WO2007057140A1 - Process for the production of carboxanilides - Google Patents

Process for the production of carboxanilides Download PDF

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Publication number
WO2007057140A1
WO2007057140A1 PCT/EP2006/010866 EP2006010866W WO2007057140A1 WO 2007057140 A1 WO2007057140 A1 WO 2007057140A1 EP 2006010866 W EP2006010866 W EP 2006010866W WO 2007057140 A1 WO2007057140 A1 WO 2007057140A1
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Prior art keywords
ferrocenyl
process according
general formula
compound
sodium
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PCT/EP2006/010866
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French (fr)
Inventor
Harald Walter
Camilla Corsi
Josef Ehrenfreund
Hans Tobler
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Syngenta Participations Ag
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Priority to EP06829028A priority Critical patent/EP1951677B1/en
Priority to DE602006008976T priority patent/DE602006008976D1/en
Priority to CA2627365A priority patent/CA2627365C/en
Priority to KR1020087011680A priority patent/KR101279344B1/en
Priority to US12/093,619 priority patent/US7820830B2/en
Priority to BRPI0618545A priority patent/BRPI0618545B1/en
Priority to AT06829028T priority patent/ATE441636T1/en
Priority to CN2006800424746A priority patent/CN101309907B/en
Priority to AU2006314825A priority patent/AU2006314825B2/en
Priority to EA200801332A priority patent/EA013354B1/en
Priority to JP2008539357A priority patent/JP5096354B2/en
Publication of WO2007057140A1 publication Critical patent/WO2007057140A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a novel process for preparing certain o-cyclopropyl- carboxanilides, which are useful as microbiocides and especially as fungicides.
  • this process involves the conversion of a 2-(2-halophenyl)- cyclopropane of the formula (A), where Hal is bromo or iodo and R 3 is, as mentioned above, a substituted cyclopropyl group, to the o-cyclopropyl-aniline (C) via the imine (B).
  • the imine (B) is formed by reacting the cyclopropane (A) with benzophenone imine for several hours in a solvent, such as benzene or toluene, at its reflux temperature in the presence of sodium tert- butoxide, tris-dibenzylideneacetone-dipalladium (Pd 2 dba 3 ) and racemic 2,2'-bis(diphenyl- phosphino)-l,l'-binaphthyl (BINAP) and then added (usually as a crude, isolated product) to a mixture of hydroxylamine hydrochloride, sodium acetate and a solvent, such as methanol, to form a cis-/trans-mixture of the aniline (C).
  • a solvent such as benzene or toluene
  • This process for preparing o-cyclopropyl-carboxanilides starting from a 2-(2-halo- phenyl)-cyclopropane of the formula (A) is expensive and not well suited to large scale production. Amongst other disadvantages, it involves three separate stages and requires the use of the expensive benzophenone imine and the isolation of the intermediate imine (B).
  • the cyclopropane (A) must be a bromo- or iodo-phenyl cyclopropane and not the corresponding, cheaper, but less reactive, chlorophenyl cyclo- propane.
  • o-cyclopropyl-carboxanilides may be prepared directly from a 2-(2 -bromo- or 2-chlorophenyl)-cyclopropane in a one-stage process, better suited to, and less costly for, use on a commercial scale.
  • R 1 is H or C 1-4 alkyl and R ⁇ is difluoromethyl or trifluoromethyl, which comprises reacting the compound of the general formula (11):
  • R i has the meaning given above and X is chloro or bromo (preferably chloro), with a compound of the general formula (III): wherein R 2 has the meaning given above, in the presence of a base, a palladium catalyst and a ferrocenyl biphoshine ligand of the Josiphos type, the reaction being carried out in an ether solvent at a reflux temperature of at least 100 0 C.
  • alkyl refers to branched or unbranched alkyl groups containing from 1 to 4 carbon atoms and is methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec- butyl, iso-butyl or tert-butyl.
  • the base used in the process of the invention is preferably a strong base, typically an alkali metal or alkaline earth metal hydroxide, carbonate or alkoxide or an alkali metal phosphate or bicarbonate, or mixtures thereof.
