(dibenzylideneacetone)- palladium(O) or tetrakis(triphenylphosphine)palladium(0).
In an especially advantageous variant of the process according to the invention, the palladium catalyst can also be prepared 'in situ' from palladium(ll) or palladium(O) compounds as a result of complexing with the desired ligands, for example by placing the palladium(ll) salt to be complexed, e.g. palladium(ll) dichloride (PdCI2) or palladium(II) acetate (Pd(OAc)2), together with the desired ligand e.g. triphenylphosphine (PPh3) or tricyclohexylphosphine (PCy3) together with the selected solvent, malonic acid dinitrile and base. Palladium(ll) dichloride, as a reasonably priced palladium salt, can advantageously also be used in the form of a 20 % PdCI2-solution in concentrated hydrochloric acid and in the presence of dimethyl acetamide (DMA) as solubility promoter (Examples P4 and P17),
whereas the more expensive palladium(ll) diacetate is substantially soluble, for example, in tetrahydrofuran. The desired ligand is advantageously added to the reaction medium in a molar excess of up to 10, based on the palladium salt. Heating the reaction medium then causes the palladium(ll) or palladium(O) complex desired for the C-C coupling reaction to form 'in situ', which then starts the C-C coupling reaction.
Examples of suitable ligands for palladium(ll) and palladium(O) complexes are trimethyl- phosphine, triethylphosphine, tris(tert-butyl)phosphine, tricyclopentylphosphine, tricyclo- hexylphosphine (PCy3), tri(methylcyclohexyl)phosphine, methyl(tetramethylene)phosphine, tert-butyl(pentamethylene)phosphine, triphenylphosphine (PPh3), tri(methylphenyl)- phosphine, 1 ,2-(diphenylphosphino)cyclohexane, 1 ,2-(diphenylphosphino)cyclopentane, 2,2'-(diphenylphosphino)biphenyl, 1 ,2-bis(diphenylphosphino)ethane, 1 ,3-bis(diphenyl- phosphino)propane, 1 ,4-bis(diphenylphosphino)butane, 3,4-bis(diphenylphosphino)- pyrrolidine, 2,2'-(diphenylphosphino)-bisnaphthalene (BINAP), 1 ,1 '-bis(diphenylphosphino)- ferrocene, 1 ,1'-bis(di-tert-butylphosphino)ferrocene, diphenyl ether bis-diphenylphosphine
dpephos), and , wherein
R10 is hydrogen or dimethylamino, and Rn is cyclohexyl or tert-butyl. These latter electron- rich and sterically bulky diphenyl derivatives are especially suitable phosphine ligands for the preparation of the present specific palladium catalysts, the so-called Buchwald catalysts. These, in turn, are especially suitable for the C-C linkage according to the invention of malonic acid dinitrile with polysubstituted aryl derivatives in combination with alkali metal hydrides or alkali metal phosphates as the base and toluene or xylenes as solvent.
The said ligands and palladium complexes are known and are described in a number of references in the literature, such as, for example, J. Am. Chem. Soc. 121. 4369-4378 (1999), EP-A-0 564 406, EP-A-O 646 590 and 'Palladium Reagents and Catalysts', Editor J. Tsuji, John Wiley & Sons, 1995.
Palladium(O) complexes with mono- and bi-dentate, tertiary or di-tertiary amines, phosphines and arsines as ligands are generally used. The N-, P- and/or As atoms of those ligands may be substituted by identical or different, straight-chain or branched aliphatic radicals containing from 1 to 18 carbon atoms, preferably from 1 to 12 carbon atoms and especially from 1 to 8 carbon atoms.
Also suitable are unsubstituted or d-C4alkyl-substituted C5-C7cycloalkyl, unsubstituted or d-C alkyl-substituted C6-Cιoaryl radicals, especially phenyl and alkylphenyl radicals, and the benzyl radical, which is unsubstituted or substituted by C C alkyl. Two of the aliphatic radicals bound to the hetero atoms N, P and/or As may together form an unsubstituted or d-C4alkyl-substituted C4- or C5-hydrocarbon bridge, thereby forming, together with the hetero atom, a 5- or 6-membered heterocyclic ring. In the case of bidentate ligands, two of the N, P and/or As atoms are (bivalently) linked by way of an aliphatic, unsubstituted or Cι-C4alkyl-substituted C2-C5hydrocarbon chain. The aliphatic, bivalent hydrocarbon chain can optionally be interrupted by 1 or 2 hetero atoms, such as, for example O, N and/or S and/or may be part of a ring or ring system. Preference is given to phosphine ligands, especially basic and sterically bulky phosphine ligands, such as, for example, tricyclohexyl- or tri-tert-butyl-phosphine, because the concentration of the corresponding palladium complexes can then be significantly reduced (by a factor of from 3 to 10) without loss of their catalytic activity.
The palladium catalysts are used in an amount of from 0.001 to 50 mol %, preferably in an amount of from 0.01 to 10 mol % and especially in an amount of from 0.1 to 3 mol %, based on the compound of formula II.
Suitable solvents for the formation of the malonic acid dinitrile anion (Step 1 in Reaction Scheme 1 ) and for the palladium-catalysed C-C linkage reaction with the compound of formula II (Step 2 in Reaction Scheme 1 ) are aliphatic, cycloaliphatic or aromatic hydrocarbons, such as, for example, pentane, hexane, petroleum ether, cyclohexane, methyl- cyclohexane, benzene, toluene and xylenes, aliphatic halohydrocarbons, such as, for example, methylene chloride, chloroform and di- or tetrachlorethane, nitriles, such as, for example, acetonitrile, propionitrile and benzonitrile, ethers, such as, for example, diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran and dioxane, alcohols, such as, for example, methanol, ethanol, propanol, butanol, ethylene glycol, diethylene glycol,
ethylene glycol monomethyl or monoethyl ether and diethylene glycol monomethyl or monoethyl ether, ketones, such as, for example, acetone and methyl isobutyl ketone, esters or lactones, such as, for example, ethyl or methyl acetate and valerolactone, N-substituted lactams, such as, for example, N-methylpyrrolidone (NMP), amides, such as, for example, N,N-dimethylformamide (DMF) and dimethyl acetamide (DMA), acyclic ureas, such as, for example, N,N'-dimethylethylene urea (DMEU), sulfoxides, such as, for example, dimethyl sulfoxide or mixtures of these solvents. Of these, special preference is given to aromatic hydrocarbons, ethers and dimethyl sulfoxide.
Suitable bases for the preparation of the malonic acid dinitrile anion are weakly nucleophilic bases, such as, for example, tri-alkali metal phosphates, alkali metal and alkaline earth metal hydrides, alkali metal and alkaline earth metal amides and alkali metal alcoholates, for example tripotassium phosphate, potassium or sodium tert-butanolate, lithium diisopropyl- amide (LDA) and potassium or sodium hydride. The said bases are preferably used in an excess of from 2 to 10 equivalents, based on malonic acid dinitrile.
Base/solvent combinations especially suitable for producing the malonic acid dinitrile anions (Step 1 in Reaction Scheme 1 ) are, for example, alkali metal alcoholates in aliphatic, cycloaliphatic or aromatic hydrocarbons, for example sodium tert-butanolate in xylene. Combinations of palladium catalysts and leaving groups X in compounds of formula II that are especially suitable for the C-C linkage reaction (Step 2 in Reaction Scheme 1 ) are palladium(ll)-bis(tricycloalkylphosphine) dihalides and halogens, for example palladium(ll)- bis(tricyclohexylphosphine) dichloride and bromide.
