WO2006087221A1 - Process for the production of nitrobenzoles - Google Patents

Process for the production of nitrobenzoles Download PDF

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WO2006087221A1
WO2006087221A1 PCT/EP2006/001506 EP2006001506W WO2006087221A1 WO 2006087221 A1 WO2006087221 A1 WO 2006087221A1 EP 2006001506 W EP2006001506 W EP 2006001506W WO 2006087221 A1 WO2006087221 A1 WO 2006087221A1
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formula
compounds
nitrophenyl
reaction
compound
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Harald Walter
Camilla Corsi
Josef Ehrenfreund
Clemens Lamberth
Hermann Schneider
Hans Tobler
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Syngenta Participations AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a process for the preparation of 2-(2-nitrophenyl)-bicyclo- propanes, and to novel nitrobenzene intermediates for use in that process.
  • 2-(2-Aminophenyl)-bicyclopropanes such as, for example, unsubstituted 2-(2-aminophenyl)- bicyclopropane, are valuable intermediates for the preparation of ortho-bicyclopropyl- carboxanilide fungicides, such as are described, for example, in WO 03/074491.
  • 2-(2- Aminophenyl)-bicyclopropanes can be prepared in simple manner from the 2-(2-nitrophenyl)- bicyclopropanes on which they are based, for example by reduction under reaction conditions such as are described in WO 03/074491 for the reduction of 2-(2-nitrophenyl)- cyclopropanes.
  • a second route is by way of application of the Simmons-Smith reaction (Zn/Cu, CH 2 I 2 with ether as solvent) to 1-((E/Z)-2-cyclopropylvinyl)-2-nitrobenzenes.
  • the reaction has been found to be unsuitable for the preparation of 2-(2-nitrophenyl)-bicyclo- propanes, since the reactivity of the double bond is too low.
  • the aim of the present invention is therefore to provide a process for the preparation of 2-(2- nitrophenyl)-bicyclopropanes that allows such compounds to be prepared in an economically advantageous manner in high yields and in good quality.
  • the present invention accordingly relates to a process for the preparation of compounds of formula I
  • Ri, R 2 and R 3 are each independently of the others hydrogen or methyl, which comprises a) reaction of a compound of formula Il
  • R 1 , R 2 and R 3 are as defined for formula I, either a1 ) with triphenylphosphine dibromide or triphenylphosphine dichloride or a2) with RSO 2 CI, wherein R is C r C 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or Ci-C 6 alkylphenyl, in the presence of a base, to form a compound of formula III
  • X is bromine, chlorine or OSO 2 R, wherein R is CrC 4 alkyl, d-C 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC 6 alkylphenyl, and R 1 , R 2 and R 3 are as defined for formula I; and b) conversion of that compound in the presence of a base into a compound of formula I.
  • Ortho-bicyclopropylcarboxanilide fungicides are generally chiral molecules that occur in isomeric forms. Accordingly they exist as trans/cis isomers based on the substitution pattern of the cyclopropyl ring linked directly to the benzene ring. It is known that the fungicidal activity of compounds such as are described, for example, in WO 03/074491 , can be influenced by the stereochemistry. It has been found in the case of the ortho-bicyclopropyl- carboxanilide fungicides described therein that the trans isomers generally have higher fungicidal activity. The development of a process that enables the production of. a marked excess of trans ortho-bicyclopropylcarboxanilide fungicides is therefore extremely desirable.
  • ortho-bicyclopropylcarboxanilide fungicides can also be prepared without the use of 2-(2-nitrophenyl)-bicyclopropanes as intermediates.
  • 2-(2-nitrophenyl)-bicyclopropanes 2-(2-nitrophenyl)-bicyclopropanes
  • ketones of formula (A), wherein R 3 may be, inter alia, unsubstituted or substituted cyclopropyl are reacted, for example, first with bromine and methanol and then with triphenylphosphine.
  • the compounds of formula (B) obtained are converted in a two-step reaction into compounds of formula (C) wherein Hal is bromine or iodine (first, reaction with sodium hydride, then reaction with 2-bromobenzaldehyde or 2-iodobenzaldehyde, respectively).
  • reaction sequence described in WO 03/074491 yields a transrcis ratio of the 2-(2-aminophenyl)-bicyclopropane isomers of about 2:1.
  • a further aim of the present invention is accordingly to provide a process for the preparation of 2-(2-nitrophenyl)-bicyclopropanes having a significantly higher proportion of trans isomers.
  • R 1 , R 2 and R 3 are each independently of the others hydrogen or methyl and wherein the ratio of compounds of formula Ia (trans)
  • alkyl groups in the definitions of the substituents may be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl and branched isomers thereof.
  • Halogen in the context of halophenyl is generally fluorine, chlorine, bromine or iodine.