  • a strong base typically an alkali metal or alkaline earth metal hydroxide, carbonate or alkoxide or an alkali metal phosphate or bicarbonate, or mixtures thereof.
  • Particularly suitable are the hydroxides or carbonates of sodium, potassium, cesium, lithium, calcium and barium, the phosphates of sodium and potassium and the Ci-C 4 alkoxides of sodium and potassium.
  • the amount of base used will depend on the particular base chosen, but will normally be from 1 to 3, conveniently from 1 to 2 and typically 1.2 to 1.6 moles per mole of compound (II).
  • the palladium catalyst used in the process of the invention is suitably palladium dichloride, palladium(II) acetate, tris-dibenzylideneacetone-dipalladium (Pd 2 dba 3 ) or bis- dibenzylideneacetone palladium (Pd(dba) 2 ).
  • Palladium(II) acetate has been found particularly convenient to use.
  • the ferrocenyl biphoshine ligand used is of the Josiphos type.
  • Such ligands are commercially available and include: (R)-(-)-l-[(S)-2-(bis(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyl-di-teA-t-butyl- phosphine; (R)-(-)-l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldicyclohexyl- phosphine;
  • racemic mixtures thereof especially racemic mixtures of 2-(di-terf-butylphosphino)- ferrocenyl]ethyl-di- ⁇ -tolylphosphine.
  • a Josiphos ligand which has been found particularly useful is (R)-(-)-l-[(S)-2-(dicyclohexyl- phosphino)ferrocenyl]ethyldi-tert-butylphosphine; which has the structural formula:
  • the palladium catalyst will normally be employed in a ratio of from 0.001 to 10 mol %, preferably from 0.01 to 1 and typically about 0.02 mol %, based on compound (II).
  • the Josiphos ligand will normally be used with one equivalent of the palladium catalyst, or thereabouts.
  • the solvent used for carrying out the process is an ether solvent, inert under the reaction conditions of the process, having a boiling point such that the reaction mixture can be refluxed at atmospheric pressure at a temperature of at least 100 0 C.
  • ether solvent inert under the reaction conditions of the process, having a boiling point such that the reaction mixture can be refluxed at atmospheric pressure at a temperature of at least 100 0 C.
  • solvents include dialkyl ethers of alkylene- and polyalkyleneglycols and, in particular, diethyleneglycol dialkylethers having the general formula:
  • the solvent is di(ethylene glycol) dimethyl ether (diglyme), which has a boiling point of about 162 0 C.
  • the process of the invention is carried out at the reflux temperature of the solvent employed, which should be at least 100 0 C, usually at least 13O 0 C, normally from 130 to 200 0 C, and typically from 140 to 18O 0 C.
  • the process may be carried out at atmospheric pressure.
  • the vessel used for the process may be purged with nitrogen before the reactants are introduced, but this is not a requirement.
  • the 2-chloro- or bromophenyl bicyclopropyl compound (II) used in the process of the invention may exist as a cis- or trans-isomer or a mixture of both.
  • the invention process includes the use of either isomer or any mixture thereof in any proportion and the compound (I) may be obtained as one or other isomer or a mixture of both, accordingly.
  • the amount of the pyrazole carboxylic acid amide (III) used in the process is conveniently from 1 to 5 moles, for example from 1 to 1.5 moles and typically from 1 to 1.2 moles, for each mole of bicyclopropyl compound (II) used.
  • reaction time will depend, inter alia, on the scale of the process and the temperature, but will usually take from 1 to 48 hours, for example, from 6 to 24 hours, and typically from 10 to 20 hours.
  • the process is conveniently carried out by adding the compounds (II) and (III) with the base, catalyst and ligand to the solvent in a suitable reaction vessel.
  • the order of addition is not critical.
  • the reaction is adjudged complete, for example, by gas chromatographic analysis of a sample of the reaction mixture, the crude product may be isolated by adding ethyl acetate to the reaction mixture, washing the organic phase with water, drying it and distilling off the solvent. It may then be purified by standard laboratory techniques, for example, by column chromatography.
  • the product (I) is a useful microbiocide, having especially good fungicidal properties as described in, for example, WO 2003/074491.