Advantageously, the formation of the malonic acid dinitrile anion is carried out at reaction temperatures of from 0° to 100°C, preferably at temperatures of from 20° to 80°C, and the reaction thereof with the compound of formula II in the presence of the palladium catalyst is carried out at reaction temperatures of from 30° to 250°C, preferably from 50° to 200°C and especially from 80° to 160°C, depending on the reaction medium and reaction pressure used.
The C-C coupling reaction of the malonic acid dinitrile anion with a compound of formula II may optionally be carried out at an elevated pressure of from 1.1 to 10 bar. That process in a closed system at an elevated pressure is suitable especially for reactions at temperatures
above the boiling point of the solvent used, for example at temperatures of 140°C in the case of toluene.
Because of the very small amount of (readily decomposable) palladium catalyst used for the C-C linkage reaction, it is advantageously introduced into the reaction mixture under an inert gas atmosphere and at the very end of the sequence of the reagent addition (Step 2 in Reaction Scheme 1 ) (Example P17).
The compounds of formula II wherein X is, for example, halogen are known or can be prepared by known methods, such as, for example, the Sandmeyer reaction, from the corresponding substituted anilines of formula VIII
The compounds of formula II wherein X is, for example, R10S(O)2O- or mono-, di- or tri- arylmethoxy can be prepared by standard methods from the corresponding phenols of formula IX
The substituted anilines of formula VIII either are known or can be prepared by known methods, for example as described in EP-A-0 362 667 via alkylation of anilines using olefins.
Similarly, the substituted phenols of formula IX either are known or can be prepared, for example, from the corresponding anilines of formula VIII or diazonium salts thereof by so- called Phenolic Boiling.
Th e following Reaction Scheme 2 illustrates the possible methods of preparing the compounds of formula II.
Reaction Scheme 2
1) NaN02, H30
2) hydrolysis (Phenolic Boiling), T
The present substituted aryl dinitriles of formula I are in particular used as intermediates for the preparation of substituted 3-hydroxy-4-aryl-5-oxopyrazoline derivatives of formula III
R4 and R5, together with the nitrogen atoms to which they are bonded, form a saturated or unsaturated, 5- to 8-membered heterocyclic ring that 1 ) may be interrupted by oxygen, sulfur or by -NR7- and/or substituted by halogen, d-C10alkyl, C C10haloalkyl, hydroxy, d- C6alkoxy, d-Cealkoxy-d-Cealkoxy, Cι-C6haloalkoxy, mercapto, Cι-C6alkylthio, C3-C7cyclo- alkyl, heteroaryl, heteroaryl-C C6alkyl, phenyl, phenyl-Cι-C6alkyl or by benzyloxy, wherein the phenyl rings of the last 3 substituents may in turn be substituted by halogen, d-C6alkyl, d-Cehaloalkyi, d-C6alkoxy, d-C6haloalkoxy or by nitro, and/or 2) may contain a fused or spiro-bound alkylene or alkenylene chain having from 2 to 6 carbon atoms that is optionally interrupted by oxygen or by sulfur, or at least one ring atom of the saturated or unsaturated heterocyclic ring bridges that alkylene or alkenylene chain; R7 is hydrogen, d-C4alkyl, Cι-C6alkylcarbonyl, Cι-C6alkylsulfonyl, C3-C6alkenyl or C3-C6alkynyl; and G is hydrogen, a metal ion equivalent or an ammonium, sulfonium or phosphonium ion, by either a) hydrolysing a compound of formula I
R6-OH (VII), wherein R6 is d-C6alkyl, d-C6haloalkyl or benzyl, to form the arylmalonic acid ester of formula V
wherein Ro, Ri, R2, R3, Re and n are as defined hereinbefore, or a2) converting that compound, using an acid halide, into the halocarbonylketene of formula X
R6-OH (VII), wherein R6 is as defined hereinbefore, to form a compound of formula V
R6
(Vlb) ,
wherein R4 and R5 are as defined hereinbefore and H»Hal is a hydrogen halide, in an inert organic solvent, optionally in the presence of a base, and then optionally converting the resulting compound of formula III wherein G is a metal ion equivalent or an ammonium cation, by salt conversion into the corresponding salt of formula III wherein G is a sulfonium or phosphonium cation, or by treatment with a Brδnsted acid into the corresponding compound of formula III wherein G is hydrogen.
Meanings corresponding to those given for compounds of formula I can be ascribed to the halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl and halocycloalkyl radicals present in the radicals R4 and R5 in compounds of formula III.
Polyalkoxy-alkyl is, for example, methoxymethoxy-methyl, ethoxymethoxy-methyl, ethoxy- ethoxy-methyl, n-propoxyethoxy-methyl, isopropoxyethoxy-methyl, methoxymethoxy-ethyl, ethoxymethoxy-ethyl, ethoxyethoxy-ethyl, n-propoxyethoxy-methyl, n-propoxyethoxy-ethyl, isopropoxyethoxy-methyl, isopropoxyethoxy-ethyl or (ethoxy)3-ethyl.
Phenyl and naphthyl may be in substituted form, in which case the substituents may, as desired, be in the ortho-, meta- and/or para-position and, in the case of the naphthyl ring system, in addition in the 5-, 6-, 7- and/or 8-position. Preferred positions for the substituents are the ortho- and para-position to the ring attachment point. Phenyl and naphthyl substituents are, for example, C C alkyl, halogen, d-C6haloalkyl, Cι-C6alkoxy, d-C6halo- alkoxy, nitro, cyano, amino, Cι-C4alkylamino and di(d-C alkyl)amino. Heterocyclyl radicals in the definition of R and R5 are preferably 4- to 8-membered rings that contain 1 or 2 hetero atoms, such as, for example, N, S and/or O. They are usually saturated.
Heteroaryl radicals in the definition of R and R5 are usually 5- or 6-membered aromatic heterocycles that preferably contain from 1 to 3 hetero atoms, such as N, S and/or O.
Examples of suitable heterocyclyl and heteroaryl radicals are pyrrolidyl, piperidyl, pyranyl, dioxanyl, azetidyl, oxetanyl, pyridyl, pyrimidyl, triazinyl, thiazolyl, triazolyl, thiadiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazinyl, furyl, thienyl, morpholyl, piperazinyl, pyrazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, indolyl and quinolyl. These heterocycles and heteroaromatic radicals may, in addition, be substituted, for example by halogen, d-C6alkyl, d-C6alkoxy, d-C6haloalkyl, d-C6halogenalkoxy, nitro or by cyano.
Metal ion equivalents, such as, for example, alkali metal or alkaline earth metal ions, and ammonium ions, for the substituent G in the compound of formula III are, for example, the cations of sodium, potassium, magnesium, calcium and ammonium, such as, for example, triethylammonium and methylammonium. Sulfonium cations include, for example, tri(d-C4- alkyl)sulfonium cations and can be obtained, for example, by converting the corresponding alkali metal salts, e.g. with the aid of a cation exchanger.
