Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups

Definitions

• the present invention relates to a process for the preparation of hydrochloride-free 2-dihalo genacyl-3-amino-acrylic acid esters by reacting acid fluorides with dialkylaminoacrylic acid derivatives.
• 2-Dihaloacyl-3-amino-acrylates of the formula (I) are valuable intermediates for the preparation of dihalomethyl-substituted pyrazolylcarboxylic acid derivatives which can serve as precursors of fungicidal active compounds (see WO 03/070705).
• EP-A-000926 teaches that trihaloacylaminopropenoates are obtained by reacting trihaloacetoacetates with dialkylformamide acetals.
• the disadvantage here is that as a by-product, the deacylated compound occurs and must be separated from the desired product, which leads to additional costs and yield losses.
• WO 03/051820 teaches that 2-perhaloacyl-3-aminoacrylic acid derivatives can be obtained by reacting 3-aminoacrylic acid esters with perhaloalkylcarboxylic acid anhydrides.
• the method described is not suitable for preparing dihaloacyl-substituted amino acrylic acid derivatives, since in the presence of an ⁇ -hydrogen, in the presence of triethylamine, hydrogen chloride is split off.
• the resulting dihalocethenes are very unstable compounds (see J. Org. Chem., 1968, 33, 816), which tend to polymerize.
• salts are formed in equimolar amounts, eg. As hydrochlorides, which must be separated from the product by filtration or aqueous workup. Is in
• hydrochlorides is used, the term is intended to encompass all impurities resulting from the reaction with the base, for example hydrochlorides, HCl, other salts
• Dihalogenmethylalkoxyacrylate are prepared from Dihalogenacetessigester.
• Dihaloacetessigester are commercially not available and their production is technically demanding, since it requires, for example, the use of ketene. The compounds are therefore not produced economically.
• WO 03/051820 discloses that 2-perhaloacyl-3-aminoacrylic acid derivatives can be reacted with hydrazines to give 3-perhalogeno-substituted pyrazoles. Although the formation of the undesired isomer can be reduced by using an aprotic solvent, this is still considerable when applied to the dihalogen compounds according to the invention.
• R 1 and R 2 are independently selected from Ci. 12- alkyl radicals, Cs.is-aryl, C 7 . 19 - alkylaryl or C 7.
• R 'and R 2 together with the nitrogen atom to which they are attached may form a 5- to 6-membered ring which may optionally contain one or two further heteroatoms selected from O, S and an SO 2 group ;
• R 3 , R 4 and R 5 are independently selected from C] .i 2 -alkyl radicals, C 5 . ) g-Aryl, C 7-19 -AllCyIaFyI- or C 7 . 19 - Arylalkyresten and R 4 and R 5 together with the N-atom to which they are attached and / or further atoms which are selected from C, N, O and S can form a five- or six-membered ring, with Ci , 6 -alkyl radicals may be substituted;
• X 1 and X 2 independently of one another represent fluorine, chlorine, bromine or iodine,
• halogens includes those elements selected from the group consisting of fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred and fluorine and chlorine being particularly preferred preferably used.
• Optionally substituted groups may be monosubstituted or polysubstituted, with multiple substituents the substituents may be the same or different.
• Alkyl groups substituted by one or more halogen atoms are for example selected from trifluoromethyl (CF 3 ), difluoromethyl (CHF 2 ), CF 3 CH 2 , ClCH 2 , CF 3 CCl 2 , CF 3 CHF.
• Alkyl groups are in the context of the present invention, unless otherwise defined, linear, branched or cyclic saturated hydrocarbon groups.
• Ci-C 2- Alkyl comprises the largest range defined herein for an alkyl group.
• this definition includes, for example, the meanings methyl, ethyl, n-, iso-propyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3- Dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.
• Alkenyl groups are in the context of the present invention, unless otherwise defined, linear, branched or cyclic hydrocarbon groups containing at least one simple unsaturation (double bond).
• C 2 -C ] 2 alkenyl includes the largest range defined herein for an alkenyl group. Specifically, this definition includes, for example, the meanings vinyl; Allyl (2-propenyl), isopropenyl (1-methylethenyl); But-1-enyl (crotyl), but-2-enyl, but-3-enyl; Hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl; Hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl; Oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl, oct-7-
• C 2 -C 2 alkynyl encompasses the largest range defined herein for an alkynyl group. Specifically, this definition includes, for example, the meanings ethynyl (acetylenyl); Prop-1-ynyl and prop-2-ynyl.
• Aryl groups in the context of the present invention are, unless otherwise defined, aromatic hydrocarbon groups which may have one, two or more heteroatoms selected from O, N, P and S.
• Aryl includes the largest range defined herein for an aryl group of 5 to 18 atoms. Specifically, this definition includes, for example, the meanings cyclopentadienyl, phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl.
• Arylalkyl groups are in the context of the present invention, unless otherwise defined, substituted by aryl groups alkyl groups which may have a Ci.g-alkylene chain and in the aryl skeleton one or more heteroatoms, which are selected from O, N, P and S.
• C 7 _i 9 aralkyl group includes the largest range defined herein for an arylalkyl group having a total of 7 to 19 atoms in the backbone and alkylene chain. Specifically, this definition includes, for example, the meanings benzyl and phenylethyl.