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  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a novel process for the preparation of a compound of general formula (I): wherein R1 is H or C1-4 alkyl and R2 is difluoromethyl or trifluoromethyl, which comprises reacting a compound of general formula (II): wherein R1 has the meaning given above and X is chloro or bromo, with a compound of general formula (III): wherein R2 has the meaning given above, in the presence of a base, a palladium catalyst and a ferrocenyl biphoshine ligand of the Josiphos type, the reaction being carried out in an ether solvent at a reflux temperature of at least 100 °C.

Description

PROCESS FOR THE PRODUCTION OF CARBOXANILIDES
The present invention relates to a novel process for preparing certain o-cyclopropyl- carboxanilides, which are useful as microbiocides and especially as fungicides.
Various o-cyclopropyl-carboxanilides, methods for their preparation and their use as microbicides are described in WO 03/074491. In one method of preparation an o-cyclopropyl- aniline of the formula (C), shown in Scheme 1 below, where R3 may be, inter alia, a substituted cyclopropyl group, is reacted with an acid chloride of the formula Het-COCl, where Het is for example a substituted pyrazolyl group, to form an o-cyclopropyl- carboxanilide of the formula (D):
Figure imgf000002_0001
The o-cyclopropyl-aniline (C) is made by a multi-stage process which culminates in the two steps shown in Scheme 1 : Scheme 1
Figure imgf000002_0002
(A) (B) (C)
As seen from Scheme 1, this process involves the conversion of a 2-(2-halophenyl)- cyclopropane of the formula (A), where Hal is bromo or iodo and R3 is, as mentioned above, a substituted cyclopropyl group, to the o-cyclopropyl-aniline (C) via the imine (B). The imine (B) is formed by reacting the cyclopropane (A) with benzophenone imine for several hours in a solvent, such as benzene or toluene, at its reflux temperature in the presence of sodium tert- butoxide, tris-dibenzylideneacetone-dipalladium (Pd2dba3) and racemic 2,2'-bis(diphenyl- phosphino)-l,l'-binaphthyl (BINAP) and then added (usually as a crude, isolated product) to a mixture of hydroxylamine hydrochloride, sodium acetate and a solvent, such as methanol, to form a cis-/trans-mixture of the aniline (C).
This process for preparing o-cyclopropyl-carboxanilides starting from a 2-(2-halo- phenyl)-cyclopropane of the formula (A) is expensive and not well suited to large scale production. Amongst other disadvantages, it involves three separate stages and requires the use of the expensive benzophenone imine and the isolation of the intermediate imine (B). In addition, according to WO 03/074491, the cyclopropane (A) must be a bromo- or iodo-phenyl cyclopropane and not the corresponding, cheaper, but less reactive, chlorophenyl cyclo- propane.
It has now been found that certain o-cyclopropyl-carboxanilides may be prepared directly from a 2-(2 -bromo- or 2-chlorophenyl)-cyclopropane in a one-stage process, better suited to, and less costly for, use on a commercial scale.
Thus, according to the present invention, there is provided a process for the preparation of the compound of the general formula (I) :
Figure imgf000003_0001
wherein R1 is H or C1-4 alkyl and R^ is difluoromethyl or trifluoromethyl, which comprises reacting the compound of the general formula (11):
Figure imgf000003_0002
wherein R , i has the meaning given above and X is chloro or bromo (preferably chloro), with a compound of the general formula (III):
Figure imgf000004_0001
wherein R2 has the meaning given above, in the presence of a base, a palladium catalyst and a ferrocenyl biphoshine ligand of the Josiphos type, the reaction being carried out in an ether solvent at a reflux temperature of at least 1000C. The term "alkyl" mentioned herein refers to branched or unbranched alkyl groups containing from 1 to 4 carbon atoms and is methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec- butyl, iso-butyl or tert-butyl.
The base used in the process of the invention is preferably a strong base, typically an alkali metal or alkaline earth metal hydroxide, carbonate or alkoxide or an alkali metal phosphate or bicarbonate, or mixtures thereof. Particularly suitable are the hydroxides or carbonates of sodium, potassium, cesium, lithium, calcium and barium, the phosphates of sodium and potassium and the Ci-C4 alkoxides of sodium and potassium. Of particular interest are potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate.