The substituent definition according to which "R4 and R5, together with the nitrogen atoms to which they are bonded, form a saturated or unsaturated, 5- to 8-membered heterocyclic ring that 1) may be interrupted by oxygen, sulfur or by -NR7- and/or substituted by halogen, d-Cι0alkyl, d-Cι0haloalkyl, hydroxy, C C6alkoxy, d-C-ealkoxy-d-Csalkoxy, d-C6halo- alkoxy, mercapto, C C6alkylthio, C3-C7cycloalkyl, heteroaryl, heteroaryl-Cι-C6alkyl, phenyl, phenyl-d-C6alkyl or by benzyloxy, wherein the phenyl rings of the last 3 substituents may in turn be substituted by halogen, d-C6alkyl, d-Cβhaloalkyl, C C6alkoxy, d-C6haloalkoxy or by nitro, and/or 2) may contain a fused or spiro-bound alkylene or alkenylene chain having from 2 to 6 carbon atoms that is optionally interrupted by oxygen or by sulfur, or at least one ring atom of the saturated or unsaturated heterocyclic ring bridges that alkylene or alkenylene chain" signifies, for example, the following heterocyclic ring systems in the compounds of formula III:
In the above polycyclic ring systems, the abbreviated representation X .nx denotes
the group
The 5- to 8-membered heterocyclic rings that the substituents R4 and R5 together may form and the fused or spiro-bound alkylene or alkenylene chains having from 2 to 6 carbon atoms may, accordingly, be interrupted once or twice by hetero atoms.
The use of compounds of formula I in the preparation of 3-hydroxy-4-aryl-5-oxopyrazoline derivatives of formula III is illustrated in Reaction Scheme 3.
Reaction Scheme 3
The hydrolysis of the arylmalonic dinitriles of formula I to form the arylmalonic acids of formula IV (Reaction Scheme 3, Route a) is carried out according to known standard procedures, such as, for example, by heating at about 50°C for several hours in dilute sulfuric acid.
The subsequent esterification of the resulting arylmalonic acid of formula IV to form the arylmalonic ester of formula V is carried out according to known standard procedures, for example by reaction with an excess of an alcohol of formula VII in the presence of catalytic amounts of acid (Reaction Scheme 3, Route a^.
Alternatively, the arylmalonic acids of formula IV can also be converted into the corresponding halocarbonylketenes of formula X, wherein R0, R^ R2, R3 and n are as defined hereinbefore and Hal is halogen, preferably chlorine or bromine, analogously to WO 97/02243 , using an acid halide, such as, for example, oxalyl chloride, thionyl chloride, thionyl bromide,
phosphorus trichloride, phosphorus pentachloride or phosgene, optionally in the presence of a catalyst, such as, for example, diethylformamide or triphenylphosphine and optionally in the presence of a base, such as, for example, pyridine or triethylamine, at temperatures of from -20°C to 200°C (Reaction Scheme 3, Route a2).
The arylmalonic dinitriles of formula I can also be converted directly into the arylmalonic acid esters of formula V via alcoholysis (Pinner reaction) with an alcohol of formula VII in the presence of catalytic amounts of acid, optionally at an elevated temperature, and subsequent working-up in an aqueous medium (Reaction Scheme 3, Route b). Such alcoholysis reactions are described, for example, in Chem. Rev. 61 , 179 (1961 ).
The condensation of the arylmalonic acid esters of formula V with a hydrazine derivative of formula VI or a salt thereof of formula Via or Vlb is carried out in a manner analogous to that described, for example, in WO 92/16510 or WO 97/02243 in an organic solvent, such as, for example, xylene, optionally in the presence of a base, such as, for example, triethylamine, and yields the desired target compound of formula III (G = H) or a salt thereof (G = alkali metal or alkaline earth metal ion equivalent or ammonium ion) depending on the working-up method and on the base used in the condensation reaction. The corresponding sulfonium and phosphonium salts can be produced by means of salt conversion, for example using a cation exchanger.
The condensation reaction of the compounds of formula V with compounds of formula VI can also be carried out in the absence of a base, whereas the same condensation reaction with compounds of formula Via or Vlb (instead of a compound of formula VI) is advantageously carried out in the presence of a base (in an equimolar amount).
The condensation of the halocarbonylketenes of formula X with a hydrazine derivative of formula VI or a salt thereof of formula Via or Vlb to form compounds of formula III is carried out in a manner analogous to that described, for example, in WO 97/02243, optionally in an organic solvent, such as, for example, toluene or xylene and in the presence of a base, such as an alkaline earth metal carbonate, pyridine or triethylamine, at temperatures of from -20°C to 250°C.
If the starting materials employed are not enantiomerically pure, the compounds of formula III obtained in the above-described process are generally in the form of racemates or diastereoisomeric mixtures which, if desired, can be separated on the basis of their physicochemical properties according to known methods, such as, for example, fractional crystallisation following salt formation with optically pure bases, acids or metal complexes, or by chromatographic procedures, such as, for example, high-pressure liquid chromatography (HPLC) on acetyl cellulose.
Depending on the substituents R0 to R5 and G, the compounds of formula III may be in the form of geometric and/or optical isomers and isomeric mixtures (atropisomers) or as tautomers and tautomeric mixtures.
The compounds of formulae VI, Via and Vlb either are known or can be prepared analogously to known methods as described, for example, in WO 95/00521 and WO 99/47525. The alcohols of formula VII are known.
The Examples that follow further illustrate the invention without limiting it.
Preparation Examples:
Example P1 : Preparation of 2,6-diethyl-4-methylbromobenzene
A solution of 8.83 g (0.128 mol) of sodium nitrite in 200 ml of water is added dropwise, at 4°C, within a period of 4 hours, to a suspension of 20 g (0.1225 mol) of 2,6-diethyl-4- methylaniline in 500 ml of 48 % hydrobromic acid and the brown solution is then heated to 80°C. After stirring for one hour at that temperature, the reaction mixture is cooled to 20°C, diluted with 1 litre of water and extracted 3 times with hexane. The combined organic phases are washed twice with brine, dried over sodium sulfate and concentrated in vacuo at 60°C. 27.5 g of crude product are obtained, purification of which by silica gel chromatography (500 g of silica gel; eluant: hexane) yields 19.89 g (71 % of theory) of the desired target compound in the form of a colourless oil. 1H-NMR (CDCI3): 6.89 ppm (s, 2H); 2.75 ppm (q, 4H); 2.27 ppm (s, 3H); 1.22 ppm (t, 6H).
Example P2: Preparation of 2.6-diethyl-4-methyliodobenzene
100 g of 4-methyl-2,6-diethylaniline and then 480 g of ice are added to a solution of 91.4 ml of sulfuric acid in 370 ml of water. To the resulting reaction solution there are added drop-
wise, at from 0 to 5°C, a solution of 44.6 g of sodium nitrite in 110 ml of water within a period of 45 minutes and, subsequently, a solution of 136.4 g of potassium iodide in 150 ml of water. After stirring for 15 hours at 20°C, the reaction mixture is extracted 3 times with a total of 3 litres of tert-butyl methyl ether (TBME); the combined organic phases are washed once with 8 % hydrochloric acid and water, dried and concentrated. 137.75 g of crude product are obtained, purification of which by distillation (boiling point 125°C/5 mbar) yields 57.8 g of the desired target compound in the form of a colourless liquid. 1H-NMR (CDCI3): 6.90 ppm (s, 2H); 2.75 ppm (q, 4H); 2.30 ppm (s, 3H); 1 .23 ppm (t, 6H).