  • Fluoroalkyl groups having a chain length of from 1 to 4 carbon atoms are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifIuoroethyl, 1 -fluoroethyl, 2-fluoroethyl, 2- fluoroprop-2-yl, pentafluoroethyl, 2,2,3,3-tetrafluoroethyl, pentafluoroethyl or heptafluoro-n- propyl; fluoroalkyl groups are preferably trichloromethyl, fluoromethyl, dichlorofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or heptafluoro-n-propyl.
  • the process according to the invention includes the preparation of those stereoisomeric forms of formulae l ⁇ , Iu, Im and hv, wherein R 1 , R 2 and R 3 are as defined for formula I, and the preparation of mixtures of those stereoisomeric forms in any ratio.
  • compounds of formula Ia (trans)
  • R 1 , R 2 and R 3 are as defined for formula I, are understood to be compounds of formula l ⁇ , wherein R 1 , R 2 and R 3 are as defined for formula I; compounds of formula Iu, wherein R 1 , R 2 and R 3 are as defined for formula I; or a mixture, in any ratio, of compounds of formula l ⁇ , wherein R 1 , R 2 and R 3 are as defined for formula I, and compounds of formula In, wherein R 1 , R 2 and R 3 are as defined for formula I.
  • R 1 , R 2 and R 3 are as defined for formula I, are understood to be, preferably, a racemic mixture of compounds of formula I 1 , wherein R 1 , R 2 and R 3 are as defined for formula I, and compounds of formula In, wherein R 1 , R 2 and R 3 are as defined for formula I.
  • R 1 , R 2 and R 3 are as defined for formula I, are understood to be compounds of formula Im, wherein R 1 , R 2 and R 3 are as defined for formula I; compounds of formula hv, wherein R 1 , R 2 and R 3 are as defined for formula I; or a mixture, in any ratio, of compounds of formula Im, wherein R 1 , R 2 and R 3 are as defined for formula I, and compounds of formula hv, wherein R 1 , R 2 and R 3 are as defined for formula I.
  • compounds of formula Ib (cis) wherein Ri, R 2 and R 3 are as defined for formula I, are understood to be, preferably, a racemic mixture of compounds of formula Im, wherein Ri, R 2 and R 3 are as defined for formula I, and compounds of formula hv, wherein R 1 , R 2 and R 3 are as defined for formula I.
  • a "racemic mixture” of two enantiomers is understood to be a mixture of the two enantiomers in a ratio substantially equal to 1 :1.
  • the process according to the invention is suitable more especially for the preparation of compounds of formula I wherein R 1 , R 2 and R 3 are hydrogen.
  • the process according to the invention is suitable more especially for the preparation of compounds of formula I wherein R 1 is methyl and R 2 and R 3 are hydrogen.
  • a compound of formula Il is reacted with triphenylphosphine dibromide or triphenylphosphine dichloride.
  • triphenylphosphine dibromide or triphenylphosphine dichloride is added directly to the compounds of formula II, or triphenylphosphine dibromide or triphenylphosphine dichloride is generated in situ in the reaction mixture by the addition of bromine or chlorine in the presence of triphenylphosphane.
  • Suitable amounts of triphenylphosphine dibromide or triphenylphosphine dichloride for that reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.5 equivalents.
  • an amount, for example, of from 1 to 3 equivalents, especially from 1 to 1.5 equivalents, of bromine or chlorine is suitable.
  • Suitable amounts of triphenylphosphane for that variant of the reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.5 equivalents.
  • the reaction can be carried out in the presence of an inert solvent.
  • suitable solvents are, for example, ethers, for example tetrahydrofuran or dioxane, or CH 3 CN, and mixtures thereof; CH 3 CN is preferred.
  • Temperatures are generally from -20 0 C to 80 0 C, with a range from -2O 0 C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
  • reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours:
  • a compound of formula Il is reacted in the presence of a base with RSO 2 CI, wherein R is Ci-C 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or Ci-C 6 alkylphenyl, especially d-C 4 alkyl, more especially methyl.
  • RSO 2 CI wherein R is C r C 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or d-C 6 alkylphenyl, are, for example, from 1 to 3 equivalents, especially from 1 to 1.2 equivalents.
  • Suitable bases are, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (H ⁇ nig's base), tri-n-butylamine, N,N-dimethylaniline or N-methylmorpholine, or inorganic bases, such as carbonates, e.g. K 2 CO 3 or Na 2 CO 3 , or hydroxides, e.g. NaOH or KOH, with preference being given to trialkylamines and special preference being given to triethylamine.