• Alkylaryl groups are in the context of the present invention, unless otherwise defined, substituted by alkyl groups aryl groups which may have a C ] -8 - alkylene chain and in the aryl skeleton one or more heteroatoms selected can have from O, N, P and S.
• C 7 .i 9 -alkylaryl group includes the largest range defined herein for an alkylaryl group having a total of 7 to 19 atoms in the backbone and alkylene chain. Specifically, this definition includes, for example, the meanings tolyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl.
• the compounds according to the invention can be present as mixtures of various possible isomeric forms, in particular of stereoisomers, such as, for example, E and Z, threo and erythro, as well as optical isomers, but optionally also of tautomers.
• stereoisomers such as, for example, E and Z, threo and erythro
• optical isomers such as, for example, erythro
• tautomers such as, for example, threo and erythro, as well as optical isomers, but optionally also of tautomers.
• E and the Z isomers as well as the threo- and erythro-
• - - Optical isomers any mixtures of these isomers, as well as the possible tautomeric forms disclosed and claimed.
• the acid fluorides used as starting materials in carrying out the process according to the invention are generally defined by the formula (H).
• the radicals X 1 and X 2 are each independently fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably both groups are fluorine.
• Acid fluorides of the formula (II) are known synthetic chemicals and can be prepared, for example, in a simple manner from tetrafluoroethylmethyl ethers, according to Scheme IH (D England, J. Org. Chem. 1984, 49, 4007-4008).
• the dialkylaminoacrylic acid derivatives used as starting materials in carrying out the process according to the invention are generally defined by the formula (HI).
• HI dialkylaminoacrylic acid derivatives used as starting materials in carrying out the process according to the invention
• R 1 and R 2 are independently selected from C 1 .i 2 -alkyl radicals, C 5 .i 8 -aryl, C 7 . 19 - Alkylaryl or C 7 .i 9 -Arylalkyresten, or
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 6-membered ring which may optionally contain one or two further heteroatoms selected from O, S and an SC ⁇ group,
• R 1 and R 2 are independently selected from methyl, ethyl, n-propyl or iso-propyl,
• R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl or pyrrolidinyl ring,
• R 1 and R 2 are methyl and
• Dialkylaminoacrylic acid esters of formula (HI) are known synthetic chemicals and are commercially available.
• dialkylaminoacrylic acid esters which are suitable according to the invention are ethyl 3- (N, N-dimethylamino) acrylate, ethyl 3- (N, N-dimethylamino) acrylate, ethyl 3- (N, N-diethylamino) acrylate, (N, N-dimethylamino) -acrylic acid nitrile, 3- (N, N-dimethylamino) -acrylic acid dimethyl- and 3- (N, N-dimethylamino) -acrylic acid diethylamide with 3- (N, N-dimethylamino) -acrylklathylester is particularly preferred ,
• dialkylaminoacrylic acid derivatives can be purified by distillation, for example. However, this is generally not necessary in connection with the reaction according to the invention.
• the molar ratio of dialkylaminoacrylic acid derivatives (III) to acid fluorides (II) used can be, for example, 0.5 to 3, preferably 0.8 to 2, particularly preferably 1.0 to 1.5.
• the process according to the invention is preferably carried out in an organic diluent.
• organic diluent Particularly suitable for this purpose are, for example, aliphatic, alicyclic or aromatic hydrocarbons, such as e.g. Petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, e.g. Chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane.
• aliphatic, alicyclic or aromatic hydrocarbons such as e.g. Petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, x
• toluene xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, most preferably toluene, chlorobenzene, acetonitrile or xylene, nitriles, amides, ethers.
• Base may be any inorganic or organic base in the context of the process of the invention.
• organic bases are tertiary nitrogen bases, such as tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted quinolines, triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N Methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N, N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3-, 4-picoline, 2-methyl-5- ethyl-pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinoline, quinaldine, N, N, N, N, N-tetramethylethyldiamine, N, N-dimethyl-1,4
• inorganic bases are alkali or alkaline earth metal hydroxides, bicarbonates or carbonates and other inorganic aqueous bases, preferred are e.g. Sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and sodium acetate.
• Base-free therefore means that the proportion of bases in the reaction mixture is not greater than 1%, preferably not greater than 0.1%, more preferably not greater than 0.01%, based on the reaction mixture.
• the process according to the invention is generally carried out under normal pressure. However, it is also possible to work under elevated pressure, for. B. when the volatile difluoroacetyl fluoride is used.
• Increased pressure in this context means 0.1 to 5 bar, preferably 0.15 to 4 bar, more preferably 0.2 to 1 bar.
• reaction time is not critical and can be chosen in a wider range depending on the batch size. Basically, the reaction time is in the range of 30 minutes to 4 hours, preferably between 45 minutes and 2 hours.
• reaction mixture can in principle be used without further purification in the following reaction stage (pyrazole synthesis). It is surprising to see that

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