EP0946522A1

EP0946522A1 - Method for producing 1-phenyl-uracil derivatives

Info

Publication number: EP0946522A1
Application number: EP97954360A
Authority: EP
Inventors: Heinz-Jürgen Wroblowsky
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1996-12-17
Filing date: 1997-12-05
Publication date: 1999-10-06
Also published as: DE19652433A1; AU5854598A; WO1998027067A1; JP2001506247A; BR9714407A; IL130205A0

Abstract

The invention relates to a novel method for producing 1-phenyl-uracil derivatives of formula (I), wherein R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the meanings cited in the description, and substituted phenyloxazine-dione of formula (II) is reacted with amino compounds of formula (III): H2N-R<6> or with acid adducts of amino compounds of formula (III), optionally in the presence of an acid acceptor and optionally in the presence of a diluent.

Description

Process for the preparation of 1-phenyl-uraciI derivatives

The present invention relates to a new process for the preparation of known 1-phenyl-uracιl derivatives. The invention also relates to new intermediates and a process for their preparation

It has already become known that certain phenyl uracils can be prepared by reacting corresponding aminoalkenoic esters with substituted pheny socyanates or with substituted phenyl urethanes in the presence of bases, such as, for example, sodium hydride (cf. EP-A 0 408 382, EP-A 0 648 749 and WO 95-

32 952) A disadvantage of these processes is that the desired substances are obtained in a relatively low yield and not always in sufficient purity. In addition, the starting materials required are not very suitable for syntheses on an industrial scale

Furthermore, it is already known that certain phenyl-uracils can be prepared by reacting aminoalkenoic acid-phenylamides with carbonic acid derivatives (cf. WO 95-32 952). What is disadvantageous about this method is that many stages have to be run through and the synthesis is therefore very expensive

It has also been described that a number of uracil derivatives can be obtained by isomerizing corresponding imino-oxazinones (cf. US Pat. No. 3,352,662). However, this process is impaired by the fact that it can only be used for the production of special substances Compounds substituents that are sensitive to hydrolysis, there is a risk of undesirable side reactions

In addition, it appears from the literature that a number of uracil can be prepared by reacting 1,3-oxazion-2,4 (3H) -dione with primary amines (cf. J Chem Soc 1954, 845-849, J Chem Soc Perkin I 1976. 1969 - 1975 and Chem Pharm Bull 37 (1989), 2026 - 2029) However, the reaction is only described for those oxazinediones that have a non-electron-withdrawing substituent or hydrogen on the double bond adjacent to the oxygen atom. hold. Moreover, the yields on the desired products are not always satisfactory.

Finally, it is already known that certain 1,3-oxazin-2,4 (3H) -diones, which are unsubstituted on the nitrogen atom, react with hydrazine to uracilene, which carry an amino group as a substituent. In the corresponding reaction of 1,3-oxazin-2,4 (3H) -dions which are substituted on the nitrogen atom, however, no uracils are formed, but only pyrazole derivatives (cf. J. Heterocycl. Chem.! 5_ (1978) , 1475-1478).

It has now been found that 1-phenyluracil derivatives of the formula

in which

R ^{1 represents} hydrogen, cyano, nitro or halogen,

R ^{2 represents} cyano, nitro, halogen or optionally substituted alkyl or alkoxy,

R ³ for hydrogen, hydroxy, mercapto, amino, hydroxyamino, halogen, or for one of the radicals -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ -R ⁷ , - N (SO ₂ - _R 7) _2J -CQl-R ⁷ , -CQi-Q ^ R ⁷ , -CQi-NH-R ⁷ , -Q ^ CQ ^ R ⁷ , -NH-CQ ^ R ⁷ , - N ( SO ₂ -R ⁷ ) (CQ ¹ -R ⁷ ), or -Q ² -CQ ¹ -NH- R ⁷ ,

wherein Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and

R ⁷ represents optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,

R ^{4 represents} hydrogen, halogen or optionally substituted alkyl,

R ^{5 represents} alkyl substituted by fluorine and / or chlorine and

R ^{6 represents} hydrogen, hydroxy or in each case optionally substituted alkyl, alkoxy, alkenyl or alkynyl,

obtained when substituted phenyloxazin-diones of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given above,

with amino compounds of the formula

H ₂ NR ⁶ (III)

in which R ^{6 has} the meaning given above,

or with acid adducts of amino compounds of the formula (III), if appropriate in the presence of an acid acceptor and if appropriate in the presence of a diluent, at temperatures between -50 ° C. and + 100 ° C.