  • trialkylamines e.g. trimethylamine, triethylamine, diisopropylethylamine (H ⁇ nig's base), tri-n-butylamine, N,N-dimethylaniline or N-methylmorpholine
  • inorganic bases such as carbonates, e.g. K 2 CO 3 or Na 2 CO 3
  • hydroxides e.g. NaOH
  • Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.3 equivalents.
  • the reaction is preferably carried out in the presence of an inert solvent.
  • Suitable solvents are, for example, dichloromethane, pyridine or ethers, for example tetrahydrofuran, and mixtures thereof, with preference being given to dichloromethane or pyridine, and special preference being given to dichloromethane.
  • Temperatures are generally from -20 0 C to 80 0 C, with a range from -20 0 C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
  • the reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • the resulting compounds of formula Vl can be reacted to form compounds of formula Il by addition of sodium borohydride in a protic solvent R b OH, wherein R b is Ci-C 6 alkyl, such as, for example, isopropanol.
  • R b is Ci-C 6 alkyl, such as, for example, isopropanol.
  • Compounds of formula IV, wherein Xi is chlorine or bromine, are known and are obtainable commercially.
  • Suitable bases for Process Step b) are, for example, nitrogen-containing organic bases, such as, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (H ⁇ nig's Base), or tri-n-butylamine, N,IM-dimethylaniIine or N-methyl- morpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, such as, for example, lithium, sodium or potassium alcoholates, especially methanolates, ethanolates or butanolates, or inorganic bases, such as hydroxides, e.g. NaOH or KOH, or hydrides, such as, for example, NaH.
  • tertiary amines such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (H ⁇ nig's Base), or tri-n-but
  • Bases to which preference is given are hydroxides, especially KOH, hydrides, especially NaH, or alkali metal alcoholates, especially potassium tert-butanolate.
  • Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1.1 to 1.8 equivalents.
  • the reaction is preferably carried out in the presence of an inert solvent.
  • suitable solvents are, for example, alcohols, such as methanol, ethanol, propanol or isopropanol, or aprotic solvents, such as tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methyl- pyrrolidone or dimethyl sulfoxide, and also mixtures thereof; dimethyl sulfoxide or dimethylformamide is especially preferred.
  • Temperatures are generally from 0 0 C to 80 0 C, with a range from 0 0 C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
  • the reaction time for the reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • the compound of formula ill obtained in Reaction Step a) can be converted directly to a compound of formula I without isolation of intermediates. That reaction procedure is a particular advantage of the process according to the invention.
  • the process according to the invention is suitable for the preparation of compounds of formula I, wherein R 1 , R 2 and R 3 are each independently of the others hydrogen or methyl, very especially by a) reaction of a compound of formula II, wherein R 1 , R 2 and R 3 are each independently of the others hydrogen or methyl, with RSO 2 CI, wherein R is C r C 4 alkyl, in the presence of triethylamine in a temperature range of from -20°C to 25°C, using dichloromethane as solvent, to form a compound of formula III, wherein X is OSO 2 -C 1 -C 4 alkyl and R 1 , R 2 and R 3 are as defined for formula I; and b) conversion of that compound into a compound of formula I in the presence of a base selected from KOH, NaH and potassium tert-butanolate, in a temperature range of from -20 0 C to 25 0 C, using a solvent selected from dimethyl sulfoxide and dimethylformamide.
  • An intermediate especially suitable for the preparation of compounds of formula I is the compound of formula III wherein X is OSO 2 CH 3 and R 1 , R 2 and R 3 are hydrogen.
  • the 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.17 g of potassium hydroxide (2.48 mmol) is added, and stirring is carried out for 5 hours at ambient temperature.
  • the reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15).
  • Example P2 Preparation of 2-(2-nitrophenyl)-bicvclopropane: A mixture of 0.5 g of 1 -cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5°C and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1 -Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
  • the 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethylformamide and 0.21 g of potassium hydroxide (3.2 mmol) is added, and stirring is carried out for 6 hours at ambient temperature.
  • the reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclopropane (61 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
  • Example P3 Preparation of 2-(2-nitrophenyl)-bicvclopropane: A mixture of 2.21 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (10 mmol), 1.21 g of triethyiamine (12 mmol) and 20 ml of dichloromethane is cooled to a temperature of 5°C and 1.26 g of methanesulfonic acid chloride (11 mmol), dissolved in 5 ml of dichloromethane, are added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
  • Example P4 Preparation of 2-(2-nitrophenvD-bicvclopropane: A mixture of 0.5 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethyiamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5°C and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-CycIopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
  • the 1-cyclopropyi-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.28 g of potassium tert-butanolate (2.48 mmol) is added, and stirring is carried out for 3 hours at ambient temperature.
  • the reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.3 g of 2-(2-nitrophenyl)-bicyclopropane (65 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.7:1).