The amount of base used will depend on the particular base chosen, but will normally be from 1 to 3, conveniently from 1 to 2 and typically 1.2 to 1.6 moles per mole of compound (II).
The palladium catalyst used in the process of the invention is suitably palladium dichloride, palladium(II) acetate, tris-dibenzylideneacetone-dipalladium (Pd2dba3) or bis- dibenzylideneacetone palladium (Pd(dba)2). Palladium(II) acetate has been found particularly convenient to use.
The ferrocenyl biphoshine ligand used is of the Josiphos type. Such ligands are commercially available and include: (R)-(-)-l-[(S)-2-(bis(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyl-di-teA-t-butyl- phosphine; (R)-(-)-l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldicyclohexyl- phosphine;
(R)-(-)-l-[(S)-2-(di(3,5-bis-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi(3,5-dimethyl- phenyl)phosphine;
(R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; (R)-(-)- 1 -[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine;
(S)-(+)-l-[(R)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine;
(S)-(+)-l-[(R)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine;
(R)-(-)-l-[(S)-2-(bis(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldicyclohexyl- phosphine; (S)-(+)-l-[(R)-2-(di-furylphosphino)ferrocenyl]ethyldi-3,5-xylylphosphine;
(R)-(-)-l-[(S)-2-(diphenylphosphino)ferτocenyl]ethyldi-tert-butylphosphine;
(S)-(+)-l-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;
(R)-(-)- 1 -[(S)-2-(diphenylphosphino)ferτocenyl] ethyldicyclohexylphosphine;
(R)-(+)-l-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (S)-(+)- 1 -[(R)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine;
(R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine;
(R)-(-)-l-[(S)-2-(diphenyl)phosphino)ferrocenyl]ethyldi(3,5-dimethylphenyl)phosphine; and racemic mixtures thereof, especially racemic mixtures of 2-(dicyclohexylphosphino)- ferrocenyl]ethyldi-tert-butylphosphine. Other Josiphos ligands which may be used include:
(R)-(-)- 1 -[(S)-2-(di-tert-butyl-phosphino)ferrocenyl] ethyl-di-o-tolylphosphine
Figure imgf000005_0001
(R)-(-)-l-[(S)-2-(bis(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]-ethyl-di-/ert- butylphosphine
Figure imgf000006_0001
(R)-(-)-l-[(S)-2-(diethylphosphino)ferrocenyl]-ethyl-di-/ert-butylphosphine
Figure imgf000006_0002
(R)-(-)-l-[(S)-2-(/J-methyl-P-/5opropyl-phosphino)ferrocenyl]ethyldicyclohexylphosphine
Figure imgf000006_0003
(R)-(-)-l-[(S)-2-(P-methyl-P-phenyl-phosphino)ferrocenyl]ethyl-di-tert-butylphosphine
Figure imgf000006_0004
and racemic mixtures thereof, especially racemic mixtures of 2-(di-terf-butylphosphino)- ferrocenyl]ethyl-di-ø-tolylphosphine.
A Josiphos ligand which has been found particularly useful is (R)-(-)-l-[(S)-2-(dicyclohexyl- phosphino)ferrocenyl]ethyldi-tert-butylphosphine; which has the structural formula:
Figure imgf000007_0001
hi the invention process, the palladium catalyst will normally be employed in a ratio of from 0.001 to 10 mol %, preferably from 0.01 to 1 and typically about 0.02 mol %, based on compound (II).
The Josiphos ligand will normally be used with one equivalent of the palladium catalyst, or thereabouts.
The solvent used for carrying out the process is an ether solvent, inert under the reaction conditions of the process, having a boiling point such that the reaction mixture can be refluxed at atmospheric pressure at a temperature of at least 1000C. Such solvents include dialkyl ethers of alkylene- and polyalkyleneglycols and, in particular, diethyleneglycol dialkylethers having the general formula:
ROCH2CH2OCH2CH2OR wherein R is C1-4 alkyl. Most conveniently, the solvent is di(ethylene glycol) dimethyl ether (diglyme), which has a boiling point of about 1620C.
The process of the invention is carried out at the reflux temperature of the solvent employed, which should be at least 1000C, usually at least 13O0C, normally from 130 to 2000C, and typically from 140 to 18O0C.
The process may be carried out at atmospheric pressure. The vessel used for the process may be purged with nitrogen before the reactants are introduced, but this is not a requirement.
The 2-chloro- or bromophenyl bicyclopropyl compound (II) used in the process of the invention may exist as a cis- or trans-isomer or a mixture of both. The invention process includes the use of either isomer or any mixture thereof in any proportion and the compound (I) may be obtained as one or other isomer or a mixture of both, accordingly. The amount of the pyrazole carboxylic acid amide (III) used in the process is conveniently from 1 to 5 moles, for example from 1 to 1.5 moles and typically from 1 to 1.2 moles, for each mole of bicyclopropyl compound (II) used.
