HK1069167A - Method for the production of 1-amino-3-phenyl-uracil derivatives - Google Patents

Description

Process for preparing 1-amino-3-phenyluracil derivatives

The present invention relates to a novel process for the preparation of known 1-amino-3-phenyl-uracil derivatives (1-amino-3-phenyl-2, 4(1H, 3H) pyrimidinedione derivatives) and novel 1-amino-6-hydroxy-3-phenyl-dihydro-2, 4(1H, 3H) -pyrimidinedione derivatives as intermediates thereof and a process for their preparation.

It is known that certain 3-amino-1-phenyl-uracils can be reacted with substituted phenyl isocyanates or with substituted phenyl urethanes viｃA esters of amino acids (alkenoic) in the presence of bases and that the 1-phenyluracils obtained are reacted with 1-aminooxy-2, 4-dinitro-benzene (cf. EP-A-648749, U.S. Pat. No. 3, 5593945, U.S. Pat. No. 3, 5681794, U.S. Pat. No. 3, 6110870, WO-A-95/29168, U.S. Pat. No. 3, 5759957, U.S. Pat. No. 5962372). However, this process has the disadvantage that the yield of the desired product is low and sufficient quality cannot always be achieved. In addition, the starting materials required are not suitable for industrial scale production.

It is also known to react certain 1, 3-oxazine-2, 4(3H) -diones, unsubstituted on the nitrogen atom, with hydrazines to produce uracils bearing an amino group as a substituent. In contrast, uracil is not obtained in the reaction of the corresponding 1, 3-oxazine-2, 4(3H) -diones substituted on the nitrogen atom, but only pyrazole derivatives are produced (cf. J.heterocyclic. chem.15(1978), 1475-1478).

Finally, it is known that 3-amino-1-phenyl-uracil derivatives can also be prepared by reacting substituted phenyl oxazinediones with hydrazine hydrate or an acid adduct of hydrazine (cf. WO-A-98/27068). However, the yield and quality of the product obtained in this way are not entirely satisfactory.

It has now been found that 1-amino-3-phenyl-uracil derivatives of the general formula (I) (1-amino-3-phenyl-2, 4(1H, 3H) -pyrimidinedione derivatives)

Wherein

R¹Is hydrogen, cyano, nitro or halogen,

R²is cyano, nitro, halogen or in each case optionally substituted alkyl or alkoxy,

R³is hydrogen, hydroxy, mercapto, amino, hydroxylamino, hydrazino, halogen, or is a group-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them is that the first one is,

wherein

Q is O, S, SO or SO₂，

Q¹And Q²Each independently of the other being oxygen or sulfur and

R⁶is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl radical,

R⁴is hydrogen, halogen or optionally substituted alkyl, and

R⁵is a fluorine-and/or chlorine-substituted alkyl group,

by 1-amino-6-hydroxy-3-phenyl-dihydro-2, 4(1H, 3H) pyrimidinedione derivatives of the general formula (II)

Wherein

R¹，R²，R³，R⁴And R⁵The definition is as above-mentioned,

with a dehydrating agent, optionally in the presence of one or more reaction auxiliaries and optionally in the presence of one or more diluents, at a temperature of from-30 ℃ to +180 ℃.

Preferred definitions of the radicals contained in formula (I) are as follows.

R¹Preference is given to hydrogen, cyano, nitro, fluorine, chlorine or bromine.

R²Preferably cyano, nitro, fluorine, chlorine, bromine or in each case optionally fluorine-and/or chlorine-substituted alkyl or alkoxy having 1 to 4 carbon atoms.

R³Preferably hydrogen, hydroxy, mercapto, amino, hydroxylamino, halogen, or is a radical-R⁶， -Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them.

Q is preferably O, S or SO₂。

Q¹And Q²Oxygen is preferred.

R⁴Preferably hydrogen, fluorine, chlorine, bromine or optionally fluorine-and/or chlorine-substituted alkyl of 1 to 6 carbon atoms.

R⁵Preference is given to alkyl of 1 to 6 carbon atoms which is substituted by fluorine and/or chlorine.

R⁶Preferably optionally cyano-, halogen-, C₁-C₄- -alkoxy- -, C₁-C₄-alkylthio-, C₁-C₄-alkyl-carbonyl-, C₁-C₄-alkoxy-carbonyl or C₁-C₄-alkylamino-carbonyl-substituted alkyl of 1 to 6 carbon atoms,

or each of which is optionally cyano-, carboxy-, halogen-, C₁-C₄-alkyl-carbonyl-, C₁-C₄-alkoxy-carbonyl or C₁-C₄-alkylamino-carbonyl-substituted alkenyl or alkynyl groups having 2 to 6 carbon atoms respectively,

or each optionally substituted by cyano, carboxyl, halogen, C₁-C₄-alkyl-carbonyl or C₁-C₄-alkoxy-carbonyl-substituted cycloalkyl or cycloalkylalkyl, each having 3 to 6 carbon atoms in the cycloalkyl group and optionally 1 to 4 carbon atoms in the alkyl moiety,