  • the starting materials for the process of the present invention are distinguished by ease of availability and good handling properties and are moreover reasonably priced.
  • a further advantage of the process is that the ratio of trans isomers of formula Ia to cis isomers of formula Ib at the 2-(2-nitrophenyl)-bicyclopropane Step is sufficiently high for 2-(2- aminophenyl)-bicyclopropanes having a trans:cis ratio significantly higher than described in the prior art to be prepared by simple subsequent conversion reactions, such as, for example, reduction reactions. Generally, trans:cis ratios of the prepared 2-(2-nitrophenyl)- bicyclopropanes of more than 3:1 are achieved.
  • compounds of formula I can be prepared in simple manner wherein the ratio of compounds of formula Ia (trans) to compounds of formula Ib (cis) is from 3:1 to 5:1.

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Abstract

The present invention relates to a process for the preparation of compounds of formula (I) wherein the substituents are as defined in claim 1, by reaction of a compound of formula (II) wherein the substituents are as defined in claim 1, either a1) with triphenylphosphine dibromide or triphenylphosphine dichloride or a2) with RSO2CI, wherein R is C1C4alkyl, C1-C4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or C1-C6alkylphenyl, in the presence of a base, to form a compound of formula (III) wherein the substituents are as defined in claim 1 ; and conversion of that compound in the presence of a base into a compound of formula I, and also to novel nitrobenzene intermediates for use in that process.

Description

Process for the production of nitrobenzoles
The present invention relates to a process for the preparation of 2-(2-nitrophenyl)-bicyclo- propanes, and to novel nitrobenzene intermediates for use in that process.
2-(2-Aminophenyl)-bicyclopropanes, such as, for example, unsubstituted 2-(2-aminophenyl)- bicyclopropane, are valuable intermediates for the preparation of ortho-bicyclopropyl- carboxanilide fungicides, such as are described, for example, in WO 03/074491. 2-(2- Aminophenyl)-bicyclopropanes can be prepared in simple manner from the 2-(2-nitrophenyl)- bicyclopropanes on which they are based, for example by reduction under reaction conditions such as are described in WO 03/074491 for the reduction of 2-(2-nitrophenyl)- cyclopropanes.
The preparation of 2-(2-aminophenyl)-bicyclopropanes using 2-(2-nitrophenyl)-bicyclo- propane intermediates is described in WO 03/074491 with reference to two possible routes. A first route is by way of nitration of bicyclopropyl-benzenes. It has been found, however, that the reaction is not workable in view of the fact that the cyclopropyl ring linked directly to the benzene ring has increased reactivity in bicyclopropyl-benzenes with respect to electrophiles. A second route is by way of application of the Simmons-Smith reaction (Zn/Cu, CH2I2 with ether as solvent) to 1-((E/Z)-2-cyclopropylvinyl)-2-nitrobenzenes. In that case, too, the reaction has been found to be unsuitable for the preparation of 2-(2-nitrophenyl)-bicyclo- propanes, since the reactivity of the double bond is too low.
The aim of the present invention is therefore to provide a process for the preparation of 2-(2- nitrophenyl)-bicyclopropanes that allows such compounds to be prepared in an economically advantageous manner in high yields and in good quality.
The present invention accordingly relates to a process for the preparation of compounds of formula I
Figure imgf000003_0001
wherein Ri, R2 and R3 are each independently of the others hydrogen or methyl, which comprises a) reaction of a compound of formula Il
Figure imgf000004_0001
wherein R1, R2 and R3 are as defined for formula I, either a1 ) with triphenylphosphine dibromide or triphenylphosphine dichloride or a2) with RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or Ci-C6alkylphenyl, in the presence of a base, to form a compound of formula III
Figure imgf000004_0002
wherein X is bromine, chlorine or OSO2R, wherein R is CrC4alkyl, d-C4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, and R1, R2 and R3 are as defined for formula I; and b) conversion of that compound in the presence of a base into a compound of formula I.
Ortho-bicyclopropylcarboxanilide fungicides are generally chiral molecules that occur in isomeric forms. Accordingly they exist as trans/cis isomers based on the substitution pattern of the cyclopropyl ring linked directly to the benzene ring. It is known that the fungicidal activity of compounds such as are described, for example, in WO 03/074491 , can be influenced by the stereochemistry. It has been found in the case of the ortho-bicyclopropyl- carboxanilide fungicides described therein that the trans isomers generally have higher fungicidal activity. The development of a process that enables the production of. a marked excess of trans ortho-bicyclopropylcarboxanilide fungicides is therefore extremely desirable.