The reaction time will depend, inter alia, on the scale of the process and the temperature, but will usually take from 1 to 48 hours, for example, from 6 to 24 hours, and typically from 10 to 20 hours.
The process is conveniently carried out by adding the compounds (II) and (III) with the base, catalyst and ligand to the solvent in a suitable reaction vessel. The order of addition is not critical. When the reaction is adjudged complete, for example, by gas chromatographic analysis of a sample of the reaction mixture, the crude product may be isolated by adding ethyl acetate to the reaction mixture, washing the organic phase with water, drying it and distilling off the solvent. It may then be purified by standard laboratory techniques, for example, by column chromatography.
The product (I) is a useful microbiocide, having especially good fungicidal properties as described in, for example, WO 2003/074491.
The following non-limiting examples illustrate the invention in more detail.
EXAMPLE 1
Preparation of 3 -difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid (2-bicycloprop-2- yl-phenyl) amide from 2-(2-chlorophenyQbicvclopropyl using sodium fer/-butoxide as base
In a sulfonation flask 2-(2-chlorophenyl)bicyclopropyl (0.58g; 0.0028mol; trans/cis mixture ca. 2:1), 3 -difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid amide (0.5g; 0.003mol), sodium tert-butoxide (0.38g; 0.004mol), palladium(II) acetate (13mg; 0.057 mmol) and (R)-(-)- 1 -[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (31mg; 0.057mmol) were added to di(ethylene glycol) dimethyl ether (15ml). The mixture was heated and stirred at its reflux temperature for 16 hours. After cooling, ethyl acetate was added and the organic phase was washed three times with water. After drying and distilling off the solvent in a water jet vacuum a brownish residue remained. This crude product was purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1 :1). Yield: 0.64g 3 -difluoromethyl-1 -methyl- lH-pyrazol-4-carboxylic acid (2-bicycloprop-2-yl- phenyl) amide (68% theory) in the form of a brown solid (trans/cis ratio: ca. 2.7:1).
EXAMPLE 2
Preparation of 3-difluoromethyl-l-methyl-l/-/-pyrazole-4-carboxylic acid (2-bicvcloprop-2- yl-phenyl) amide from 2-(2-bromophenyl)bicyclopropyl using sodium fert-butoxide as base In a sulfonation flask 2-(2-bromophenyl)bicyclopropyl (0.7 Ig; 0.0028mol; trans/cis mixture ca. 2:1), 3-difluoromethyl-l-methyl-lH-pyrazole-4-carboxylic acid amide (0.5g; 0.003mol), sodium tert-butoxide (0.38g; 0.004mol), palladium(II) acetate (13mg; 0.057 mmol) and (R)-(-)- 1 -[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (31mg; 0.057mmol) were added to di(ethylene glycol) dimethyl ether (15ml). The mixture was heated and stirred at its reflux temperature for 16 hours. After cooling, ethyl acetate was added and the organic phase was washed three times with water. After drying and distilling off the solvent in a water jet vacuum a brownish residue remained. This crude product was purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:1). Yield: 0.62g 3 -difluoromethyl-1 -methyl- lH-pyrazol-4-carboxylic acid (2-bicycloprop-2-yl- phenyl) amide (67% theory) in the form of a brown solid (trans/cis ratio: ca. 2.7:1). EXAMPLE 3
Preparation of 3 -difluoromethyl-1 -methyl- lH-pyrazole-^carboxylic acid (2-bicycloprop-2- yl-phenyl) amide from 2-(2-chlorophenvObicyclopropyl using cesium carbonate as base In a sulfonation flask 2-(2-chlorophenyl)bicyclopropyl (0.3g; O.OOlβmol; trans/cis mixture ca. 2:1), 3 -difluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid amide (0.37g; O.OOlβmol), cesium carbonate (0.7 Ig; 0.0022mol), palladium(II) acetate (7mg; 0.031 mmol) and (R)-(-)- 1 -[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-ter/-butylphosphine (18mg; 0.031 mmol) were added to di(ethylene glycol) dimethyl ether (15ml). The mixture was heated and stirred at its reflux temperature for 16 hours. After cooling, ethyl acetate was added and the organic phase was washed three times with water. After drying and distilling off the solvent in a water jet vacuum a brownish residue remained. This crude product was purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:1). Yield: 0.27g 3 -difluoromethyl-1 -methyl- lH-pyrazol-4-carboxylic acid (2-bicycloprop-2-yl- phenyl) amide (52% theory) in the form of a brown solid (trans/cis ratio: ca. 2:1).