or in each case optionally substituted by hydroxy-, mercapto-, amino-, cyano-, carboxy-, carbamoyl-, thiocarbamoyl-, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl radical, C₁-C₄-alkylsulfonyl, C₁-C₄-alkylamino and/or dimethylamino mono-to trisubstituted aryl or arylalkyl, each having 6 or 10 carbon atoms in the aryl radical and optionally 1 to 4 carbon atoms in the alkyl moiety, or each optionally substituted by hydroxy-, mercapto-, amino-, cyano-, carboxy-, carbamoyl-, thiocarbamoyl, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy, -C₁-C₄-haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl radical, C₁-C₄-alkylsulfonyl, C₁-C₄-alkylamino and/or dimethylamino mono-to trisubstituted heterocyclyl or heterocyclylalkyl groups having 2 to 6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atoms and/or one sulfur atom in the heterocyclyl group and optionally having 1 to 4 carbon atoms in the alkyl moiety.

R¹More preferably hydrogen, fluorine or chlorine.

R²More preferably cyano, fluoro, chloro, bromo, methyl or trifluoromethyl.

R³More preferably hydroxy, mercapto, amino, fluoro, chloro, bromo or is the group-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them.

Q is more preferably O or SO₂。

R⁴More preferably, hydrogen, fluorine, chlorine,bromo, methyl, ethyl or trifluoromethyl.

R⁵More preferably trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl.

R⁶More preferably methyl, ethyl, n-or i-propyl, n-, i-or s-butyl, each optionally substituted by cyano-, fluoro-, chloro-, methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-, propionyl-, methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl-or ethylaminocarbonyl-,

or propenyl, butenyl, propynyl or butynyl each optionally substituted by cyano, carboxy, fluoro, chloro, bromo, acetyl, propionyl, n-or isobutyryl, methoxycarbonyl, ethoxycarbonyl, n-or isopropoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-or isopropylaminocarbonyl,

or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl each optionally substituted by cyano, carboxy, fluoro, chloro, bromo, acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl,

or in each case optionally mono-to trisubstituted phenyl, benzyl or phenylethyl by hydroxyl, mercapto, amino, cyano, carboxyl, carbamoyl, thiocarbamoyl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, methylamino, ethylamino and/or dimethylamino,

or in each case optionally substituted by hydroxyl, mercapto, amino, cyano, carboxyl, 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, methylsulfonyl, ethylsulfonyl, methylamino, ethylamino-and/or dimethylamino-mono-or disubstituted heterocyclyl or heterocyclylalkyl selected from oxiranyl, oxetanyl, furyl, tetrahydrofuranyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridylmethyl, pyrimidinylmethyl.

Surprisingly, the 1-amino-3-phenyl-uracil derivatives of the general formula (I) (1-amino-3-phenyl-2, 4(1H, 3H) pyrimidinedione derivatives) can be prepared by the process according to the invention in significantly better yields and with higher purity than hitherto known processes.

The process of the present invention has a number of advantages. For example, the desired starting materials can be obtained in a simple manner and in relatively large amounts. Furthermore, the reaction according to the invention and the isolation of the desired substances do not present any significant problems.

When the starting material used is 1-amino-3- (4-cyano-2, 5-difluoro-phenyl) -dihydro-6-hydroxy-6-trifluoromethyl-2, 4(1H, 3H) -pyrimidinedione and the dehydrating agent used is oxalyl chloride, the procedure of the process according to the invention can be carried out as follows:

the 1-amino-6-hydroxy-3-phenyl-dihydro-1, 4(1H, 3H) -pyrimidinedione derivatives used as starting materials when carrying out the process according to the invention are generally defined by formula (II). Preference is given to using compounds of the formula (II) in which

R¹Is hydrogen, cyano, nitro, fluorine, chlorine or bromine,

R²is cyano, nitro, fluorine, chlorine, bromine or in each case optionally fluorine-and/or chlorine-substituted alkyl or alkoxy having 1 to 4 carbon atoms,

R²is hydrogen, hydroxy, mercapto, amino, hydroxylamino, halogen, or is a radical-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them is that the first one is,

wherein

Q is O, S, SO or SO₂，

Q¹And Q²Each independently of the other being oxygen or sulfur and

R⁶is optionally cyano-, halogen-, C₁-C₄-alkoxy-, C₁-C₄-alkylthio-, C₁-C₄-alkyl-carbonyl-, C₁-C₄-alkoxy-carbonyl-or C-C4-alkylamino-carbonyl-substituted alkyl of 1 to 6 carbon atoms,

or each of which is optionally cyano-, carboxy-, halogen-, C₁-C₄-alkyl-carbonyl-, C₁-C₄-alkoxy-carbonyl-or C₁-C₄-alkylaminocarbonyl-substituted alkenyl or alkynyl groups having 2 to 6 carbon atoms,