It is known that ortho-bicyclopropylcarboxanilide fungicides can also be prepared without the use of 2-(2-nitrophenyl)-bicyclopropanes as intermediates. For example, in WO 03/074491 a process for the preparation of 2-(2-aminophenyl)-bicyclopropane intermediates is described that uses 2-(2-halophenyl)-bicyclopropanes (see Scheme 1):
Scheme 1 :
Figure imgf000005_0001
(F) (D)
(E)
According to WO 03/074491, ketones of formula (A), wherein R3 may be, inter alia, unsubstituted or substituted cyclopropyl, are reacted, for example, first with bromine and methanol and then with triphenylphosphine. The compounds of formula (B) obtained are converted in a two-step reaction into compounds of formula (C) wherein Hal is bromine or iodine (first, reaction with sodium hydride, then reaction with 2-bromobenzaldehyde or 2-iodobenzaldehyde, respectively). Compounds of formula (C) can be converted into the corresponding 2-(2-halophenyl)-bicyclopropanes (D) by Kishner cyclisation, which proceeds by way of a Δ2-pyrazoline. For that purpose, compounds of formula (C) are reacted, with heating, with hydrazine, as a result of which the corresponding Δ2-pyrazolines are formed. Subsequently, potassium hydroxide is added for isomerisation, and renewed heating is carried out to remove N2. 2-(2-Halophenyl)-bicyclopropanes (D) can be aminated in a two- step reaction to form the corresponding 2-(2-aminophenyl)-bicyclopropanes (F). For that purpose, first of all benzophenone imine, sodium tert-butanolate, tris(dibenzylideneacetone)- dipalladium (Pd2dba3) and racemic 2,2'-bis(diphenylphosphine)-1 ,1'-binaphthyl (BINAP) are - A -
added. The resulting imines (E) are reacted in the second reaction step, for example with hydroxylamine and sodium acetate, to form the corresponding 2-(2-aminophenyl)- bicyclopropanes (F).
The reaction sequence described in WO 03/074491 (Scheme 1) yields a transrcis ratio of the 2-(2-aminophenyl)-bicyclopropane isomers of about 2:1.
In the conversion of the 2-(2-nitrophenyl)-bicyclopropanes into 2-(2-aminophenyl)- bicyclopropanes by reduction, the ratio of those cis/trans isomers to one another is essentially unaffected.
A further aim of the present invention is accordingly to provide a process for the preparation of 2-(2-nitrophenyl)-bicyclopropanes having a significantly higher proportion of trans isomers.
The process according to the invention allows compounds of formula I
Figure imgf000006_0001
to be produced wherein R1, R2 and R3 are each independently of the others hydrogen or methyl and wherein the ratio of compounds of formula Ia (trans)
(Ia, trans)
Figure imgf000006_0002
to compounds of formula Ib (cis)
Figure imgf000006_0003
is more than 2:1. The alkyl groups in the definitions of the substituents may be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl and branched isomers thereof.
Halogen in the context of halophenyl is generally fluorine, chlorine, bromine or iodine.
Fluoroalkyl groups having a chain length of from 1 to 4 carbon atoms are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifIuoroethyl, 1 -fluoroethyl, 2-fluoroethyl, 2- fluoroprop-2-yl, pentafluoroethyl, 2,2,3,3-tetrafluoroethyl, pentafluoroethyl or heptafluoro-n- propyl; fluoroalkyl groups are preferably trichloromethyl, fluoromethyl, dichlorofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or heptafluoro-n-propyl.
Compounds of formula I occur in various stereoisomeric forms, which are represented by formulae \u Iu, Im and I|V:
Figure imgf000007_0001
The process according to the invention includes the preparation of those stereoisomeric forms of formulae lι, Iu, Im and hv, wherein R1, R2 and R3 are as defined for formula I, and the preparation of mixtures of those stereoisomeric forms in any ratio. In the context of the present invention, compounds of formula Ia (trans)
(Ia, trans),
Figure imgf000008_0001
wherein R1, R2 and R3 are as defined for formula I, are understood to be compounds of formula lι, wherein R1, R2 and R3 are as defined for formula I; compounds of formula Iu, wherein R1, R2 and R3 are as defined for formula I; or a mixture, in any ratio, of compounds of formula lι, wherein R1, R2 and R3 are as defined for formula I, and compounds of formula In, wherein R1, R2 and R3 are as defined for formula I.
In the context of the present invention, compounds of formula Ia (trans)
(Ia, trans),
Figure imgf000008_0002
wherein R1, R2 and R3 are as defined for formula I, are understood to be, preferably, a racemic mixture of compounds of formula I1, wherein R1, R2 and R3 are as defined for formula I, and compounds of formula In, wherein R1, R2 and R3 are as defined for formula I.