Claims

CLAIMS A process for the preparation of the compound of the general formula (I):
Figure imgf000011_0001
wherein R1 is H or Ci-4 alkyl and R2 is difluoromethyl or trifluoromethyl, which comprises reacting the compound of the general formula (II):
Figure imgf000011_0002
wherein R1 has the meaning given above and X is chloro or bromo, with a compound of the general formula (FII):
Figure imgf000011_0003
wherein R2 has the meaning given above, in the presence of a base, a palladium catalyst and a ferrocenyl biphoshine ligand of the Josiphos type, the reaction being carried out in an ether solvent at a reflux temperature of at least 1000C.
A process according to claim 1 wherein X is chloro.
3. A process according to claim 1 or 2 wherein the base is a hydroxide or carbonate of sodium, potassium, cesium, lithium, calcium or barium, the phosphates of sodium or potassium or the Cj-C4 alkoxide of sodium or potassium.
4. A process according to any one of the preceding claims wherein the palladium catalyst is palladium dichloride, palladium(II) acetate, tris-dibenzylidene- acetone-dipalladium or bis-dibenzylideneacetone palladium.
5. A process according to any one of the preceding claims wherein the ligand is
(R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butyl- phosphine having the structural formula:
Figure imgf000012_0001
6. A process according to any one of the preceding claims wherein the solvent is diethyleneglycol dialkylethers having the general formula:
ROCH2CH2OCH2CH2OR wherein R is Ci-4 alkyl.
7. A process according to any one of claims 1 to 5 wherein the solvent is di(ethylene glycol) dimethyl ether (i.e. diglyme).
8. A process according to any one of the preceding claims wherein the reaction is carried out at a temperature of from 130 to 2000C.
PCT/EP2006/010866 2005-11-15 2006-11-13 Process for the production of carboxanilides WO2007057140A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP06829028A EP1951677B1 (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
DE602006008976T DE602006008976D1 (en) 2005-11-15 2006-11-13 PROCESS FOR THE PREPARATION OF CARBOXANILIDES
CA2627365A CA2627365C (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
KR1020087011680A KR101279344B1 (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
US12/093,619 US7820830B2 (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
BRPI0618545A BRPI0618545B1 (en) 2005-11-15 2006-11-13 process for producing carboxanilides
AT06829028T ATE441636T1 (en) 2005-11-15 2006-11-13 METHOD FOR PRODUCING CARBOXANILIDES
CN2006800424746A CN101309907B (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
AU2006314825A AU2006314825B2 (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
EA200801332A EA013354B1 (en) 2005-11-15 2006-11-13 Process for the production of carboxanilides
JP2008539357A JP5096354B2 (en) 2005-11-15 2006-11-13 Method for producing carboxanilide

