WO2006087222A1 - Process for the production of nitrobenzoles - Google Patents
Process for the production of nitrobenzoles Download PDFInfo
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- WO2006087222A1 WO2006087222A1 PCT/EP2006/001507 EP2006001507W WO2006087222A1 WO 2006087222 A1 WO2006087222 A1 WO 2006087222A1 EP 2006001507 W EP2006001507 W EP 2006001507W WO 2006087222 A1 WO2006087222 A1 WO 2006087222A1
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- 0 *C(CP(*)(c1ccccc1)(c1ccccc1)c1ccccc1)=O Chemical compound *C(CP(*)(c1ccccc1)(c1ccccc1)c1ccccc1)=O 0.000 description 7
Classifications
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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
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- 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
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- 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
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- 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 the 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)-bicyclopropanes, 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 wherein R 1 , 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; and b) reaction of that compound either b1) with triphenylphosphine dibromide or triphenylphosphine dichloride or b2) with RSO 2 CI, wherein R is CrC 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC 6 alkylphenyl, in the presence of a base, to form a compound of formula IV
- X is bromine, chlorine or OSO 2 R, wherein R is C 1 -C 4 alkyl, C r 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 c) 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).
- 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.
- 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-trifluoroethyl, 1 -f luoroethyl, 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 stereoisomer ⁇ forms of formulae l
- 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 l ⁇ , wherein Ri, R 2 and R 3 are as defined for formula I, and compounds of formula Iu, 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 I,,,, wherein R 1 , R 2 and R 3 are as defined for formula I; compounds of 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 Im, wherein R 1 , R 2 and R 3 are as defined for formula I, and compounds of 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 especially for the preparation of compounds of formula I wherein R 2 and R3 are hydrogen.
- the process according to the invention is suitable more especially for the preparation of compounds of formula I wherein Ri, 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 Ri is methyl and R 2 and R 3 are hydrogen.
- the reducing agents used in process Step a) are preferably those capable of selective reduction of the carbonyl group in compounds of formula Il to the hydroxy group, that is to say, without substantial reduction of the nitro group.
- a suitable reducing agent is, for example, a borane, for example decaborane or diborane, complexed with tetrahydrofuran or with dimethyl sulfide; a complex hydride, for example sodium borohydride or lithium borohydride; hydrogen in the presence of deactivated metal catalysts, such as, for example, palladium on barium sulfate, deactivated by quinoline (Lindlar catalyst); or a secondary alcohol, such as, for example, isopropanol, under Meerwein-Ponndorf-Verley reduction conditions, such as, for example, aluminium isopropanolate in isopropanol.
- deactivated metal catalysts such as, for example, palladium on barium sulfate, deactivated by quinoline (Lindlar catalyst)
- a secondary alcohol such as, for example, isopropanol, under Meerwein-Ponndorf-Verley reduction conditions, such as, for example,
- a reducing agent to which special preference is given is diborane, complexed with tetrahydrofuran or dimethyl sulfide; sodium borohydride; lithium borohydride; or aluminium isopropanolate in isopropanol; very special preference is given to sodium borohydride.
- Suitable amounts of reducing agent for that reaction are, for example, from 0.25 to 3 equivalents, especially from 0.25 to 1 equivalent.
- 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, for example, tetrahydrofuran, dimethoxyethane, dioxane or toluene, and mixtures thereof.
- Special preference is given to methanol or isopropanol.
- Temperatures are generally from 0 0 C to 8O 0 C, with a range from 0 0 C to 60 0 C being preferred; special preference is given to carrying out the reaction at from 3O 0 C to 60 0 C.
- the reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 6 hours.
- a compound of formula 111 is reacted with triphenylphosphine dibromide or triphenylphosphine dichloride.
- triphenylphosphine dibromide or triphenylphosphine dichloride is added directly to the compounds of formula III, 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.
- triphenylphosphine dibromide or triphenylphosphine dichloride 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.
- 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.
- the reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
- a compound of formula III is reacted in the presence of a base with RSO 2 CI, wherein R is CrC 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC 6 alkylphenyl, especially d-C 4 alkyl, more especially methyl.