Example P3: Preparation of 4-methylphenylmalonic acid dinitrile 0.18 g of malonic acid dinitrile is dissolved in 15 ml of xylene and 0.72 g of sodium tert- butanolate is slowly added dropwise to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 0.43 g of 4-bromotoluene and 0.035 g of bis(triphenyl- phosphine)palladium(II) dichloride (Pd(PPh3)2CI2) are then added and further stirring is carried out overnight at an external temperature of 150°C. For working-up, 25 ml of water and 25 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are dried over sodium sulfate and concentrated. 0.72 g of crude product is obtained; its content of desired title compound is determined as 54 % by HPLC (high-pressure liquid chromatography on Nucleosil; eluant: acetonitriie/water + 0.1 % trifluoroacetic acid (TFA)), resulting in a yield of pure compound of 97 % of theory.
Example P4: Preparation of 4-methylphenylmalonic acid dinitrile 0.18 g of malonic acid dinitrile is dissolved in 13 ml of xylene, and 0.72 g of sodium tert- butanolate is slowly added dropwise to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 0.43 g of 4-bromotoluene and 0.2 ml of a concentrated hydrochloric acid solution of 20 % palladium(ll) dichloride (PdCI2) in DMA (about 0.01 mol), and 65 g of triphenylphosphine (PPh3) in 2 ml of xylene are then added. The yellow suspension is stirred overnight at an external temperature of 150°C. For working-up, 25 ml of water and 25 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are dried over sodium sulfate and concentrated. 0.91 g of crude product is obtained; its content of desired title compound is determined as 40.5 % by HPLC (Nucleosil; eluant: acetonitrile/water + 0.1 % trifluoroacetic acid (TFA)), resulting in a yield of pure compound of 97 % of theory.
Example P5: Preparation of 2.4.6-trimethylphenylmalonic acid dinitrile 13.2 g of malonic acid dinitrile are dissolved in 500 ml of tetrahydrofuran, and 12 g of sodium hydride (NaH, 60 %) are slowly added to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 25 g of 2,4,6-mesityl iodide and 0.738 g of palladium(ll)-bis(tricyclohexylphosphine) dichloride (Pd(PCy3)2CI2) are then added and the yellow suspension is further stirred overnight at an external temperature of 80°C. For working-up, 500 ml of water and 500 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are dried over sodium sulfate and concentrated. 32.2 g of crude product are obtained. Purification is carried out by silica gel chromatography (eluant: ethyl acetate/hexane 1/10) and yields 16 g (86 % of theory) of the desired title compound.
Example P6: Preparation of 2,6-diethyl-4-methylphenylmalonic acid dinitrile 0.66 g of malonic acid dinitrile is dissolved in 30 ml of tetrahydrofuran, and 0.6 g of sodium hydride (60 %) is slowly added to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 1.46 g of 2,6-diethyl-4-methyliodobenzene and 0.1 1 g of palladium(II)-bis(tricyclohexylphosphine) dichloride (Pd(PCy3)2CI2) ) are then added and the yellow suspension is further stirred overnight at an external temperature of 80°C. For working-up, 25 ml of water and 25 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are dried over sodium sulfate and concentrated. 1.9 g of crude product are obtained. Purification is carried out by silica gel chromatography (eluant: ethyl acetate/hexane 1/10) and yields 0.62 g (58 % of theory) of the desired title compound. 1 H-NMR (CDCI3): 7.05 ppm (s, 2H); 5.32 ppm (s, 1 H); 2.85 ppm (q, 4H); 2.37 ppm (s, 3H); 1.35 ppm (t, 6H).
Example P7: Preparation of 2.6-diethyl-4-methylphenylmalonic acid dinitrile 0.66 g of malonic acid dinitrile is dissolved in 30 ml of dimethyl sulfoxide (DMSO), and 0.6 g of sodium hydride (60 %) is slowly added to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 1.18 g of 2,6-diethyl-4-methylbromobenzene and 0.07 g of palladium(ll)-bis(tricyclohexylphosphine) dichloride (Pd(PCy3)2CI2) are then added and the yellow suspension is further stirred overnight at an external temperature of 150°C. For working-up, 25 ml of water and 25 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are
dried over sodium sulfate and concentrated. 1.5 g of crude product are obtained. Purification is carried out by silica gel chromatography (eluant: ethyl acetate/hexane 1/10) and yields 0.88 g (83 % of theory) of the desired title compound.
Example P8: Preparation of 2,6-diethyl-4-methylphenylmalonic acid dinitrile 0.18 g of malonic acid dinitrile is dissolved in 15 ml of xylene, and 0.72 g of sodium tert- butanolate is added to the resulting solution. The yellow suspension formed is stirred at 20°C for 1 hour. 0.59 g of 2,6-diethyl-4-methylbromobenzene and 0.035 g of bis(triphenyl- phosphine)palladium(ll) dichloride (Pd(PPh3)2CI2) are then added and the yellow suspension is further stirred overnight at an external temperature of 150°C. For working-up, 25 ml of water and 25 ml of 1 N hydrochloric acid are then added to the reaction mixture and extraction with diethyl ether is carried out. The combined ether phases are dried over sodium sulfate and concentrated. 0.92 g of crude product is obtained. Purification is carried out by silica gel chromatography (eluant: ethyl acetate/hexane 1/10) and yields 0.47 g (89 % of theory) of the desired title compound.
Example P9: Preparation of 4-bromo-2.6-diethylaniline
27 ml (0.5 mol) of bromine in 50 ml of glacial acetic acid are added dropwise, at 10°C, to a solution of 74.6 g (0.5 mol) of 2,6-diethylaniline in 200 ml of glacial acetic acid. Stirring is carried out at 20°C for 1 hour to complete the reaction; the reaction mixture is poured into an ice/water mixture, is rendered alkaline with sodium hydroxide solution and is extracted twice with ethyl acetate. The combined organic phases are washed with sodium thiosulfate solution and with brine, dried over sodium sulfate and concentrated. 112.4 g of crude oil are obtained, purification of which by distillation (boiling point 129-131 °C/1 mbar) yields 92 g
(81 % of theory) of the desired target compound in the form of an oil. H-NMR (CDCI3): 7.07 ppm (s, 2H); 3.60 ppm (broad signal, 2H); 2.50 ppm (q, 4H);
1.25 ppm (t, 6H).
Example P10: Preparation of 4-phenyl-2.6-diethylaniline
912 mg (0.004 mol) of 4-bromo-2,6-diethylaniline, 732 mg (0.006 mol) of phenylboric acid and 1820 mg (0.012 mol) of caesium fluoride (CsF) are placed in 20 ml of degassed dioxane, and a solution of 18 mg (0.00008 mol) of Pd(OAc)2 and 47 mg (0.00012 mol) of (2'-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine in 1 ml of dioxane is added; stirring is carried out at 20°C for 16 hours. The reaction mixture is poured into dilute sodium
hydroxide solution and is extracted twice with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 1.0 g of crude oil is obtained, which is chromatographed over silica gel, resulting in a yield of pure compound of 742 mg (82 % of theory) of an oil.
1H-NMR (CDCI3): 7.55 ppm (m, 2H); 7.39 ppm (m, 2H); 7.25 ppm (m, 1 H); 7.21 ppm (s, 2H); 3.70 ppm (broad signal, 2H); 2.60 ppm (q, 4H); 1.28 ppm (t, 6H).