It is extremely surprising that 1-phenyl-uracil derivatives of the formula (I) can be prepared by the process according to the invention, because based on the prior art it was assumed that only those 1,3-oxazine-2 , 4 (3H) -diones, which contain a non-electron-withdrawing substituent adjacent to the oxygen atom, react with primary amines to form uracil. It is also unexpected that 1-phenyl-uracile can be prepared in a significantly higher yield by the process according to the invention than by the most similar previously known methods.

The method according to the invention is characterized by a number of advantages. So the required starting materials are easily accessible and also in larger quantities. Furthermore, the implementation of the reaction and the isolation of the desired substances pose no problems. It is particularly favorable that the 1-phenyluracil derivatives are obtained in very high yield and excellent purity. Otherwise, the method is widely applicable.

If 3 - (4-cyano-2,5-difluorophenyl) -3, 4-dihydro-6-trifluoromethyl-2H-1,3-oxazin-2,4-dione and methylamine are used as starting materials, the course can be changed of the method according to the invention are outlined by the following formula:

Formula (II) provides a general definition of the phenyloxazin-diones required as starting materials when carrying out the process according to the invention. Compounds of the formula (II) in which

R ^{1 represents} hydrogen, cyano, nitro, fluorine, chlorine or bromine,

R ^{2 represents} cyano, nitro, fluorine, chlorine, bromine or in each case optionally substituted by fluorine and / or chlorine alkyl or alkoxy having 1 to 4 carbon atoms,

R ³ for hydrogen, hydroxy, mercapto, amino, hydroxyamino, halogen, or for one of the radicals -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ -R ⁷ , - N (SO ₂ -

R7) ₂₎ -CQl-R ⁷ , -CQi-Q ^ R ⁷ , -CQ! -NH-R ⁷ , -Q ² -CQ ¹ -R ⁷ , -NH-CQ ⁱ -R ⁷ , -

N (SO ₂ -R ⁷ ) (CQ ¹ -R ⁷ ), -Q ^ CQi-Q ^ R ⁷ , -NH-CQi-Q ^ R ⁷ or -Q -CQ ¹ -NH- R ⁷ ,

wherein

Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and

R ⁷ for optionally substituted by cyano, halogen, C1-C4-alkoxy, C1-C4-alkylthio, -C-C4-alkyl-carbonyl, C \ -C4-alkoxy-carbonyl or Ci - C4-alkylamino-carbonyl alkyl with 1 to 6 carbon atoms,

or represents in each case optionally substituted by cyano, carboxy, halogen, C 1 -C 4 -alkylcarbonyl, CJ-C4-alkoxycarbonyl or Cj-C4-alkylaminocarbonyl alkenyl or alkynyl each having 2 to 6 carbon atoms,

or for in each case optionally substituted by cyano, carboxy, halogen, C 4 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl cycloalkyl or cycloalkylalkyl, each having 3 to 6 carbon atoms in the Cycloalkyl group and optionally 1 to 4 carbon atoms in the alkyl part,

or for each case optionally up to three times by hydroxy,

Mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, C \ - C alkyl, Cι -C ₄ haloalkyl, C! -C - alkoxy, C _j ^ haloalkoxy, C \ -C4 alkylthio, C] -C4 haloalkylthio, C; , -C4- alkylsulfinyl, Cj-C4-alkylsulfonyl, C \ -C4-alkylamino and / or dimethylamino-substituted aryl or arylalkyl each having 6 or 10 carbon atoms in the aryl group and optionally 1 to 4 carbon atoms in the alkyl part ,

or for each optionally single to triple by hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, C 4 -C 4 alkyl, C 4 -C 4 haloalkyl, C 4 -C 4 alkoxy, C ", C 4 halogen - Alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio, C 1 -C 4 -alkyl sulfinyl, C 4 -C 4 alkyl sulfonyl, C 1 -C 4 alkylamino and / or dimethylamino substituted heterocyclyl or heterocyclylalkyl having 2 to 6 carbon atoms and 1 to 3 nitrogen atoms and / or 1 or 2 acidic atoms and / or a sulfur atom in the heterocyclyl group and optionally 1 to 4 carbon atoms in the alkyl part,