- RSO 2 CI wherein R is CrC 4 alkyl, C r C 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC 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.
- Suitable bases for Process Step c) 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,N-dimethylaniline or N-methylmorpholine, 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.
- Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1.1 to 1.8 equivalents.
- Bases to which preference is given are hydroxides, especially KOH, hydrides, especially NaH, or alkali metal alcoholates, especially potassium tert-butanolate.
- 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 that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
- the compound of formula IV obtained in Reaction Step b) 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 Ri, R 2 and R3 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 as defined for formula I, with sodium borohydride in a temperature range of from 3O 0 C to 6O 0 C, using methanol or isopropanol as solvent, to form a compound of formula III wherein Ri, R 2 and R 3 are as defined for formula I; and b) reaction of that compound with RSO 2 CI, wherein R is CrC 4 alkyl, in the presence of triethylamine in a temperature range of from -20 0 C to 25°C, using dichloromethane as solvent, to form a compound of formula IV, wherein X is OSO 2 -Ci -C 4 alkyl and R 1 , R 2 and R 3 are as defined for formula I; and c) conversion of that compound into a compound of formula
- X is bromine, chlorine or OSO 2 R, wherein R is CrC 4 alkyl, CrC 4 fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or d-C 6 alkylphenyl, and R 1 , R 2 and R 3 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.
- An intermediate especially suitable for the preparation of compounds of formula I is the compound of formula IV wherein X is OSO 2 CH 3 and R 1 , R 2 and R 3 are hydrogen.
- Example P1 Preparation of 1 -cvclopropyl-3-(2-nitrophenv ⁇ -propan-1 -ol: In a sulfonating flask, 1.26 g of sodium borohydride (33 mmol) are introduced into 200 ml of isopropanol. A solution consisting of 26.6 g of 1-cyc!opropyl-3-(2-nitrophenyl)propan-1-one (120 mmol) and 100 ml of isopropanol is added dropwise at ambient temperature. After stirring for 3 hours at 50 0 C, 0.5 g of sodium borohydride (13 mmol) is added. Stirring is carried out for one hour at 50 0 C.
- the 1-cyclopropyl-3-(2-nitrophenyl)-propyI 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 P3 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 0 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)-bicycIopropane (61 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
- Example P4 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 triethylamine (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 P5 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 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)-bicycIopropane (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 a) reaction of a compound of formula (II) wherein the substituents are as defined in claim 1 , with a reducing agent to form a compound of formula (III) wherein the substituents are as defined in claim 1 , and b) reaction of that compound either b1 ) with triphenylphosphine dibromide or triphenylphosphine dichloride or b2) with RSO2CI, wherein R is Ci-C4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, in the presence of a base, to form a compound of formula (IV) wherein the substituents are as defined in claim 1 ; and c) 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 the 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)-bicyclopropanes, 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
wherein R1, R2 and R3 are each independently of the others hydrogen or methyl, which comprises a) reaction of a compound of formula Il
wherein R1, R2 and R3 are as defined for formula I, with a reducing agent to form a compound of formula III
wherein R1, R2 and R3 are as defined for formula I; and b) reaction of that compound either b1) with triphenylphosphine dibromide or triphenylphosphine dichloride or b2) with RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, in the presence of a base, to form a compound of formula IV
wherein X is bromine, chlorine or OSO2R, wherein R is C1-C4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, and R1, R2 and R3 are as defined for formula I; and
c) 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 :
(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)-bicycIopropanes (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 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)-bicyclo- propanes (F).
The reaction sequence described in WO 03/074491 (Scheme 1 ) yields a trans:cis 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)-bicyclo- propanes 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
to be produced wherein Ri, R2 and R3 are each independently of the others hydrogen or methyl and wherein the ratio of compounds of formula Ia (trans)
(Ia, trans)
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-trifluoroethyl, 1 -f luoroethyl, 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 lι, In, Im and I|V:
The process according to the invention includes the preparation of those stereoisomer^ forms of formulae l|, In, 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),
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 l(, 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),
wherein R1, R2 and R3 are as defined for formula I, are understood to be, preferably, a racemic mixture of compounds of formula lι, wherein Ri, R2 and R3 are as defined for formula I, and compounds of formula Iu, 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 I,,,, wherein R1, R2 and R3 are as defined for formula I; compounds of formula I|V, 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 I|V, 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, preferably, a racemic mixture of compounds of formula Im, wherein R1, R2 and R3 are as defined for formula I, and compounds of formula I|V> 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 Ri, R2 and R3 are hydrogen.