Example P1 1 : Preparation of 1 ,4-dibromo-2,6-diethylbenzene
5.7 g (0.025 mol) of 4-bromo-2,6-diethylaniline are placed in 10 ml of water and 10 ml of 48 % hydrobromic acid, and 5.25 ml (0.02625 mol) of a 5 molar sodium nitrite solution are added dropwise at about 0CC. Stirring is carried out in an ice bath for 30 minutes and then at 100°C for 45 minutes. The reaction mixture is diluted with water and extracted twice with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 6.48 g of a crude oil are obtained, yielding, after chromatography over silica gel, 3.62 g (50 % of theory) of the desired product in the form of an oil. 1H-NMR (CDCI3): 7.20 ppm (s, 2H); 2.75 ppm (q, 4H); 1.22 ppm (t, 6H).
Example P12: Preparation of 4-(2-pyridv0-1 -bromo-2.6-diethylbenzene 790 mg (0.005 mol) of 2-bromopyridine are placed in 7 ml of tetrahydrofuran at -70°C, and 6.7 ml (0.010 mol) of a 1.5 molar solution of tert-butyllithium in pentane are added dropwise. Stirring is carried out in a CO2 bath for 15 minutes; a solution of 1.12 g (0.005 mol) of zinc bromide in 8 ml of tetrahydrofuran is then added dropwise and the batch is stirred without further cooling. Then, at 20°C, 1.46 g (0.005 mol) of 1 ,4-dibromo-2,6-diethylbenzene and 288 mg (0.00025 mol) of tetrakis(triphenylphenylphosphine)palladium(0) are added and then the batch is stirred at a bath temperature of 60°C for 1.5 hours. The reaction mixture is poured onto saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated. 1.79 g of crude oil are obtained, yielding, after chromatography over silica gel, 700 mg (48 % of theory) of the desired title compound in the form of an oil. 1H-NMR (CDCI3): 7.74 ppm (m, 2H); 7.70 ppm (s, 2H); 7.23 ppm (m, 1 H); 2.87 ppm (q, 4H); 1.30 ppm (t, 6H).
Example P13: Preparation of 4-phenyl-1-bromo-2.6-diethylbenzene (4-bromo-3,5-diethyl- biphenyl)
609 mg (0.0027 mol) of 4-phenyl-2,6-diethylaniline are emulsified in 2 ml of water and, at 0°C, 2 ml of hydrogen bromide solution (48 %) are added. 0.568 ml (0.002842 mol) of 5 molar sodium nitrite solution is then added thereto and stirring is carried out in an ice bath for 30 minutes and then at 100°C for 45 minutes. The reaction mixture is cooled, diluted with ice-water and extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulfate and concentrated. 730 mg of a crude product are obtained, yielding, after chromatography over silica gel, the desired target compound, having a melting point of 72-74°C, in a yield of 347 mg (44 % of theory). 1H-NMR (CDCI3): 7.58 ppm (m, 2H); 7.43 ppm (m, 2H); 7.35 ppm (m, 1 H); 7.28 ppm (s, 2H); 2.87 ppm (q, 4H); 1.28 ppm (t, 6H).
Example P14: Preparation of 2,6-diethyl-4-phenylphenylmalonic acid dinitrile 84 mg (0.00128 mol) of malonic acid dinitrile are dissolved in 7 ml of degassed xylene, 84 mg (0.00349 mol) of sodium tert-butanolate are added and stirring is carried out at 20°C for 30 minutes. 336 mg (0.00116 mol) of 4-phenyl-1-bromo-2,6-diethylbenzene and 16.3 mg (0.0000232 mol) of bis(triphenylphosphine)palladium(ll) dichloride are then added and stirring is carried out at 150°C for 17 hours. The reaction mixture is poured into ice-water acidified with hydrochloric acid and is extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried over sodium sulfate and concentrated. The desired title compound is obtained in a yield of 315 mg (99 % of theory). 1H-NMR (CDCI3): 7.35-7.50 ppm (m, 3H); 7.40 ppm (s, 2H); 5.35 ppm (s, 1 H); 2.93 ppm (q, 4H); 1.39 ppm (t, 6H).
Analogously to the Examples hereinbefore, the following compounds (Examples P15 and
P16) are also obtained:
2.6-diethyl-4-,2-pyridvD-phenylmalonic acid dinitrile. 1H-NMR (CDCI3): 8.72 ppm (m, 1 H);
7.82 ppm (s, 2H); 7.77 ppm (m, 2H); 7.28 ppm (m, 1 H); 5.37 ppm (s, 1 H); 2.95 ppm (q, 4H);
1 .41 ppm (t, 6H), and
2.6-dimethyl-4-(4-pyridyl)-phenylmalonic acid dinitrile. 1H-NMR (CDCI3): 8.70 ppm (d, 2H);
7.47 ppm (d, 2H); 7.40 ppm (s, 2H); 5.39 ppm (s, 1 H); 2.64 ppm (s, 6H).
Example P17: Preparation of 2,6-diethyl-4-methyl-phenyl-malonic acid dinitrile 198.8 g (2.06 mol) of sodium tert-butanolate and 600 ml of xylene are placed in a 2.5 litre sulfonation flask having an internal thermometer, argon gas connection and reflux condenser or distillation head and then, at 60°C, a melt of 50.4 g (0.76 mol) of malonic acid dinitrile is added to the resulting solution, the reaction temperature increasing to 103°C. About 50 ml of the tert-butanol formed are distilled off at 80°C within a period of 70 minutes under a gentle stream of argon gas and then 496 g of 2,6-diethyl-4-methylbromobenzene (31.4 % in xylene) are added at the same temperature. The reaction solution is then heated at 130°C for 2 hours.
At the same time, 1.98 g of tricyclohexylphosphine are placed in a separate 100 ml round- bottom flask under argon gas; a mixture of 35 ml of dry xylene and 27 ml of N,N-dimethyl acetamide (DMA) is introduced by syringe and the resulting solution is degassed. 0.73 g of a 20 % palladium(ll) chloride solution (cone, hydrochloric acid) is then added by syringe and the resulting yellow suspension is stirred at 20°C for 1 hour. The catalyst solution prepared in that manner is introduced into the above reaction solution at 105°C by syringe and the suspension formed is then stirred at from 120 to 130°C for 2 hours. A sample analysed by gas chromatography shows 100 % reaction without by-products or starting materials. For working-up, the reaction mixture is cooled to 40°C and 800 ml of ice/water mixture are added. The aqueous phase (about 1.4 litres) is separated off and 365 ml of water/xylene mixture are distilled off using a rotary evaporator. The aqueous phase is then cooled further to 15°C and subsequently 142 g of 32 % hydrochloric acid solution are added so that the pH-value is from 5 to 5.5. The crystalline crude product precipitates out and can readily be filtered off and then washed with 250 ml of water. The resulting 163 g (1 12 % of theory) of crude product are dried overnight in a vacuum drying cabinet at 60°C, yielding 143.8 g (99 % of theory) of the desired title compound having a purity of 98.8 %.