R ^{4 represents} hydrogen, fluorine, chlorine, bromine or alkyl which has 1 to 6 carbon atoms and is optionally substituted by fluorine and / or chlorine and

R ^{5 represents} fluorine and / or chlorine-substituted alkyl having 1 to 6 carbon atoms.

Substituted phenyloxazin-diones of the formula (II) in which

R ^{1 represents} hydrogen, fluorine or chlorine,

R ^{2 represents} cyano, fluorine, chlorine, bromine, methyl or trifluoromethyl, for hydroxy, mercapto, amino, fluorine, chlorine, bromine or for one of the radicals -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ -R ⁷ , -N (SO ₂ -R ⁷ ) ₂ , -CQ ^! -R ⁷ , -CQ! -Q ² -R ⁷ , -CQ! -NH-R ⁷ , -Q -CQ! -R ⁷ , -NH-CQ ^ R ⁷ , -N (SO ₂ -R ⁷ ) ( CQ ¹ - R ⁷ ), -Q ² -CQ ¹ -Q ² -R ⁷ , -NH-CQi-Q ^ R ⁷ or -Q ² -CQ ^! -NH-R ⁷ stands,

wherein

Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and

R ⁷ for each methyl, ethyl, n- or i-propyl, n-, i- , s- or t-butyl,

or for in each case optionally substituted by cyano, carboxy, fluorine, chlorine, bromine, acetyl, propionyl, n- or i-butyroyl, methoxycarbonyl, ethoxycarbonyl, n- or i-propoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n- or i-propylaminocarbonyl penyl, butenyl, propynyl or butynyl, or for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexyl- optionally substituted by cyano, carboxy, fluorine, chlorine, bromine, acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl is methyl, or in each case optionally up to three times by hydroxyl, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethyl , Methylsulfinyl, ethylsulfinyl, methylsulfonyl, methylamino, ethylamino and / or dimethylamino substituted phenyl, benzyl or Phe stands for nylethyl, or in each case optionally once or twice by hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl,

Methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, difluoromethyl, Dichloromethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, fluorodichloromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methyl or sulfonylethylamethylamethylamethylamethylamethylamethylamethylamethylamethyl the series oxiranyl, oxetanyl, furyl, tetrahydrofuryl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridylolyl, pyridylolyl, pyrid Thienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl,

R ^{4 represents} hydrogen, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl and

R ^{5 represents} trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl.

The substituted phenyloxazin-diones of the formula (II) have hitherto been known in some cases (cf. EP-A 0 371 240 and EP-A 0 638 563).

The substituted phenyloxazin-diones of the formula are new

in which

A ^{1 represents} fluorine or chlorine,

A ^{2 represents} cyano, A ^{3 represents} fluorine or chlorine,

A ^{4 represents} hydrogen, fluorine, chlorine or methyl and

A ^{5 represents} trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl.

The substituted phenyloxazin-diones of the formula (Ila) can be prepared by

a) substituted ß-keto-carboxanilides of the formula

in which

A ¹ , A ² , A ³ , A ⁴ and A ^{5 have} the meanings given above,

with carbonic acid derivatives of the formula

in which

Z ¹ and Z ^{2 are the} same or different and represent halogen, alkoxy, aryloxy,

Imidazolyl or triazolyl, if appropriate in the presence of an acid binder, such as sodium hydride, pyridine or 4-dimethylaminopyridine, and optionally in the presence of a diluent, such as toluene or tetrahydrofuran, at temperatures between -20 ° C and + 150 ° C (see the preparation examples)

The remaining substituted phenyloxazin-diones of the formula (II) can be prepared in the same way by substituting substituted β-keto-carboxylic acid anilides of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given above,

implemented by the process (a) with carbonic acid derivatives of the formula (V).