In the context of the present invention, compounds of formula Ib (cis)
wherein R1, R2 and R3 are as defined for formula I, are understood to be compounds of formula Im, wherein R1, R2 and R3 are as defined for formula I; compounds of formula hv, wherein R1, R2 and R3 are as defined for formula I; or a mixture, in any ratio, of compounds of formula Im, wherein R1, R2 and R3 are as defined for formula I, and compounds of formula hv, wherein R1, R2 and R3 are as defined for formula I.
In the context of the present invention, compounds of formula Ib (cis)
Figure imgf000009_0001
wherein Ri, R2 and R3 are as defined for formula I, are understood to be, preferably, a racemic mixture of compounds of formula Im, wherein Ri, R2 and R3 are as defined for formula I, and compounds of formula hv, wherein R1, R2 and R3 are as defined for formula I.
In the context of the present invention, a "racemic mixture" of two enantiomers is understood to be a mixture of the two enantiomers in a ratio substantially equal to 1 :1.
The process according to the invention is suitable especially for the preparation of compounds of formula I wherein R2 and R3 are hydrogen.
The process according to the invention is suitable more especially for the preparation of compounds of formula I wherein R1, R2 and R3 are hydrogen.
The process according to the invention is suitable more especially for the preparation of compounds of formula I wherein R1 is methyl and R2 and R3 are hydrogen.
Process Step a):
In an embodiment (a1) of the process according to the invention, in Process Step a), a compound of formula Il is reacted with triphenylphosphine dibromide or triphenylphosphine dichloride.
In that embodiment, either triphenylphosphine dibromide or triphenylphosphine dichloride is added directly to the compounds of formula II, or triphenylphosphine dibromide or triphenylphosphine dichloride is generated in situ in the reaction mixture by the addition of bromine or chlorine in the presence of triphenylphosphane.
Suitable amounts of triphenylphosphine dibromide or triphenylphosphine dichloride for that reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.5 equivalents. When triphenylphosphine dibromide or triphenylphosphine dichloride is generated in situ, an amount, for example, of from 1 to 3 equivalents, especially from 1 to 1.5 equivalents, of bromine or chlorine is suitable. Suitable amounts of triphenylphosphane for that variant of the reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.5 equivalents.
In that embodiment, the reaction can be carried out in the presence of an inert solvent. Suitable solvents are, for example, ethers, for example tetrahydrofuran or dioxane, or CH3CN, and mixtures thereof; CH3CN is preferred.
Temperatures are generally from -200C to 800C, with a range from -2O0C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
The reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours:
In a further embodiment (a2) of the process according to the invention, in Process Step a), a compound of formula Il is reacted in the presence of a base with RSO2CI, wherein R is Ci-C4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or Ci-C6alkylphenyl, especially d-C4alkyl, more especially methyl.
For that reaction, suitable amounts of RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or d-C6alkylphenyl, are, for example, from 1 to 3 equivalents, especially from 1 to 1.2 equivalents.
Suitable bases are, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hϋnig's base), tri-n-butylamine, N,N-dimethylaniline or N-methylmorpholine, or inorganic bases, such as carbonates, e.g. K2CO3 or Na2CO3, or hydroxides, e.g. NaOH or KOH, with preference being given to trialkylamines and special preference being given to triethylamine.
Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1 to 1.3 equivalents. The reaction is preferably carried out in the presence of an inert solvent. Suitable solvents are, for example, dichloromethane, pyridine or ethers, for example tetrahydrofuran, and mixtures thereof, with preference being given to dichloromethane or pyridine, and special preference being given to dichloromethane.
Temperatures are generally from -200C to 800C, with a range from -200C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
The reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
The starting compounds of formula II, wherein R1, R2 and R3 are as defined for formula I, can be prepared, for example, in accordance with the following reaction sequence (see Scheme 2):
Scheme 2:
Figure imgf000011_0001
Compounds of formula IV, wherein X1 is chlorine or bromine, are reacted with compounds of formula V, wherein R1, R2 and R3 are as defined for formula I and R3 is CrC6alkyl, in a two- step reaction sequence to form compounds of formula Vl, wherein R1, R2 and R3 are as defined for formula I. In the first reaction step, compounds of formula IV are reacted with compounds of formula V under basic conditions, for example obtained by addition of NaH, NaOH or K2CO3. After isolation of the crude product, heating in dimethyl sulfoxide (DMSO) in the presence of LiCI is carried out in the second reaction step. The resulting compounds of formula Vl can be reacted to form compounds of formula Il by addition of sodium borohydride in a protic solvent RbOH, wherein Rb is Ci-C6alkyl, such as, for example, isopropanol. Compounds of formula IV, wherein Xi is chlorine or bromine, are known and are obtainable commercially.