Claims
1. A compound of formula I
R0 is, each independently of any other, halogen, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, d-C6haloalkyl, cyano-Cι-C6alkyl, C2-C6haioalkenyi, cyano-C2-C6alkenyl, C2-C6haloalkynyl, cyano-C2-C6alkynyl, hydroxy, hydroxy-C -C6alkyl, Cι-C6alkoxy, nitro, amino, d- C6alkylamino, di(d-C6alkyl)amino, d-C6alkylcarbonylamino, Cι-C6alkylsulfonylamino, d- C6alkylaminosulfonyl, d-C6alkylcarbonyl, Cι-C6alkylcarbonyl-Cι-C6alkyl, C C6alkoxycarbonyl-Cι-C6alkyl, Cι-C6alkylcarbonyl-C2-C6alkenyl, CrC6alkoxycarbonyl, Ci- C6alkoxycarbonyl-C2-C6alkenyl, d-C6alkylcarbonyl-C2-C6alkynyl, Cι-C6alkoxycarbonyl-C2- C6alkynyl, cyano, carboxyl, phenyl or an aromatic ring that contains 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the latter two aromatic rings may be substituted by d-C3alkyl, C C3haloalkyl, C C3alkoxy, d- C3haloalkoxy, halogen, cyano or by nitro; or
R0, together with the adjacent substituents R1 f R2 and R3, forms a saturated or unsaturated C3-C6hydrocarbon bridge that may be interrupted by 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur and/or substituted by C C4alkyl; Ri, R and R3 are, each independently of the others, hydrogen, halogen, C C6alkyl, C2-C6- alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, d-C6haloalkyl, C2-C6haloalkenyl, d-C6alkoxy- carbonyl-C2-C6alkenyl, Cι-C6alkylcarbonyl-C2-C6alkenyl, cyano-C2-C6alkenyl, nitro-C2-C6- alkenyl, C2-C6haloalkynyl, Cι-C6alkoxycarbonyl-C2-C6alkynyl, d-C6alkylcarbonyl-C2-C6- alkynyl, cyano-C2-C6alkynyl, nitro-C2-C6alkynyl, C3-C6halocycloalkyl, hydroxy-C C6alkyl, Cι-C6alkoxy-Cι-C6alkyl, d-C6alkylthio-Cι-C6alkyl, cyano, C C4alkylcarbonyl, d-C6- alkoxycarbonyl, hydroxy, d-Cι0alkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, d-C6haloalkoxy, C3-C6haloalkenyloxy, Cι-C6alkoxy-Cι-C6alkoxy, mercapto, d-C6alkylthio, d-C6haloalkylthio, Cι-C6alkylsulfinyl, d-C6alkylsulfonyl, nitro, amino, d-C6alkylamino, di(C C6alkyl)amino or phenoxy in which the phenyl ring may be substituted by d-C3alkyl, d-C3haloalkyl, C1-C3- alkoxy, d-C3haloalkoxy, halogen, cyano or by nitro;
R2 also may be phenyl, naphthyl or a 5- or 6-membered aromatic ring that may contain 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by halogen, C3-C8cycloalkyl, hydroxy, mercapto, amino, cyano, nitro or by formyl; and/or the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by d-C6alkyl, d-C6alkoxy, hydroxy-d-C6alkyl, d-Cealkoxy-CrCealkyl, d-C6- alkoxy-d-C6alkoxy, d-C6alkylcarbonyl, d-C6alkylthio, d-C6alkylsulfinyl, d-C6alkylsulfonyl, mono-Cι-C6alkylamino, di(Cι-C6alkyl)amino, d-C6alkylcarbonylamino, d-C6alkylcarbonyl- (Cι-C6alkyl)amino, C2-C6alkenyl, C3-C6alkenyloxy, hydroxy-C3-C6alkenyl, d-C6alkoxy-C2-C6- alkenyl, Cι-C6alkoxy-C3-C6alkenyloxy, C2-C6alkenylcarbonyl, C2-C6alkenylthio, C2-C6alkenyl- sulfinyl, C2-C6alkenylsulfonyl, mono- or di-(C2-C6alkenyl)amino, Cι-C6alkyl(C3-C6alkenyl)- amino, C2-C6alkenylcarbonylamino, C2-C6alkenylcarbonyl(Cι-C6alkyl)amino, C2-C6alkynyl, C3-C6alkynyloxy, hydroxy-C3-C6alkynyl, CrC6alkoxy-C3-C6alkynyl, d-C6alkoxy-C4-C6- alkynyloxy, C2-C6alkynylcarbonyl, C2-C6alkynylthio, C2-C6alkynylsulfinyl, C2- C6alkynylsulfonyl, mono- or di-(C3-C6alkynyl)amino, Cι-C6alkyl(C3-C6alkynyl)amino, C2- C6alkynylcarbonylamino or by C2-C6alkynylcarbonyl(Cι-C6alkyl)amino; and/or the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by halo-substituted d-C6alkyl, d-C6alkoxy, hydroxy-Cι-C6alkyl, d-C6alkoxy- d-C6alkyl, CrCealkoxy-CrCealkoxy, C C6alkylcarbonyl, d-C6alkylthio, d-C6alkylsulfinyl, Cι-C6alkylsulfonyl, mono-d-Cealkylamino, di(Cι-C6alkyl)amino, d-C6alkylcarbonylamino, Cι-C6alkylcarbonyl(Cι-C6alkyl)amino, C2-C6alkenyl, C3-C6alkenyloxy, hydroxy-C3-C6alkenyl, Cι-C6alkoxy-C2-C6alkenyl, Cι-C6alkoxy-C3-C6alkenyloxy, C2-C6alkenylcarbonyl, C2-C6- alkenylthio, C2-C6alkenylsulfinyl, C2-C6alkenylsulfonyl, mono- or di-(C2-C6alkenyl)amino, d-C6-alkyl(C3-C6alkenyl)amino, C2-C6alkenylcarbonylamino, C2-C6alkenylcarbonyl(Cι-C-6- alkyl)amino, C2-C6alkynyl, C3-C6alkynyloxy, hydroxy-C3-C6alkynyl, Cι-C6alkoxy-C3-C6alkynyl, Cι-C6alkoxy-C4-C6alkynyloxy, C2-C6alkynylcarbonyl, C2-C6alkynylthio, C2-C6alkynylsulfinyl, C2-C6alkynylsulfonyl, mono- or di-(C3-C6alkynyl)amino, Cι-C6alkyl(C3-C6alkynyl)amino, C2-C6alkynylcarbonylamino or C2-C6alkynylcarbonyl(Ci-C6alkyl)amino; and/or the phenyl ring, the naphthyl ring system and the 5- or 6-membered aromatic ring may be substituted by a radical of formula COOR50, CONR51, SOuNRsaR^ or SO2OR55, wherein R50, R51, R52, R53, RM and R55 are, each independently of the others, d-C6alkyl, C2-C6alkenyl or C3-C6alkynyl or halo-, hydroxy-, alkoxy-, mercapto-, amino-, cyano-, nitro-, alkylthio-, alkylsulfinyl- or alkylsulfonyl-substituted d-C6alkyl, C2-C6alkenyl or C3-C6alkynyl; and n is O, 1 or 2.
2. A compound according to claim 1 , wherein R0 is, each independently of any other, halogen, d-C6alkyl, d-C6haloalkyl, hydroxy, C C6alkoxy, nitro, amino, d-C6alkylamino, di- (Cι-C6alkyl)amino, d-C6alkylcarbonyiamino, Cι-C6alkylsulfonylamino, d-C6alkylamino- sulfonyl, Cι-C4alkylcarbonyl, C C6alkoxycarbonyl or carboxyl; and R1 ( R2 and R3 are, each independently of the others, hydrogen, halogen, C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, d-C6-haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C3-C6halocycloalkyl, d-Ceaikoxy-CrCealkyl, Cι-C6alkylthio-Cι-C6alkyl, cyano, C C4alkylcarbonyl, Cι-C6alkoxy- carbonyl, hydroxy, Cι-Cιoalkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, d-C6haloalkoxy, C3-C6- haloalkenyloxy, Cι-C6alkoxy-Cι-C6alkoxy, mercapto, C C6alkylthio, C C6haloalkylthio, C C6alkylsulfinyl, C C6alkylsulfonyl, nitro, amino, C C4alkylamino or di(Cι-C4alkyl)amino.