Formula (V) provides a general definition of the carbonic acid derivatives required as reaction components in process (a). In this formula, Z ¹ and Z ^{2 are the} same or different and are preferably chlorine, methoxy, ethoxy, phenoxy, imidazol-1-yl or 1,2,4-triazol-l-yl.

The carbonic acid derivatives of the formula (V) are known.

The substituted β-keto-carboxylic acid anilides are generally defined by the formula (IV). In this formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ preferably have those

Meanings which have already been mentioned as preferred for these radicals in connection with the description of the phenyloxazin-diones of the formula (II). The substituted β-keto-carboxylic acid anilides of the formula (IV) have hitherto been known in some cases (cf. J. Heterocycl. Chem. 2, 113 (1965), Synthesis 1992, 1213-1214 and DE-A 42 18 159).

The substituted ß-keto-carboxanilides of the formula are new

in which

A ^{1 represents} fluorine or chlorine,

A ^{2 represents} cyano,

A ^{6 represents} fluorine, chlorine, methylsulfonylamino or ethylsulfonylamino,

A ^{4 represents} hydrogen, fluorine, chlorine or methyl and

The substituted β-keto-carboxylic acid anilides of the formula (IVb) can be prepared by

(b) β-keto ester of the formula

in which

A ⁴ and A ^{5 have} the meanings given above and

R represents alkyl having 1 to 4 carbon atoms,

with substituted anilines of the formula

in which

A ¹ , A ² and A ^{6 have} the meanings given above,

optionally in the presence of a diluent, e.g. N, N-dimethylformamide or N-methyl-pyrrolidone, at temperatures between 50 ° C and 150 ° C, or if one

(c) substituted aminoalkenoic anilides of the formula

in which

A ¹ , A ² , A ³ , A ⁴ and A ^{6 have} the meanings given above,

with water, optionally in the presence of an acid catalyst, such as hydrochloric acid, sulfuric acid or methanesulfonic acid, and optionally in In the presence of an organic solvent, such as methanol, ethanol, n- or i-propanol, n-, i-, s- or t-butanol, at temperatures between 0 ° C and 100 ° C (see the manufacturing examples)

The other β-keto-carboxylic acid anilides of the formula (IV) can be prepared in the same way

The β-keto esters required as starting materials in carrying out process (b) are generally defined by the formula (VI). In this formula, A ⁴ and A ^{5 have} the meanings given above R preferably represents methyl or ethyl

The amino compounds required as reaction components when carrying out the process according to the invention are generally defined by the formula (III). Compounds of the formula (III) in which

R ⁶ for hydrogen, hydroxyl, each optionally with hydroxyl, cyano,

Halogen or Cj-C4-alkoxy substituted alkyl or alkoxy, each with 1 to

6 carbon atoms, or each optionally by cyano or

Halogen substituted alkenyl or alkynyl each having 2 to 6 carbon atoms

Amino compounds of the formula (III) in which

R ⁶ for hydrogen, hydroxy, for each optionally by hydroxy, cyano,

Fluorine, chlorine, methoxy or ethoxy substituted methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, methoxy, ethoxy, n- or i-propoxy, n-, I-, s - or t-butoxy, or stands for propenyl, butenyl, propynyl or butynyl which is optionally substituted by cyano, fluorine, chlorine or bromine

The amino compounds of the formula (III) can also be used in the form of their acid adducts, preference being given to addition salts with hydrochloric acid The amino compounds of the formula (III) and also their acid addition salts are known or can be prepared by known methods.

