EP2111389A1 - Procédé de préparation d'esters d'acide 2-arylmalonique substitués - Google Patents

Procédé de préparation d'esters d'acide 2-arylmalonique substitués

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Publication number
EP2111389A1
EP2111389A1 EP08701608A EP08701608A EP2111389A1 EP 2111389 A1 EP2111389 A1 EP 2111389A1 EP 08701608 A EP08701608 A EP 08701608A EP 08701608 A EP08701608 A EP 08701608A EP 2111389 A1 EP2111389 A1 EP 2111389A1
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EP
European Patent Office
Prior art keywords
sub
reaction
general formula
base
alkyl
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EP08701608A
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German (de)
English (en)
Inventor
Volker Maywald
Christian Ott
Bernd Wolf
Manfred Ehresmann
Michael Rack
Michael Keil
Sebastian Peer Smidt
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BASF SE
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BASF SE
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Priority to EP08701608A priority Critical patent/EP2111389A1/fr
Publication of EP2111389A1 publication Critical patent/EP2111389A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the present invention relates to a process for the preparation of substituted
  • 2-Arylmalonklareester wherein reacting a malonic acid ester with a base and an aryl bromide in the presence of a copper salt.
  • Substituted 2-arylmalonic acid esters are valuable intermediates in the preparation of numerous organic compounds, such as agrochemicals or pharmaceuticals, and in particular in the production of fungicidal triazolopyrimidines, as z.
  • EP 0 550 1 13 EP 0 782 997, EP 0 770 615, EP 0 975 634 or WO 98/46607.
  • DE 199 38 736 describes a process for the preparation of bis (trifluoromethyl) phenylacetic acids and their alkyl esters by decarboxylation of intermediately formed bis (trifluoromethyl) phenylmalonic acid diesters.
  • DE 199 38 736 teaches, for the preparation of the dialkyl malonates, to react a corresponding phenyl bromide or iodide with a dialkyl malonate in the presence of a deprotonating reagent, a copper salt and a solvent.
  • EP 1 002 788 and US Pat. No. 6,156,925 describe a process for the preparation of 2-phenylmalonic acid esters, wherein one molar equivalent of a phenyl bromide with 2 to 4 molar equivalents of a dialkyl malonate in an inert solvent in the presence of 2 to 3.8 molar equivalents of a base, especially NaH, and a copper salt is reacted.
  • the base is used approximately equimolar, based on the malonic acid ester.
  • the present invention thus provides a process for preparing substituted 2-arylmalonic acid esters of general formula I,
  • R is d-Ce-alkyl or Ci-C4-alkoxy-Ci-C 4 -alkyl
  • Ar is phenyl or a heteroaromatic 5- or 6-membered ring containing as ring members 1 or 2 heteroatoms selected from N, S and O, wherein each carbon atom contained in the aforementioned radicals optionally bears a substituent R A , wherein
  • R A is independently of one another fluorine, chlorine, cyano, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 6 -alkoxycarbonyl,
  • R has the previously given meaning, with a base and an aryl bromide of the formula III,
  • Ar has one of the meanings given above, in the presence of a copper salt, characterized in that one uses 0.1 to 0.65 molar equivalents of the base based on 1 molar equivalent of the malonic ester of the formula II.
  • the terms used in the definition of the substituents for organic groups are collective terms that stand for the individual members of these groups of organic entities.
  • the prefix C x -Cy denotes the number of possible carbon atoms in each case.
  • C 1 -C 6 -alkyl as used herein and in the terms Ci-C ⁇ -alkylaminocarbonyl and
  • Di (Ci-C6-alkyl) aminocarbonyl denotes a saturated, straight-chain or branched hydrocarbon group comprising 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2 Methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl , 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1
  • C 1 -C 4 -haloalkyl describes straight-chain or branched alkyl groups having 1 to 4 carbon atoms, the hydrogen atoms of these groups being partially or completely replaced by halogen atoms
  • Ci-C4-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromothyl, 1-fluoroethyl, 2-fluoroethyl, 2,2 Difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-d
  • C 1 -C 4 -alkoxy as used herein and in the alkoxy moieties of C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and C 1 -C 4 -alkoxycarbonyl herein describes straight-chain or branched saturated alkyl groups comprising 1 to 4 carbon atoms, which are bonded via an oxygen atom. Examples include Ci-C 4 alkoxy such as methoxy, ethoxy, OCH 2 -C 2 H 5, OCH (CHs) 2, n-butoxy, OCH (CHs) -C 2 H 5, OCH 2 -CH (CHs) 2 , OC (CHs) 3 .