Some of the compounds of formula V, wherein R1, R2 and R3 are as defined for formula I and Ra is CrC6alkyl, are known and are obtainable commercially. The remaining compounds of formula V, wherein Ri, R2 and R3 are as defined for formula I and R3 is C-i-Cealkyl, can be prepared in an analogous manner to preparation processes such as are described, for example, in Journal of Organic Chemistry 68(1), 27-34 (2003) and in Organic Preparations and Procedures International 10(5), 221-224 (1978).
Process Step b):
Suitable bases for Process Step b) are, for example, nitrogen-containing organic bases, such as, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hϋnig's Base), or tri-n-butylamine, N,IM-dimethylaniIine or N-methyl- morpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, such as, for example, lithium, sodium or potassium alcoholates, especially methanolates, ethanolates or butanolates, or inorganic bases, such as hydroxides, e.g. NaOH or KOH, or hydrides, such as, for example, NaH.
Bases to which preference is given are hydroxides, especially KOH, hydrides, especially NaH, or alkali metal alcoholates, especially potassium tert-butanolate.
Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1.1 to 1.8 equivalents.
The reaction is preferably carried out in the presence of an inert solvent. Suitable solvents are, for example, alcohols, such as methanol, ethanol, propanol or isopropanol, or aprotic solvents, such as tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methyl- pyrrolidone or dimethyl sulfoxide, and also mixtures thereof; dimethyl sulfoxide or dimethylformamide is especially preferred. Temperatures are generally from 00C to 800C, with a range from 00C to 25°C being preferred; special preference is given to carrying out the reaction at ambient temperature.
The reaction time for the reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
By selecting suitable reaction conditions, the compound of formula ill obtained in Reaction Step a) can be converted directly to a compound of formula I without isolation of intermediates. That reaction procedure is a particular advantage of the process according to the invention.
The process according to the invention is suitable for the preparation of compounds of formula I, wherein R1, R2 and R3 are each independently of the others hydrogen or methyl, very especially by a) reaction of a compound of formula II, wherein R1, R2 and R3 are each independently of the others hydrogen or methyl, with RSO2CI, wherein R is CrC4alkyl, in the presence of triethylamine in a temperature range of from -20°C to 25°C, using dichloromethane as solvent, to form a compound of formula III, wherein X is OSO2-C1 -C4alkyl and R1, R2 and R3 are as defined for formula I; and b) conversion of that compound into a compound of formula I in the presence of a base selected from KOH, NaH and potassium tert-butanolate, in a temperature range of from -200C to 250C, using a solvent selected from dimethyl sulfoxide and dimethylformamide.
For that preferred embodiment there are especially suitable compounds of formula I wherein R2 and R3 are hydrogen.
For that preferred embodiment there are very especially suitable compounds of formula I wherein R1, R2 and R3 are hydrogen.
The compounds of formula III
Figure imgf000014_0001
wherein X is bromine, chlorine or OSO2R, wherein R is d^alkyl, C1-C4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, and R1, R2 and R3 are as defined for formula I, are valuable intermediates for the preparation of compounds of formula I and were developed specifically for the present process according to the invention. The present invention accordingly relates also to those compounds.
Especially valuable for the preparation of compounds of formula I are those compounds of formula III wherein X is OSO2CH3.
An intermediate especially suitable for the preparation of compounds of formula I is the compound of formula III wherein X is OSO2CH3 and R1, R2 and R3 are hydrogen.
Preferred compounds of formula III are listed in the following Table. In the following Table, "Ph" denotes phenyl.
Table 1: Compounds of formula III
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000015_0001
The present invention is explained in greater detail by way of the following Examples:
Example P1 : Preparation of 2-(2-nitrophenyl)-bicvclopropane:
A mixture of 0.5 g of 1 -cyclopropyl-3-(2-nitrophenyl)-propan-1 -ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 50C and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
The 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.17 g of potassium hydroxide (2.48 mmol) is added, and stirring is carried out for 5 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.28 g of 2-(2- nitrophenyl)-bicyclopropane (61 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.5:1). 1H-NMR of trans-2-(2-nitrophenyI)-bicyclopropane (CDCI3- ppm): 0.17/m/1 H, 0.19/m/1 H, 0.42/m/I H, 0.48/m/1 H, 0.83/m/1H, 0.84/m/I H, 0.99/m/I H, 1.13/m/I H, 2.17/m/1 H, 7.10/dd/I H, 7.25/m/1 H, 7.45/m/1 H, 7.78/dd/1 H); 1H-NMR of cis-2-(2-nitrophenyl)- bicyclopropane (CDCI3- ppm): -0.09/m/1H, 0.02/m/I H, 0.06/m/I H, 0.27/m/1 H, 0.71/m/1 H, 0.85/m/I H, 0.98/m/1 H, 1.10/m/1H, 2.53/m/I H, 7.35/m/1H, 7.45/m/I H, 7.52/m/1 H, 7.92/dd/1H.