Suitable acid acceptors for carrying out the process according to the invention are all customary inorganic or organic bases. Alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogen bicarbonates, hydrides, hydroxides or alkanolates, such as sodium, potassium or calcium acetate, lithium, sodium or potassium, are preferably used - or calcium amide, sodium, potassium or calcium carbonate, sodium, potassium or calcium hydrogen carbonate, lithium, sodium, potassium or calcium hydride, lithium, sodium,

Potassium or calcium hydroxide, sodium or potassium methoxide, ethanolate, n- or -i-propanolate, -n-, -i-, -s- or -t-butanolate; basic organic nitrogen compounds, such as trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N, N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N, N-dimethylaniline, N, N- Dimethylbenzylamine,

Pyridine, 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 2,6-dimethyl, 3,4-dimethyl and 3,5-dimethyl-pyridine, 5- Ethyl-2-methyl-pyridine, 4-dimethylamino-pyridine, N-methyl-piperidine, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo-

[4,3,0] non-5-ene (DBN), or 1.8 diazabicyclo [5,4,0] -undec-7-ene (DBU).

Suitable diluents for carrying out the process according to the invention are all customary inert, organic solvents and also water. Aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, gasoline, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, can preferably be used; Ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; Ketones, such as acetone, butanone or methyl isobutyl ketone; Nitriles such as acetonitrile, propionitrile or butyronitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; Esters like

Methyl acetate or ethyl acetate, sulfoxides such as dimethyl sulfoxide, alcohols such as methanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, their mixtures with water or pure water. The reaction temperatures can be varied within a substantial range when carrying out the process according to the invention. In general, temperatures between -50 ° C. and + 100 ° C., preferably between -30 ° C. and + 80 ° C.

When carrying out the process according to the invention, the procedure is generally carried out under atmospheric pressure. However, it is also possible to work under elevated pressure or, if no volatile components are used, under reduced pressure

To carry out the process according to the invention, 1 to 5 mol, preferably 1.0 to 2.5 mol, of amino compound of the formula (III) are generally employed per mol of substituted phenyloxazinedione of the formula (II).

In a preferred embodiment of the process according to the invention, the substituted phenyloxazinedione of the formula (II) is placed in a suitable diluent and the amino compound of the formula (III) is slowly metered in. The reaction mixture is then stirred - if appropriate at elevated temperature - until the end of the reaction The processing takes place according to usual methods (see the manufacturing examples)

The 1-phenyl-uracil derivatives of the formula (I) and their use as herbicides are already known (cf. EP-A 0 408 382, EP-A 0 648 749 and WO 95-32 952)

The process according to the invention is illustrated by the following examples

Manufacturing examples

example 1

7 ml of a 25% aqueous solution of ammonia (0.10 mol NH ₃ ) are added dropwise at room temperature (approx. 20 ° C.) with stirring to a mixture of 15.9 g (0.05 mol) 3- (4- Cyano-2,5-difluorophenyl) -3,4-dihydro-6-trifluoromethyl-2H-l, 3-oxazine-2,4-dione and 100 ml of ethanol were added. The reaction mixture is stirred for 20 hours at room temperature. The mixture is then concentrated in a water jet vacuum and the residue is taken up in ethyl acetate. The resulting solution is washed with water, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, the residue is digested with a little isopropanol and the crystalline product is isolated by suction.

11.8 g (74% of theory) of 1- (4-cyano-2,5-difluorophenyl) -3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidine are obtained melting point 234 ° C.

Production of raw materials

Example 2

120 g of a 20% solution of phosgene in toluene are stirred at 40 ° C. to a mixture of 60 g (0.20 mol) of N- (4-cyano-2,5-difluorophenyl) -3-oxo 4,4,4-trifluoro-1-butanoic acid amide, 40 ml of pyridine, 4 g of 4-dimethylamino-pyridine and 1.5 liters of toluene added dropwise. The reaction mixture is then stirred at 40 ° C. for a further 4 hours. Excess phosgene is then blown out with nitrogen. The remaining mixture is washed three times with water, dried over sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate in a water jet vacuum.

63.7 g (77.5% of theory) of 3- (4-cyano-2,5-difluorophenyl) -3,4-dihydro-6-trifluoromethyl-2H-1,3-oxazin-2 are obtained. 4-dione as a viscous mass, which gradually crystallizes through.

Melting point (after recrystallization from isopropanol): 127 ° C.