  • C 1 -C 4 haloalkoxy describes C 1 -C 4 alkoxy groups as described above, wherein the hydrogen atoms of these groups are partially or completely replaced by halogen atoms, such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy , Difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy .
  • halogen atoms such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy , Difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy
  • C 1 -C 4 -alkyl-C 1 -C 4 -alkyl describes an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom is replaced by an alkoxy group having 1 to 4 carbon atoms.
  • Examples include methoxymethyl, ethoxymethyl, -CH 2 OCH 2 -C 2 H 5 , -CH 2 -OCH (CHs) 2 , n-butoxymethyl, -CH 2 -OCH (CHs) -C 2 H 5 , -CH 2 -OCH 2 -CH (CHs) 2 , -CH 2 -OC (CH 3 ), methoxyethyl, ethoxyethyl, - (CH 2 ) 2 OCH 2 -C 2 H 5 , - (CH 2 ) 2 OCH (CH 3 ) 2 , n- Butoxyethyl, - (CH 2 ) 2 OCH (CH 3 ) -C 2 H 5 , - (CH 2 ) 2 OCH 2 -CH (CH 3 ) 2 or - (CHZ) 2 -OC (CH 3 ), etc.
  • the substances used in the process according to the invention are used in sufficiently high purity.
  • the malonic acid ester of the formula II is preferably essentially anhydrous, ie the water content of the malonic ester is preferably below 500 ppm.
  • the copper salt used preferably has a purity of at least 99 wt .-%, the content of Cu 2+ impurities is preferably less than 0.5%.
  • the malonic ester of the general formula II is reacted with a base and the resulting reaction product is reacted in the presence of the copper salt with the aryl bromide of the general formula III.
  • the reaction takes place essentially without the addition of an inert solvent.
  • the reaction mixture during the process according to the invention comprises less than 20% by weight, preferably less than 10% by weight and more preferably less than 2% by weight of an inert solvent.
  • the reaction takes place in the process according to the invention in substance, ie without the addition of an inert solvent.
  • inert solvent designates organic compounds or mixtures thereof which are added to a reaction without these compounds being significantly involved in or being chemically converted by the reaction
  • inert solvents are for example, aliphatic or aromatic hydrocarbons, such as n-hexane, cyclohexane, toluene or xylene, halogenated hydrocarbons, such as dichloromethane or chloroform, aromatic chlorinated hydrocarbons, such as chlorobenzene, ethers, such as diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane, or amides, such as N-methyl formamide.
  • the base is used in the process according to the invention in a substoichiometric amount based on the malonic acid ester of the formula II.
  • the base is used in an amount of from 0.1 to 0.6 molar equivalents, especially from 0.3 to 0.58 molar equivalents and especially from 0.4 to 0.55 molar equivalents, based on 1 mol of the malonic ester of formula II.
  • the base is particularly preferably used in an amount of from 0.3 to 0.55 molar equivalents, based on 1 mol of diethyl malonate.
  • the malonic acid ester of the formula II is preferably used in the process according to the invention in an amount of from 1 to 5 molar equivalents, in particular from 1.5 to 10 molar equivalents and especially from 1.5 to 5 molar equivalents, based on 1 mol of the aryl bromide of the formula III.
  • the base is used in an amount of 1 to 5 molar equivalents, preferably 1 to 5 molar equivalents.
  • Suitable bases are in the context of the present invention, for example Alkalioder alkaline earth metals, their hydrides, amides, alcoholates, silazanes, carbonates and bicarbonates and tertiary amines.
  • the base used is selected from alkali metal and alkaline earth metal alcoholates, particularly preferably from alkali metal alcoholates, such as sodium or potassium alkoxides, and very particularly preferably from sodium alcoholates.
  • alkali metal alcoholates such as sodium or potassium alkoxides
  • Particularly suitable bases for the process according to the invention are C 1 -C 4 -oxoates, preferably methanolates and ethanolates, such as sodium methoxide or sodium ethanolate.