The process according to the invention is suitable more especially for the preparation of compounds of formula I wherein Ri is methyl and R2 and R3 are hydrogen.
Process Step a):
The reducing agents used in process Step a) are preferably those capable of selective reduction of the carbonyl group in compounds of formula Il to the hydroxy group, that is to say, without substantial reduction of the nitro group.
A suitable reducing agent is, for example, a borane, for example decaborane or diborane, complexed with tetrahydrofuran or with dimethyl sulfide; a complex hydride, for example sodium borohydride or lithium borohydride; hydrogen in the presence of deactivated metal catalysts, such as, for example, palladium on barium sulfate, deactivated by quinoline (Lindlar catalyst); or a secondary alcohol, such as, for example, isopropanol, under Meerwein-Ponndorf-Verley reduction conditions, such as, for example, aluminium isopropanolate in isopropanol.
A reducing agent to which special preference is given is diborane, complexed with tetrahydrofuran or dimethyl sulfide; sodium borohydride; lithium borohydride; or aluminium isopropanolate in isopropanol; very special preference is given to sodium borohydride.
Suitable amounts of reducing agent for that reaction are, for example, from 0.25 to 3 equivalents, especially from 0.25 to 1 equivalent.
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, for example, tetrahydrofuran, dimethoxyethane, dioxane or toluene, and mixtures thereof. Special preference is given to methanol or isopropanol.
Temperatures are generally from 00C to 8O0C, with a range from 00C to 600C being preferred; special preference is given to carrying out the reaction at from 3O0C to 600C.
The reaction time for that reaction is generally from 1 to 48 hours, preferably from 1 to 6 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:
Compounds of formula V, wherein X1 is chlorine or bromine, are reacted with compounds of formula Vl, 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 II, wherein R1, R2 and R3 are as defined for formula I. In the first reaction step, compounds of formula V are reacted with compounds of formula Vl 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.
Compounds of formula V, wherein X1 is chlorine or bromine, are known and are obtainable commercially.
Some of the compounds of formula Vl, 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 Vl, wherein R1, R2 and R3 are as defined for formula I and R3 is CrC6alkyl, 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):
In an embodiment (b1) of the process according to the invention, in Process Step b), a compound of formula 111 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 III, 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 (b2) of the process according to the invention, in Process Step b), a compound of formula III is reacted in the presence of a base with RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, especially d-C4alkyl, more especially methyl.
For that reaction, suitable amounts of RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, 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.
Process Step c):
Suitable bases for Process Step c) 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,N-dimethylaniline or N-methylmorpholine, 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.
Suitable amounts of base for that reaction are, for example, from 1 to 3 equivalents, especially from 1.1 to 1.8 equivalents.
Bases to which preference is given are hydroxides, especially KOH, hydrides, especially NaH, or alkali metal alcoholates, especially potassium tert-butanolate.
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 that reaction is generally from 1 to 48 hours, preferably from 1 to 18 hours.
By selecting suitable reaction conditions, the compound of formula IV obtained in Reaction Step b) 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 Ri, 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 as defined for formula I, with sodium borohydride in a temperature range of from 3O0C to 6O0C, using methanol or isopropanol as solvent, to form a compound of formula III wherein Ri, R2 and R3 are as defined for formula I; and b) reaction of that compound with RSO2CI, wherein R is CrC4alkyl, in the presence of triethylamine in a temperature range of from -200C to 25°C, using dichloromethane as solvent, to form a compound of formula IV, wherein X is OSO2-Ci -C4alkyl and R1, R2 and R3 are as defined for formula I; and
c) 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 25°C, 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 Ri, R2 and R3 are hydrogen.
The compounds of formula III
wherein Ri, 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 Ri, R2 and R3 are hydrogen.