- left

Example 3

Method (b)

A mixture of 9.7 g of ethyl 4,4,4-trifluoroacetate (approx. 95%), 7.8 g of 4-cyano-2,5-difluoro-aniline and 25 ml of N-methyl-pyrrolidone is at 110 for 23 hours ° C stirred After the addition of a further 4.8 g of 4,4,4-trifluoroacetessιgsaureethylester the mixture is stirred for a further 7 hours at 110 ° C. After cooling, the crystalline product is isolated by suction

4.0 g (22% of theory) of N- (4-cyano-2,5-difluorophenyl) -3-oxo-4,4,4-trifluoro-1-butane acid amide with a melting point of 189 ° C. are obtained

Procedure (c

A mixture of 29.1 g (0.10 mol) of N- (4-cyano-2,5-difluorophenyl) -3-amino-4,4,4-tπfluoro-2-butenoic acid amide, 150 ml of water, 19th , 2 g methanesulfonic acid and 450 ml n-

Butanol is stirred for 20 hours at room temperature (approx. 20 ° C). Then the organic phase is separated off, washed twice with 150 ml of water each time, dried over sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate in a water jet vacuum. The residue is mixed with 200 ml of cyclohexane - Stirs, and the crystalline product is isolated by suction

27.2 g (92% of theory) of N- (4-cyano-2,5-difluorophenyl) -3-oxo-4,4,4-trifluoro-1-butane acid amide with a melting point of 189 ° C. are obtained

A mixture of 1.58 g (5 mmol) of N- (4-cyano-2,5-difluorophenyl) -3-amino-4,4,4-tπfluoro-2-butenoic acid amide, 5 ml of water, 5 ml of IN -Saltic acid and 15 ml of n-butanol is stirred for 20 hours at room temperature (approx. 20 ° C). Then 10 ml of water are added given. The organic phase is separated off, washed twice with water, dried over sodium sulfate and filtered. The solvent is carefully distilled off from the filtrate in a water jet vacuum. The residue is stirred with 5 ml of cyclohexane and the crystalline product is isolated by suction.

1.4 g (90% of theory) of N- (4-cyano-2,5-difluorophenyl) -3-oxo-4,4,4-trifluoro-1-butanoic acid amide with a melting point of 189 ° C. are obtained.

Claims

claims

Process for the preparation of 1-phenyl-uracil derivatives of the formula

in which

R ^{1 represents} hydrogen, cyano, nitro or halogen,

R ³ for hydrogen, hydroxy, mercapto, amino, hydroxyamino, halogen, or for one of the radicals -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ - R ⁷ , - N (SO ₂ -R ⁷ ) ₂ , -CQ! -R ⁷ , -CQ! -Q ² -R ⁷ , -CQi-NH-R ⁷ , -Q -CQ! -R ⁷ , -NH-CQi-R ⁷ , -N (SO ₂ -R ⁷ ) (CQ! -R ⁷ ), -Q ² -CQ! -Q ² -R ⁷ , -NH-CQ ⁱ -Q ² - R ⁷ or -Q ² -CQ! -NH-R ⁷ stands,

woπn

Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and R ⁷ represents optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,

R ^{4 represents} hydrogen, halogen or optionally substituted alkyl,

R ^{5 represents} alkyl substituted by fluorine and / or chlorine and

R ^{6 represents} hydrogen, hydroxy or in each case optionally substituted

Alkyl, alkoxy, alkenyl or alkynyl,

characterized in that substituted phenyloxazin-diones of the formula

in which

R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given above,

with amino compounds of the formula

H ₂ NR ⁶ (III)

in which

R ^{6 has} the meaning given above,

or with acid adducts of amino compounds of the formula (III), if appropriate in the presence of an acid acceptor and optionally in the presence a diluent at temperatures between -50 ° C and + 100 ° C.