  • the carbon-containing radical of the alkoxide used as the base and the radical R in the compound of the general formula II have the same meaning. Accordingly, the carbonaceous radical of the alcoholate and the radical R are particularly preferably methyl or ethyl.
  • the alkoxide used as the base can be used in the process of the invention both in the form of a solid and as a solution in the associated alcohol.
  • the solution generally has a weight fraction of alkoxide of at least 10% by weight and in particular at least 20% by weight.
  • alkaline earth alcoholates these can be generated in situ from the alkaline earth metal and the alcohol.
  • alkoxides as base in the process according to the invention offers significant advantages over the use of sodium hydride, especially on an industrial scale.
  • Sodium hydride is much harder to handle due to its reactivity and also much more expensive than, for example, sodium ethoxide or sodium methoxide.
  • the malonic acid ester of the general formula II and the base are reacted.
  • the reaction product is then mixed with a copper salt and the aryl bromide of the formula III.
  • the reaction product of malonic acid ester and base is further reacted without first being isolated or purified.
  • the reaction temperature for the reaction of the malonic ester II with the base is usually at room temperature or above and is limited upwards by the boiling point of the components contained in the reaction mixture. Specifically, the reaction temperature is in a range of 20 to 200 ° C., and more preferably in the range of 20 to 90 ° C.
  • the reaction is usually carried out at atmospheric pressure, but may be carried out at a reduced pressure.
  • an alcohol released during the reaction from the alcoholate and / or added with the base is removed by distillation from the reaction mixture.
  • the distillative removal of the alcohol is substantially complete, ie at least 90%, preferably at least 95% and particularly preferably at least 98% of the alcohol contained in the reaction mixture are removed by distillation.
  • the distillative removal of the alcohol preferably takes place at a temperature above the boiling point of the alcohol at the particular pressure used for the distillation and below the boiling point of the malonic ester of the formula II used at the particular pressure used for the distillation.
  • At least a portion of the alcohol is removed by distillation under reduced pressure, ie at a pressure in the range from 1 to 1000 mbar, preferably from 2 to 800 mbar and more preferably at a pressure of from 5 to 500 mbar.
  • the reduction of the pressure during the distillation is preferably carried out continuously or stepwise.
  • stirrer which is suitable for use with a wall.
  • Wall-mounted stirrers are, for example, anchor stirrers or oblique stirrers. These may additionally be equipped with a device for more efficient removal of the wall, such as wiper blades.
  • Coaxial agitator systems with two independently operating agitators, whereby one of the agitators is preferably designed to be wall-mounted, can also be advantageously used.
  • the copper salt required for the reaction and the aryl bromide are added to the reaction vessel after the reaction of the malonic ester of the formula II with the base.
  • the addition of the copper salt and of the aryl bromide is preferably carried out after completion of the reaction of the malonic acid ester of the formula II with the base and in particular after removal of the alcohol.
  • the distillative removal of the alcohol takes place before the addition of the copper salt used as catalyst for the substitution reaction on the aryl bromide of the formula III.
  • the copper salt used as catalyst can be added in the process according to the invention both in one time and in portions.
  • part of the catalyst used is added before addition of the aryl bromide of the formula III and the remaining amount of the catalyst is added in aliquots in the course of the reaction.
  • the copper salt used as catalyst for the substitution reaction on the aryl bromide of the formula III ie the reaction of the deprotonated malonic ester of the formula II with the aryl bromide of the formula III, preferably has an oxidation state of 1.
  • Suitable catalysts for the substitution reaction are copper salts of the formula CuX, where X is a monovalent anion, especially Cl, Br, I or CN. Preference is given to using CuBr or CuCl and particularly preferably CuBr as the catalyst.
  • the copper salt can be used in the process according to the invention both in free form and in complexed form, especially as dialkylsulphide complex.
  • the copper salt is used in an amount of 0.05 to 0.5 molar equivalents, preferably 0.1 to 0.35 molar equivalents, based on one molar equivalent of aryl bromide of the formula III.
  • the substitution reaction on the aryl bromide of the formula III is preferably carried out in a temperature range from 40 to 200 ° C.
  • the upper limit for the reaction temperature results from the boiling points of the malonic ester of the formula II used and of the aryl bromide of the formula III.
  • the substitution reaction takes place at a temperature of 60 to 120 ° C.