3. A compound according to claim 2, wherein R1 ( R2 and R3 are, each independently of the others, hydrogen, halogen, Cι-C4alkyl, C C4haloalkyl, C2-C4alkenyl, C2-C haloalkenyl, C2-C4alkynyl, C3-C6cycloalkyl, d-C4alkylcarbonyl, d-C6alkoxycarbonyl, hydroxy, C C4- alkoxy, C3- or C4-alkenyloxy, C3- or C4-alkynyloxy, C C4haloalkoxy, nitro or amino.
4. A compound according to claim 1 , wherein Ri is C2-C6alkyl.
5. A compound according to claim 1 , wherein n is 0.
6. A compound according to claim 5, wherein Ri is C2-C4alkyl, Cι-C4alkoxy, C2-C4alkynyl or C3-C6cycloalkyl and R3 is Cι-C4alkyl, C C4alkoxy, C2-C4alkynyl or C3-C6cycloalkyl.
7. A compound according to claim 1 , wherein Ri is C2-C6aikynyl.
8. A compound according to claim 1 , wherein Ri and R3 are, each independently of the other, C -C6alkyl, C2-C6alkynyl, CrCι0alkoxy or C3-C6cycloalkyl.
9. A compound according to claim 8, wherein Ri is C2-C6alkyl and R3 is C2-C6alkyl, C2-C6- alkynyl or Cι-Cιoalkoxy.
10. A process for the preparation of a compound of formula I according to claim 1 , which comprises reacting a compound of formula II
11. A process according to claim 10, wherein in the compound of formula II X is halogen, R10S(O)2O- (wherein R10 is methyl, halomethyl, n-C4F9, phenyl or phenyl mono- to tri- substituted by halogen, methyl or by halomethyl) or mono-, di- or tri-arylmethoxy.
12. A process according to claim 11 , wherein X is chlorine, bromine, iodine, CF3S(O)2O- (triflate), CF3(CF2)3S(O)2O- (nonaflate), p-tolyl-S(O)2O- (tosylate), (C6H5)2CHO-, (CH3-C6H4)2CHO-, (C6H5)3CO- (trityl) or (CH3-C6H4)3CO-.
13. A process according to claim 12, wherein X is chlorine, bromine or iodine.
14. A process according to claim 10, wherein a palladium(ll) or palladium(O) complex is used as palladium catalyst.
15. A process according to claim 14, wherein a palladium(II) dihalide, palladium(ll) acetate, palladium(ll) sulfate, bis(triphenylphosphine)palladium(ll) dichloride, bis(tricyclopentyl- phosphine)palladium(ll) dichloride, bis(tricyclohexylphosphine)palladium(ll) dichloride, bis- (dibenzylideneacetone)palladium(O) or tetrakis(triphenylphosphine)palladium(0) is used as palladium catalyst.
16. A process according to claim 10, wherein the palladium catalyst is prepared 'in situ' from a palladium(ll) or palladium(O) compound by complexing with the desired ligand.
17. A process according to claim 10, wherein the palladium catalyst is used in an amount of from 0.001 to 50 mol %, preferably from 0.01 to 10 mol % and especially from 0.1 to
3 mol %, based on the compound of formula II.
18. A process according to claim 10, wherein an aliphatic, cycloaliphatic or aromatic hydrocarbon, aliphatic halohydrocarbon, nitrile, ether, alcohol, ketone, ester or lactone, N-substituted lactam, amide, acyclic urea, sulfoxide or a mixture of these solvents is used as solvent.
19. A process according to claim 18, wherein an aromatic hydrocarbon, an ether or dimethyl sulfoxide is used.
20. A process according to claim 10, wherein a tri-alkali metal phosphate, alkali metal or alkaline earth metal hydride, alkali metal or alkaline earth metal amide, or alkali metal alcoholate is used as the base.
21. A process according to claim 20, wherein the base is used in an equivalent amount or in an excess of from 2 to 10 equivalents, based on malonic acid dinitrile.
22. A process according to claim 10, wherein the formation of the malonic acid dinitrile anion is carried out at a temperature of from 0° to 100°C and the reaction thereof with the compound of formula II is carried out at a reaction temperature of from 30° to 250°C.
23. A process according to claim 10, wherein the reaction of the malonic acid dinitrile anion with a compound of formula II is carried out at an elevated pressure of from 1.1 to 10 bar.
24. The use of a compound of formula I according to claim 1 as an intermediate in the preparation of a substituted 3-hydroxy-4-aryl-5-oxopyrazoline derivative of formula III 
wherein R0, Ri, R2, R3 and n are as defined in claim 1 , and R4 and R5 are, each independently of the other, hydrogen, Cι-C12alkyl, Cι-C12haloalkyl, C2-C8alkenyl, C2-C8- alkynyl, d-Cι0alkoxy-Cι-C8alkyl, poly-Cι-Cι0alkoxy-Cι-C8alkyl, Cι-Cιoalkylthio-C C8alkyl, C3-C8cycloalkyl, C3-C8halocycloalkyl, 4- to 8-membered heterocyclyl, phenyl, ct- or β-naphthyl, phenyl-d-C6alkyl, oc- or β-naphthyl-Cι-C6alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl-Cι-C6alkyl, wherein the aromatic and heteroaromatic rings may be substituted by halogen, C C6alkyl, d-C6haloalkyl, d-C6alkoxy, Cι-C6haloalkoxy, nitro or by cyano, or
R4 and R5, together with the nitrogen atoms to which they are bonded, form a saturated or unsaturated, 5- to 8-membered heterocyclic ring that 1) may be interrupted by oxygen, sulfur or by -NR7- and/or substituted by halogen, d-Cι0alkyl, C Cι0haloalkyl, hydroxy, C C6alkoxy, d-C6alkoxy-Cι-C6alkoxy, d-C6haloalkoxy, mercapto, d-Cealkylthio, C3-C7cyclo- alkyl, heteroaryl, heteroaryl-Cι-C6alkyl, phenyl, phenyl-d-C6alkyl or by benzyloxy, wherein the phenyl rings of the last 3 substituents may in turn be substituted by halogen, Cι-C6alkyl, d-C-ehaioalkyl, d-C6alkoxy, d-C6haloalkoxy or by nitro, and/or 2) may contain a fused or spiro-bound alkylene or alkenylene chain having from 2 to 6 carbon atoms that is optionally interrupted by oxygen or by sulfur, or at least one ring atom of the saturated or unsaturated heterocyclic ring bridges that alkylene or alkenylene chain; R7 is hydrogen, d-dalkyl, Cι-C6alkylcarbonyl, d-C6alkylsulfonyl, C3-C6alkenyl or C3-C6alkynyl; and G is hydrogen, a metal ion equivalent or an ammonium, sulfonium or phosphonium ion, which comprises either a) hydrolysiπg a compound of formula I
H
R6-OH (VII), wherein R6 is d-C6alkyl, C C6haloalkyl or benzyl, to form the arylmalonic acid ester of formula V
b) subjecting a compound of formula I 
wherein R0, Ri, R2, R3 and n are as defined hereinbefore, to alcoholysis directly with a compound of formula VII
R6-OH (VII), wherein R6 is as defined hereinbefore, to form a compound of formula V
R
- 2(H Hal) (Vlb) , 