2. The method according to claim 1, characterized in that substituted phenyloxazin-diones of the formula (II) are used as starting materials, in which

R ^{1 represents} hydrogen, cyano, nitro, fluorine, chlorine or bromine,

R ³ for hydrogen, hydroxy, mercapto, amino, hydroxyamino, halogen, or for one of the radicals -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ -

R ⁷ , -N (SO ₂ -R ⁷ ) ₂ , -CQi-R ⁷ , -CQi-Q ^ R ⁷ , -CQ ⁱ -NH-R ⁷ , -Q ² -CQ ^! -R ⁷ , -NH-CQ! -R ⁷ , -N (SO ₂ -R ⁷ ) (CQ ¹ -R ⁷ ), -Q ² -CQ! -Q ² -R ⁷ , -NH-CQ! -Q ² - R ⁷ or -Q ² -CQ ¹ -NH-R ⁷ ,

wherein

Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and

R ⁷ for optionally substituted by cyano, halogen, Cj-C4-alkoxy, C \ - C4-alkylthio, C ;, -C4-alkyl-carbonyl, CJ-C4-alkoxy-carbonyl or C _j -C4-alkylamino-carbonyl substituted alkyl has 1 to 6 carbon atoms,

or for each optionally by cyano, carboxy, halogen, -C -C4 alkyl carbonyl, C j -C4 alkoxy carbonyl or -C-C4-alkylamino-carbonyl-substituted alkenyl or alkynyl each having 2 to 6 carbon atoms,

or for each optionally by cyano, carboxy,

Halogen, C}, -C4-alkyl-carbonyl or C1 -C4-alkoxy-carbonyl-substituted cycloalkyl or cycloalkylalkyl, each with 3 to

6 carbon atoms in the cycloalkyl group and optionally 1 to 4 carbon atoms in the alkyl part,

or for each optionally single to triple by hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, C1-C4- alkyl, Cι-C4-haloalkyl, C1 -C4-

Alkoxy, -C-C4-haloalkoxy, Cι-C4-alkylthio, Cj-C4-halogenoalkylthio, Cι-C4-alkylsulfinyl, Cj-C4-alkylsulfonyl, C \ - C4-alkylamino and / or dimethylamino substituted aryl or arylalkyl, each with 6 or 10 carbon atoms in the aryl group and optionally 1 to 4 carbon atoms in the

Alkyl part stands,

or for each optionally single to triple by hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, C1-C4-alkyl, C \ -C4-haloalkyl, C1-C4-alkoxy, C \ -C4-haloalkoxy, Cι- C4-alkylthio, C1-C4-

Haloalkylthio, -C-C4-alkylsulfinyl, -C-C4-alkylsulfonyl, C 1 -C4-alkylamino and / or dimethylamino substituted heterocyclyl or heterocyclylalkyl having 2 to 6 carbon atoms and 1 to 3 nitrogen atoms and / or 1 or 2 oxygen atoms and / or a sulfur atom in the heterocyclyl group and optionally 1 to 4 carbon atoms in the alkyl part,

represents hydrogen, fluorine, chlorine, bromine or alkyl having 1 to 6 carbon atoms which is optionally substituted by fluorine and / or chlorine and R ^{5 represents} fluorine and / or chlorine-substituted alkyl having 1 to 6 carbon atoms.

3. The method according to claim 1, characterized in that substituted phenyloxazine-diones of the formula (II) are used as starting materials, in which

R ^{1 represents} hydrogen, fluorine or chlorine,

R ^{2 represents} cyano, fluorine, chlorine, bromine, methyl or trifluoromethyl,

R ³ for hydroxy, mercapto, amino, fluorine, chlorine, bromine or for one of the

Residues -R ⁷ , -QR ⁷ , -NH-R ⁷ , -NH-OR ⁷ , -NH-SO ₂ -R ⁷ , -N (SO ₂ -R ⁷ ) ₂ , -

CQi-R ⁷ , -CQ! -Q ² -R ⁷ , -CQ ^ NH-R ⁷ , -Q ² -CQ ¹ -R ⁷ , -NH-CQ ^ R ⁷ , - N (SO ₂ -R ⁷ ) (CQ ¹ -R ⁷ ), -Q -CQ ^! -Q -R ⁷ , -NH-CQi-Q ^ R ⁷ or -Q ² -