  • reaction temperature is increased continuously or in steps over the course of the substitution reaction.
  • substitution reaction is usually carried out on the aryl bromide of the formula III under atmospheric pressure. In a specific embodiment of the process according to the invention, however, the substitution reaction can also be carried out under elevated or reduced pressure.
  • the substitution reaction is carried out under stripping, i. H. Passing an inert gas such as nitrogen.
  • the reaction mixture is preferably aqueous, more preferably aqueous acid, worked up, ie, the reaction mixture is mixed with water or added to water, the pH is adjusted if necessary, and the resulting aqueous phase is separated from the organic phase, the 2- Arylmalonklareester of formula I contains, separated.
  • the isolation of the substituted 2-arylmalonic acid ester of the general formula I is carried out by customary processes, for example crystallization, filtration, extraction and distillation.
  • the Action obtained reaction mixture with an aqueous solution and the 2-arylmalonic acid is obtained from the resulting organic phase, optionally after drying, by distillation, preferably under reduced pressure.
  • the aryl bromide of the general formula III is additionally provided by bromination of a compound of the general formula Ar-H in which Ar has one of the meanings given above.
  • the bromination of aryl compounds of the formula Ar-H is known in principle.
  • the aryl compound of the formula Ar-H or a solution of this compound in an inert solvent in the presence of a catalyst, especially FeCb or AICb, is reacted with Br2.
  • the Br2 is preferably used in substoichiometric amounts relative to the aryl compound to be brominated.
  • the bromination is usually carried out at a temperature in the range -10 to 60 0 C.
  • the upper limit of the temperature range is determined by the boiling point of Br2.
  • the reaction is carried out at a temperature in the range of 30 to 50 ° C.
  • the bromination takes place in bulk, d. H. without the addition of an inert solvent.
  • reaction mixture is preferably aqueous, especially preferably in the presence of sodium bisulfite, worked up.
  • isolation of the aryl bromide of the general formula III is carried out by customary processes, such as, for example, extraction and distillation.
  • an optionally formed during the reaction of the aryl bromide of the general formula III compound of the formula Ar-H and optionally unreacted aryl bromide of the general formula III are separated and subjected to bromination again or be introduced into the workup of the bromination.
  • inventive method is also advantageously suitable for execution in the form of a continuous process. Therefore, another object of the present invention relates to a process according to the invention, wherein at least a part of the reactions or work-ups is operated continuously. In a specific embodiment of the method according to the invention, the entire process is operated continuously.
  • continuous process refers to a process in which at least one of the compounds involved in the reaction is continuously fed to the reaction and at least one of the intermediates or products of the reaction is withdrawn continuously in the form of a discharge from a reaction mixture.
  • the radical Ar is preferably selected from phenyl, pyridin-2-yl, pyridin-4-yl, pyrazine-2-yl, pyrimidin-2-yl, pyrimidine-4 -yl, pyridazin-3-yl or pyridazin-4-yl, wherein each carbon atom contained in the aforementioned radicals may optionally bear a substituent R A.
  • Ar is more preferably selected from optionally substituted phenyl, pyridin-2-yl or pyridin-4-yl. Specifically, Ar represents optionally substituted phenyl.
  • R A in the compounds of general formula I are optionally substituted independently preferably selected from fluoro, chloro, cyano, Ci -C4 -alkyl, Ci-C 4 haloalkyl, Ci-C4-alkoxy, Ci-C 4 -haloalkoxy. More preferably, R A is fluorine or chlorine.
  • the process according to the invention is used for preparing 2-arylmalonic acid esters of the general formula I in which Ar is phenyl which optionally contains 1, 2 or 3 substituents R A independently selected from fluorine or chlorine.
  • Unreacted 1,3,5-trifluorobenzene is recovered upon rectification and, if desired, can be recycled to the bromination.
  • Dry diethyl malonate (2883.1 g, 18.00 mol) is initially charged at room temperature in a 6 l apparatus with anchor stirrer and solid sodium ethylate (673.7 g, 9.90 mol) is added. Due to the released heat of reaction, the internal temperature rises to about 60 0 C. After completion of the reaction, the resulting ethanol is distilled off as much as possible under reduced pressure (400 mbar) while increasing the temperature from 60 to 80 0 C. At 80 0 C, the pressure is gradually reduced to 10 mbar. Subsequently, the residue is cooled at normal pressure at 75 0 C and treated successively with CuBr (148.5 g, 1 04 mol) and 2,4,6-trifluorobromobenzene (949.4 g,
  • 2,4,6-trifluorophenylmalonate was in a yield of 81, 0% (1057.9 g, 3.645 mol) was obtained (b.p. 83 0 C at 0.5 mbar, mp. 52 0 C).