Example P2: Preparation of 2-(2-nitrophenyl)-bicvclopropane: A mixture of 0.5 g of 1 -cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethylamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5°C and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1 -Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
The 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethylformamide and 0.21 g of potassium hydroxide (3.2 mmol) is added, and stirring is carried out for 6 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclopropane (61 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
Example P3: Preparation of 2-(2-nitrophenyl)-bicvclopropane: A mixture of 2.21 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (10 mmol), 1.21 g of triethyiamine (12 mmol) and 20 ml of dichloromethane is cooled to a temperature of 5°C and 1.26 g of methanesulfonic acid chloride (11 mmol), dissolved in 5 ml of dichloromethane, are added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-Cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
0.48 g of sodium hydride (12 mmol) is introduced into 10 ml of dimethyl sulfoxide and a solution consisting of the 1 -cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate and 15 ml of DMSO is added. Stirring is then carried out for 5 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.28 g of 2-(2-nitrophenyl)-bicyclo- propane (64 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.1 :1).
Example P4: Preparation of 2-(2-nitrophenvD-bicvclopropane: A mixture of 0.5 g of 1-cyclopropyl-3-(2-nitrophenyl)-propan-1-ol (2.26 mmol), 0.26 g of triethyiamine (2.6 mmol) and 12 ml of dichloromethane is cooled to a temperature of 5°C and 0.28 g of methanesulfonic acid chloride, dissolved in 3 ml of dichloromethane, is added dropwise. The resulting mixture is stirred for 16 hours at ambient temperature. The organic phase is washed with ice-water and dried over sodium sulfate and concentrated by evaporation. 1-CycIopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is obtained in the form of a crude product, which is used directly in the cyclisation.
The 1-cyclopropyi-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.28 g of potassium tert-butanolate (2.48 mmol) is added, and stirring is carried out for 3 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate / hexane 1 :15). After removal of the eluant, 0.3 g of 2-(2-nitrophenyl)-bicyclopropane (65 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.7:1).
The following compounds of formula I can be prepared according to the above Examples:
Table 2: Compounds of formula I
Figure imgf000018_0001
Figure imgf000018_0002
The starting materials for the process of the present invention are distinguished by ease of availability and good handling properties and are moreover reasonably priced.
A further advantage of the process is that the ratio of trans isomers of formula Ia to cis isomers of formula Ib at the 2-(2-nitrophenyl)-bicyclopropane Step is sufficiently high for 2-(2- aminophenyl)-bicyclopropanes having a trans:cis ratio significantly higher than described in the prior art to be prepared by simple subsequent conversion reactions, such as, for example, reduction reactions. Generally, trans:cis ratios of the prepared 2-(2-nitrophenyl)- bicyclopropanes of more than 3:1 are achieved. In accordance with the present process, compounds of formula I can be prepared in simple manner wherein the ratio of compounds of formula Ia (trans) to compounds of formula Ib (cis) is from 3:1 to 5:1.

Claims

What is claimed is:
1. A process for the preparation of a compound of formula
Figure imgf000020_0001
wherein R1, R2 and R3 are each independently of the others hydrogen or methyl, which comprises a) reaction of a compound of formula Il
Figure imgf000020_0002
wherein R1, R2 and R3 are as defined for formula I, either a1 ) with triphenylphosphine dibromide or triphenylphosphine dichloride or a2) with RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6aIkylphenyl, in the presence of a base, to form a compound of formula III
Figure imgf000020_0003
wherein X is OSO2R wherein R is CrC4alkyl, CrC^fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, or is bromine or chlorine and R1, R2 and R3 are as defined for formula I; and b) conversion of that compound in the presence of a base into a compound of formula I.
2. A compound of formula
Figure imgf000021_0001
wherein R1, R2 and R3 are as defined for formula I in claim 1 and X is as defined for formula III in claim 1.
3. Use of a compound of formula III
Figure imgf000021_0002
wherein R1, R2 and R3 are as defined for formula I in claim 1 and X is as defined for formula III in claim 1 , in the preparation of a compound of formula I according to claim 1.
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WO2008006576A1 (en) * 2006-07-14 2008-01-17 Bayer Cropscience Ag A method for producing alkenyl nitrobenzol derivatives unbranched in the 1-position
JP2008530166A (en) * 2005-02-21 2008-08-07 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト Method for producing aniline

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JP2008530166A (en) * 2005-02-21 2008-08-07 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト Method for producing aniline
WO2008006576A1 (en) * 2006-07-14 2008-01-17 Bayer Cropscience Ag A method for producing alkenyl nitrobenzol derivatives unbranched in the 1-position

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