Preferred compounds of formula III are listed in the following Table.
Table 1 : Compounds of formula III
(III)
The compounds of formula IV
wherein X is bromine, chlorine or OSO2R, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or d-C6alkylphenyl, 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 IV wherein X is OSO2CH3.
An intermediate especially suitable for the preparation of compounds of formula I is the compound of formula IV wherein X is OSO2CH3 and R1, R2 and R3 are hydrogen.
Preferred compounds of formula IV are listed in the following Table. In the following Table, "Ph" denotes phenyl.
Table 2: Compounds of formula IV
The present invention is explained in greater detail by way of the following Examples:
Example P1 : Preparation of 1 -cvclopropyl-3-(2-nitrophenvπ-propan-1 -ol: In a sulfonating flask, 1.26 g of sodium borohydride (33 mmol) are introduced into 200 ml of isopropanol. A solution consisting of 26.6 g of 1-cyc!opropyl-3-(2-nitrophenyl)propan-1-one (120 mmol) and 100 ml of isopropanol is added dropwise at ambient temperature. After stirring for 3 hours at 500C, 0.5 g of sodium borohydride (13 mmol) is added. Stirring is carried out for one hour at 500C. After cooling, a saturated ammonium chloride solution is added dropwise. After the addition of ethyl acetate, washing is carried out with water. The organic phase is dried over sodium sulfate and concentrated by evaporation. The product is purified by chromatography on silica gel (eluant: ethyl acetate/hexane 1 :2). 26.7 g of 1- cyclopropyl-3-(2-nitrophenyl)-propan-1 -ol (99 % of theory) are obtained in the form of a light- brown oil (1H-NMR (CDCI3 - ppm)): -0.05-0.05/m/2H; 0.3/m/2H, 0.7/m/1H, 1.7/m/2H, 2.65- 2.9/m/3H, 7.1-7.2/m/2H, 7.30/t/1 H, 7.67/d/1 H).
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-CyclopropyI-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)-propyI 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-nitrophenyl)-bicyclopropane (CDCI3- ppm): 0.17/m/I H, 0.19/m/I H, 0.42/m/1 H, 0.48/m/1 H, 0.83/m/1 H, 0.84/m/1 H, 0.99/m/1 H, 1.13/m/1 H, 2.17/m/1 H, 7.10/dd/1 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/1 H, 0.02/m/1 H, 0.06/m/1H, 0.27/m/1H, 0.71/m/1H, 0.85/m/1 H, 0.98/m/1 H, 1.10/m/1 H, 2.53/m/I H, 7.35/m/1 H, 7.45/m/1 H, 7.52/m/1 H, 7.92/dd/1 H.
Example P3: 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 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)-bicycIopropane (61 % of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.4:1).
Example P4: 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 triethylamine (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 P5: 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 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)-bicycIopropane (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 3: Compounds of formula I
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
1. A process for the preparation of a compound of formula
wherein Ri, R2 and R3 are each independently of the others hydrogen or methyl, which comprises a) reaction of a compound of formula Il
wherein Ri, R≥ and R3 are as defined for formula I, with a reducing agent to form a compound of formula III
wherein Ri, R≥ and R3 are as defined for formula I; and b) reaction of that compound either b1) with triphenylphosphine dibromide or triphenylphosphine dichloride or b2) with RSO2CI, wherein R is CrC4alkyl, CrC4fluoroalkyl, benzyl, phenyl, nitrophenyl, halophenyl or CrC6alkylphenyl, in the presence of a base, to form a compound of formula IV
2. A compound of formula III
3. Use of a compound of formula III
4. A compound of formula IV
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WO2003074491A1 (en) * | 2002-03-05 | 2003-09-12 | Syngenta Participations Ag | O-cyclopropyl-carboxanilides and their use as fungicides |
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Title |
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TURNBULL M D: "Productivity in synthesis: a mixture protocol to raise compound output iss demonstrated for asymmetric cyclopropanation of allyl alcohols", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, no. 8, 21 April 1997 (1997-04-21), pages 1241 - 1248, XP002175166, ISSN: 0300-922X * |
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