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US8124786B2 (en) * 2006-07-14 2012-02-28 Bayer Cropscience Ag Mental-catalyzed process for preparation of substituted pyrazolecarboxamides
WO2013167544A1 (en) 2012-05-09 2013-11-14 Bayer Cropscience Ag 5-halogenopyrazole indanyl carboxamides
WO2013167545A1 (en) 2012-05-09 2013-11-14 Bayer Cropscience Ag Pyrazole indanyl carboxamides

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WO2004039799A1 (en) * 2002-11-01 2004-05-13 Syngenta Participations Ag Cyclopropyl-thienyl-carboxamide as fungicides

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WO2003074491A1 (en) * 2002-03-05 2003-09-12 Syngenta Participations Ag O-cyclopropyl-carboxanilides and their use as fungicides
WO2004039799A1 (en) * 2002-11-01 2004-05-13 Syngenta Participations Ag Cyclopropyl-thienyl-carboxamide as fungicides

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124786B2 (en) * 2006-07-14 2012-02-28 Bayer Cropscience Ag Mental-catalyzed process for preparation of substituted pyrazolecarboxamides
CN101490011B (en) * 2006-07-14 2012-08-29 拜尔农作物科学股份公司 Method for producing alkylanilides from halobenzene derivatives
WO2010072632A1 (en) * 2008-12-24 2010-07-01 Syngenta Limited Methods for the preparation of aryl amides
US20110263869A1 (en) * 2008-12-24 2011-10-27 Syngenta Crop Protection, Llc Methods for the preparation of aryl amides
JP2012513962A (en) * 2008-12-24 2012-06-21 シンジェンタ リミテッド Method for producing arylamide
US8637678B2 (en) 2008-12-24 2014-01-28 Syngenta Limited Methods for the preparation of aryl amides
US9169233B2 (en) 2008-12-24 2015-10-27 Syngenta Limited Methods for the preparation of aryl amides
WO2013167544A1 (en) 2012-05-09 2013-11-14 Bayer Cropscience Ag 5-halogenopyrazole indanyl carboxamides
WO2013167545A1 (en) 2012-05-09 2013-11-14 Bayer Cropscience Ag Pyrazole indanyl carboxamides

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DE602006008976D1 (en) 2009-10-15
KR101279344B1 (en) 2013-07-04
EP1951677A1 (en) 2008-08-06
JP2009515843A (en) 2009-04-16
JP5096354B2 (en) 2012-12-12
ATE441636T1 (en) 2009-09-15
US7820830B2 (en) 2010-10-26
BRPI0618545B1 (en) 2015-10-13
EA013354B1 (en) 2010-04-30
CN101309907B (en) 2011-06-22
UA88992C2 (en) 2009-12-10
AU2006314825A1 (en) 2007-05-24
KR20080068713A (en) 2008-07-23
CA2627365C (en) 2013-11-12
ES2330890T3 (en) 2009-12-16
BRPI0618545A2 (en) 2011-09-06
EP1951677B1 (en) 2009-09-02
CN101309907A (en) 2008-11-19
CA2627365A1 (en) 2007-05-24

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