  • the reaction solution is cooled to 15 0 C and added with stirring to a cooled to 10 0 C mixture of hydrochloric acid (36%, 732.2 g) and water (1451, 0 g).
  • the reaction mixture is filtered.
  • the organic phase is treated with water (1454 g) and the pH is adjusted to 3.5 to 4 by addition of potassium carbonate (30.4 g, 50% aqueous solution). After renewed separation of the phases, the organic phase is rectified under reduced pressure (0.5 mbar).
  • 2,4,6-trifluorophenylmalonic acid diethyl ester was obtained in a yield of 80.7% (1054.2 g, 3.632 mol) (bp 83 0 C at 0.5 mbar, mp 52 0 C).
  • Table 2 The results summarized in Table 2 were obtained by analogous procedure with variation of the molar ratio of diethyl malonate (DEM) to sodium ethoxide (NaOEt) and the amount of catalyst.
  • CuBr was used in the form of CuBr-dimethyl sulfide complex * * )
  • CuCr was used instead of CuBr
  • Dry diethyl malonate (1212.3 g, 7.57 mol) is initially charged in dry dioxane (3 I) at 50 0 C.
  • Sodium ethylate (441.0 g, 6.48 mol) is added portionwise over 1 h. After a further hour at 50 to 55 0 C is distilled until a Kopftempe- temperature corresponding to the boiling point of pure dioxane is reached. The residue is cooled to 90 ° C., copper (I) bromide (176 g, 1.23 mol), copper (I) iodide (176 g, 0.924 mol) and 2,4,6-trifluorobromobenzene (1238, 5 g, 5.87 mol) were added.
  • reaction mixture is cooled to 15 0 C and treated with a cooled to 10 0 C mixture of water (1465 ml) and concentrated hydrochloric acid (36%, 1172 ml). Then the reaction mixture is filtered, diluted with water (2.5 l) and the filtrate extracted with tert-butyl methyl ether (twice with 1, 5 l). The organic phase is washed twice with water (1, 5 I), dried and distilled under reduced pressure (0.5 mbar). Diethyl 2,4,6-trifluorophenylmalonate was obtained in a yield of 42.4% (722.3 g, 2.49 mol) (bp 83 ° C. at 0.5 mbar).
  • Example B.5a Preparation of 2,4,6-trifluorophenylmalonic acid dimethyl ester (Base: sodium methoxide (NaOMe), 30% methanolic solution, catalyst: 0.23 equivalent of CuBr)
  • Dry dimethylmalonate (3630.7 g, 27.48 mol) is initially charged at room temperature in a 6 l apparatus with an anchor stirrer and sodium methylate (1484.5 g, 8.24 mol, 30% strength methanolic solution) is added. Then, at reduced pressure (500 mbar) and simultaneous increase in temperature from 35 to 80 0 C methanol is distilled off. At 80 0 C, the pressure is gradually reduced to 10 mbar. The residue is cooled to 75 0 C and treated successively with CuBr (1 13.4 g, 0.789 mol) and 2,4,6-trifluorobromobenzene (724.7 g, 3.435 mol) was added over a period of 20 min.
  • the reaction mixture is cooled to 15 0 C and added with stirring to a cooled to 10 0 C mixture of hydrochloric acid (36%, 610.2 g) and water (1209.2 g).
  • the reaction mixture is filtered.
  • the organic phase is treated with water (1210.0 g) and the pH is adjusted to 3.5 to 4 by addition of potassium carbonate (50% aqueous solution, 31.9 g).
  • potassium carbonate 50% aqueous solution, 31.9 g
  • Example B.6 Preparation of 2,4-dichlorophenylmalonic acid diethyl ester (base: sodium ethoxide (NaOEt), catalyst: 0.23 equivalent of CuBr) Dry diethyl malonate (1 139.7 g, 7.12 mol) is initially charged at room temperature in a 1.6 l apparatus with anchor stirrer and sodium ethoxide (244.1 g, 3.59 mol) is added as a solid. Due to the released energy of reaction, the internal temperature rises to about 60 0 C. After completion of the reaction (400 mbar) and distilled off under vermin- dertem pressure while increasing the temperature from 60 to 80 0 C Resultant ethanol.