wherein R4 and R5 are as defined hereinbefore and H»Hal is a hydrogen halide, in an inert organic solvent, optionally in the presence of a base, and then optionally converting the resulting compound of formula III wherein G is a metal ion equivalent or an ammonium cation, by salt conversion into the corresponding salt of formula III wherein G is a sulfonium or phosphonium cation, or by treatment with a Brόnsted acid into the corresponding compound of formula III wherein G is hydrogen.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MXPA01012485A MXPA01012485A (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the prepartion of herbicides. |
| AU56822/00A AU5682200A (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the preparation of herbicides |
| BR0011700-5A BR0011700A (en) | 1999-06-16 | 2000-06-14 | Dinitriles of arylmalonic acid substituted as intermediates for the preparation of herbicides |
| PL00352102A PL352102A1 (en) | 1999-06-16 | 2000-06-14 | Novel semi-finished products |
| KR1020017016087A KR20020012274A (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the preparation of herbicides |
| JP2001504881A JP2003502403A (en) | 1999-06-16 | 2000-06-14 | New intermediate |
| CA002368827A CA2368827A1 (en) | 1999-06-16 | 2000-06-14 | New intermediates |
| IL14633700A IL146337A0 (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the preparation of herbicides |
| EP00942072A EP1185506A1 (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the preparation of herbicides |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1121/99 | 1999-06-16 | ||
| CH112199 | 1999-06-16 |
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| WO2000078712A1 true WO2000078712A1 (en) | 2000-12-28 |
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| PCT/EP2000/005477 WO2000078712A1 (en) | 1999-06-16 | 2000-06-14 | Substituted arylmalonic acid dinitriles as intermediates for the prepartion of herbicides |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1185506A1 (en) |
| JP (1) | JP2003502403A (en) |
| KR (1) | KR20020012274A (en) |
| CN (1) | CN1355786A (en) |
| AR (1) | AR029165A1 (en) |
| AU (1) | AU5682200A (en) |
| BR (1) | BR0011700A (en) |
| CA (1) | CA2368827A1 (en) |
| HU (1) | HUP0201486A2 (en) |
| IL (1) | IL146337A0 (en) |
| MX (1) | MXPA01012485A (en) |
| PL (1) | PL352102A1 (en) |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001017972A2 (en) * | 1999-09-07 | 2001-03-15 | Syngenta Participations Ag | Novel herbicides |
| WO2001017973A2 (en) * | 1999-09-07 | 2001-03-15 | Syngenta Participations Ag | Novel herbicides |
| WO2004050607A1 (en) * | 2002-12-05 | 2004-06-17 | Syngenta Participations Ag | Process for the preparation of phenylmalonic acid dinitriles |
| WO2006084663A1 (en) | 2005-02-09 | 2006-08-17 | Syngenta Participations Ag | Process for the preparation of intermediates |
| EP2218710A1 (en) | 2004-11-04 | 2010-08-18 | Bayer CropScience AG | Procedure for the preparation of 2,6-diethyl-4-methylphenylacetic acid |
| WO2010102761A1 (en) | 2009-03-12 | 2010-09-16 | Bayer Cropscience Aktiengesellschaft | Method for producing aromatic chlorine and bromine compounds |
| US7915199B1 (en) | 1999-09-07 | 2011-03-29 | Syngenta Crop Protection, Inc. | Herbicidal composition |
| WO2018015489A1 (en) | 2016-07-22 | 2018-01-25 | Syngenta Participations Ag | Process for the preparation of phenylmalonic acid dinitriles |
| WO2018184196A1 (en) | 2017-04-07 | 2018-10-11 | 泸州东方农化有限公司 | Method for preparing 2-arylmalonamide and applications of method |
| WO2018210616A1 (en) | 2017-05-15 | 2018-11-22 | Bayer Cropscience Aktiengesellschaft | Process for producing (4-halogeno-2,6-dialkylphenyl)malononitriles |
| CN110950778A (en) * | 2019-12-24 | 2020-04-03 | 安徽省化工研究院 | Process and catalyst system for preparing aromatic malononitrile |
| WO2020199081A1 (en) | 2019-04-01 | 2020-10-08 | 泸州东方农化有限公司 | Method for preparing 2-arylmalonic acid derivative, intermediate, and application thereof |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| US11970507B2 (en) | 2021-09-29 | 2024-04-30 | Oriental (Luzhou) Agrochemicals Co., Ltd. | Method for preparing 2-arylmalonic acid derivative and intermediate, and use thereof |
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| JP2021527691A (en) * | 2018-06-22 | 2021-10-14 | バイエル・アクチエンゲゼルシヤフト | Method for producing tricyclic compound |
| CN109320435B (en) * | 2018-11-30 | 2021-11-23 | 江苏富鼎化学有限公司 | Synthesis method of 2- (2, 6-diethyl-4-methylbenzene) malononitrile |
| CN109627184A (en) * | 2019-01-04 | 2019-04-16 | 浙江中山化工集团股份有限公司 | A kind of preparation method of 2,6- diethyl -4- aminomethyl phenyl malononitrile |
| CN110218153A (en) * | 2019-07-10 | 2019-09-10 | 江苏丰山集团股份有限公司 | A kind of preparation method of midbody compound 2,6- diethyl -4- methylbenzene malonate |
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2000
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- 2000-06-14 AU AU56822/00A patent/AU5682200A/en not_active Abandoned
- 2000-06-14 WO PCT/EP2000/005477 patent/WO2000078712A1/en not_active Application Discontinuation
- 2000-06-14 IL IL14633700A patent/IL146337A0/en unknown
- 2000-06-14 CN CN00808905A patent/CN1355786A/en active Pending
- 2000-06-14 BR BR0011700-5A patent/BR0011700A/en not_active Application Discontinuation
- 2000-06-14 JP JP2001504881A patent/JP2003502403A/en active Pending
- 2000-06-14 CA CA002368827A patent/CA2368827A1/en not_active Abandoned
- 2000-06-14 EP EP00942072A patent/EP1185506A1/en not_active Withdrawn
- 2000-06-14 KR KR1020017016087A patent/KR20020012274A/en not_active Application Discontinuation
- 2000-06-14 MX MXPA01012485A patent/MXPA01012485A/en unknown
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2001
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Also Published As
| Publication number | Publication date |
|---|---|
| AR029165A1 (en) | 2003-06-18 |
| PL352102A1 (en) | 2003-07-28 |
| KR20020012274A (en) | 2002-02-15 |
| BR0011700A (en) | 2002-03-05 |
| EP1185506A1 (en) | 2002-03-13 |
| MXPA01012485A (en) | 2002-06-04 |
| ZA200109838B (en) | 2002-09-25 |
| AU5682200A (en) | 2001-01-09 |
| CN1355786A (en) | 2002-06-26 |
| IL146337A0 (en) | 2002-07-25 |
| CA2368827A1 (en) | 2000-12-28 |
| HUP0201486A2 (en) | 2002-08-28 |
| JP2003502403A (en) | 2003-01-21 |
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