CQi-NH-R ⁷ stands,

wherein

Q represents O, S, SO or SO ₂ ,

Q ¹ and Q ² independently of one another represent oxygen or sulfur and

R ⁷ for each optionally by cyano, fluorine, chlorine, methoxy,

Ethoxy, methylthio, ethylthio, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl or ethylaminocarbonyl substituted methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, or for each optionally by cyano, Carboxy, fluorine,

Chlorine, bromine, acetyl, propionyl, n- or i-butyroyl, methoxycarbonyl, ethoxycarbonyl, n- or i-propoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n- or i-propylaminocarbonyl-substituted propenyl, butenyl, propynyl or butynyl, or for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, each optionally substituted by cyano, carboxy, fluorine, chlorine, bromine, acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl, or for each optionally by up to three times Hydroxyl, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethylthio, methylsulfinyl,

Ethylsulfinyl, methylsulfonyl, methylamino, ethylamino and / or dimethylamino substituted phenyl, benzyl or phenylethyl, or for each optionally mono- or disubstituted by hydroxyl, mercapto, amino, cyano, carboxy, carbamoyl,

Thiocarbamoyl, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, fluorodichloromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio Ethyl thio, difluoromethylthio, trifluoromethylthio, methylsulfinyl,

Ethylsulfinyl, methylsulfonyl, ethylamino, ethylamino and / or dimethylamino substituted heterocyclic or heterocyclylalkyl from the series oxiranyl, oxetanyl, furyl, tetrahydrofüryl, dioxolanyl, thyrylyl, oxyrylolyl, pyrrolyl

Thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridinylmethyl, pyrimidinylmethyl,

R ^{5 represents} trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl. Process according to Claim 1, characterized in that amino compounds of the formula (III) are used as reaction components, in which

R ^{6 represents} hydrogen, hydroxy, alkyl or alkoxy, each optionally substituted by hydroxy, cyano, halogen or C 1 -C ₄ alkoxy, each having 1 to 6 carbon atoms, or alkenyl or alkynyl, each optionally substituted by cyano or halogen, each having 2 is up to 6 carbon atoms.

Process according to Claim 1, characterized in that amino compounds of the formula (III) are used as reaction components, in which

R ⁶ for hydrogen, hydroxyl, for each methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl, methoxy, ethoxy which is optionally substituted by hydroxyl, cyano, fluorine, chlorine, methoxy or ethoxy is n- or i-propoxy, n-, i-, s- or t-butoxy, or is propenyl, butenyl, propynyl or butynyl which is optionally substituted by cyano, fluorine, chlorine or bromine.

Phenyloxazin-diones of the formula

in which

A ^{1 represents} fluorine or chlorine,

A ^{2 represents} cyano, A ^{3 represents} fluorine or chlorine,

A ^{4 represents} hydrogen, fluorine, chlorine or methyl and

7. Process for the preparation of phenyloxazin-diones of the formula (Ila) according to

Claim 6, characterized in that one

a) substituted ß-keto-carboxanilides of the formula

in which

A ¹ , A ² , A ³ , A ⁴ and A ^{5 have} the meanings given above,

with carbonic acid derivatives of the formula

1 ι 2 (V)

-c - z ²

in which

Z ¹ and Z ^{2 are} identical or different and represent halogen, alkoxy, aryloxy, imidazolyl or triazolyl, optionally in the presence of an acid binder and optionally in the presence of a diluent.

β-keto-carboxylic acid anilides of the formula

in which

A ^{1 represents} fluorine or chlorine,

A ^{2 represents} cyano,

A ^{4 represents} hydrogen, fluorine, chlorine or methyl and

A process for the preparation of β-keto-carboxylic acid anilides of the formula (IVb) according to claim 8, characterized in that

(b) β-keto ester of the formula

in which A ⁴ and A ^{5 have} the meanings given above and

R represents alkyl having 1 to 4 carbon atoms,

with substituted anilines of the formula

in which

A ¹ , A ² and A ^{6 have} the meanings given above,

if appropriate in the presence of a diluent, or

(c) substituted aminoalkenoic anilides of the formula

in which

A ¹ , A ² , A ³ , A ⁴ and A ^{6 have} the meanings given above,

with water, optionally in the presence of an acid catalyst and optionally in the presence of an organic solvent.