  • base sodium ethoxide (NaOEt)
  • catalyst 0.23 equivalent of CuBr
  • the pressure is gradually reduced to 10 mbar at 80 ° C.
  • the residue is cooled at atmospheric pressure to 75 ° C and treated successively with CuBr (53.3 g, 0.37 mol) and 2,4-dichlorobromobenzene (361, 2 g, 1, 60 mol) over a period of 20 minutes.
  • the reaction mixture is cooled to 15 ° C and cooled with stirring to a cooled to 10 0 C mixture of hydrochloric acid (36%, 260.9 g) and water (512 , 8 g).
  • the resulting reaction mixture is filtered.
  • the organic phase is treated with water (514.0 g) and the pH is adjusted to 4 by addition of potassium carbonate (4.0 g, 50% solution in water). After renewed separation of the phases, the organic phase is freed under reduced pressure (0.5 mbar) and up to an internal temperature of 123 ° C from volatile components. According to quantitative 1 H-NMR spectroscopy, the residue (501, 5 g) consisted of 83.7% of diethyl 2,4-dichlorophenylmalonate. This corresponds to a yield of diethyl 2,4-dichlorophenylmalonate of 86.0%.
  • Example B.7 Preparation of 3,4,5-trifluorophenylmalonic acid diethyl ester (base: sodium ethoxide (NaOEt); catalyst: 0.23 equivalent of CuBr)
  • Dry diethyl malonate (1140.2 g, 7.12 mol) is initially charged at room temperature in a 1.6 l apparatus with anchor stirrer and sodium ethylate (244.5 g, 3.59 mol) is added as a solid. Due to the liberated reaction energy, the internal temperature rises to about 60 0 C. After completion of the reaction, ethanol formed is distilled off under reduced pressure (400 mbar) while increasing the temperature from 60 to 80 0 C. The pressure is gradually reduced to 10 mbar at 80 ° C. The residue is then cooled to 75 ° C.

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  • Organic Chemistry (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de préparation d'esters d'acide 2-arylmalonique substitués de la formule générale (I), dans laquelle R représente un groupe alkyle en C1-C6 ou un groupe (alcoxy en C1-C4)alkyle en C1-C4 ; Ar représente du phényle ou un cycle hétéroaromatique de 5 ou 6 membres ; chacun des atomes de carbone présents dans les restes cités ci-dessus portant le cas échéant un substituant RA ; RA représentant F, Cl, CN, NO2, un groupe alkyle en C1-C4, haloalkyle en C1-C4, alcoxy en C1-C4, haloalcoxy en C1-C4, etc. ou deux substituants RA voisins forment un cycle avec les atomes de carbone sur lesquels ils sont liés. On fait réagir un ester d'acide malonique avec une base et un bromure d'aryle en présence d'un sel de cuivre. Le procédé est caractérisé en ce que l'on met en œuvre 0,1 à 0,65 équivalent molaire de la base par rapport à 1 équivalent molaire de l'ester d'acide malonique. .
EP08701608A 2007-01-22 2008-01-21 Procédé de préparation d'esters d'acide 2-arylmalonique substitués Withdrawn EP2111389A1 (fr)

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EP07100926 2007-01-22
PCT/EP2008/050651 WO2008090127A1 (fr) 2007-01-22 2008-01-21 Procédé de préparation d'esters d'acide 2-arylmalonique substitués
EP08701608A EP2111389A1 (fr) 2007-01-22 2008-01-21 Procédé de préparation d'esters d'acide 2-arylmalonique substitués

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JP (1) JP2010516656A (fr)
CN (1) CN101589016A (fr)
AR (1) AR064977A1 (fr)
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CN113024412A (zh) * 2021-03-23 2021-06-25 上海立科化学科技有限公司 2,4,6-三氯苯腈的制备方法

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WO2008090127A1 (fr) 2008-07-31
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US20100056820A1 (en) 2010-03-04
BRPI0806301A2 (pt) 2011-09-06

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