or each of which is optionally cyano-, carboxy-, halogen-, C₁-C₄-alkyl-carbonyl-or C₁-C₄-alkoxy-carbonyl-substituted cycloalkyl or cycloalkylalkyl, each having 3 to 6 carbon atoms in the cycloalkyl group and optionally 1 to 4 carbon atoms in the alkyl moiety,

or in each case optionally substituted by hydroxy-, mercapto-, amino-, cyano-, carboxy-, carbamoyl-, thiocarbamoyl-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, C₁-C₄-alkylthio-, C₁-C₄-haloalkylthio-, C₁-C₄-alkylsulfinyl-, C₁-C₄-alkylsulfonyl-, C₁-C₄-alkylamino-and/or-dimethylamino mono-to trisubstituted aryl or arylalkyl, each having 6 or 10 carbon atoms in the aryl group and optionally 1 to 4 carbon atoms in the alkyl moiety,

or each independently of the others optionally substituted by hydroxy, mercapto, amino, cyano, carboxy, carbamoyl, thiocarbamoyl, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, C₁-C₄-alkylthio-, C₁-C₄-haloalkylthio-, C₁-C₄-alkylsulfinyl-, C₁-C₄-alkylsulfonyl-, C₁-C₄-alkylamino-and/or dimethylamino-mono-to trisubstituted heterocyclyl or heterocyclylalkyl having 2 to 6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atoms and/or one sulfur atom in the heterocyclyl and optionally having 1 to 4 carbon atoms in the alkyl moiety,

R⁴is hydrogen, fluorine, chlorine, bromine or optionally fluorine-and/or chlorine-substituted alkyl of 1 to 6 carbon atoms and

R⁵is a fluorine-and/or chlorine-substituted alkyl group of 1 to 6 carbon atoms.

Particularly preferred definitions of the radicals in the formula (II) are given below.

R¹Preference is given to hydrogen, fluorine or chlorine.

R²Preferably cyano, fluoro, chloro, bromo, methyl or trifluoromethyl.

R³Preferably hydroxy, mercapto, amino, fluoro, chloro, bromo or is the group-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q2-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(S₂-R)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them.

Q is preferably O, S or SO₂。

Q¹And Q²Each independently is preferably oxygen.

R⁴Preference is given to hydrogen, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl.

R⁵Preferably trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl.

R⁶Preferably methyl, ethyl, n-or i-propyl, n-, i-or s-butyl, each of which is optionally substituted by cyano-, fluoro-, chloro-, methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-, propionyl-, methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl-or ethylaminocarbonyl-,

or propenyl, butenyl, propynyl or butynyl each optionally substituted by cyano, carboxy, fluoro, chloro, bromo, acetyl, propionyl, n-or isobutyryl, methoxycarbonyl, ethoxycarbonyl, n-or isopropoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-or isopropylaminocarbonyl,

or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl each optionally substituted by cyano-, carboxy-, fluoro-, chloro-, bromo-, acetyl-, propionyl-, methoxycarbonyl or ethoxycarbonyl,

or in each case optionally mono-to trisubstituted phenyl, benzyl or phenylethyl by hydroxy, 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,

or phenyl, benzyl or phenylethyl which are in each case optionally mono-to trisubstituted by hydroxyl, mercapto, amino, cyano, carboxyl, carbamoyl, thiocarbamoyl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, methylamino, phenylamino and/or dimethylamino,

or in each case optionally substituted by hydroxyl, mercapto, amino, cyano, carboxyl, 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, methylsulfonyl, ethylsulfonyl, methylamino-, ethylamino-and/or dimethylamino-mono-or disubstituted heterocyclyl or heterocyclylalkyl selected from the group consisting of oxiranyl, oxetanyl, furanyl, tetrahydrofuranyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridylmethyl, pyrimidinylmethyl.

R¹More preferably hydrogen, fluorine or chlorine.

R²More preferably a cyano group.

R³More preferably-NH-R⁶，-NH-O-R⁶，NH-SO₂-R⁶-，-NH-CQ¹-R⁶or-N (SO)₂-R⁶)(CQ¹-R⁶) One of them.

Q is more preferably O or SO₂。

R⁶More preferably methyl, ethyl or n-or isopropyl each optionally substituted by fluorine-and/or chlorine-are preferred,

or propenyl or butenyl each optionally substituted by cyano-, fluoro-and/or chloro-groups,

or cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, each of which is optionally substituted by cyano, fluorine, chlorine or acetyl, or phenyl, benzyl or phenylethyl, each of which is optionally mono-to trisubstituted by hydroxyl, carboxyl, methyl, ethyl, trifluoromethyl, methoxy or ethoxy, or heterocyclyl or heterocyclylalkyl, each of which is optionally mono-or disubstituted by hydroxyl, amino, methyl, ethyl, trifluoromethyl, methoxy or ethoxy, selected from furanyl, tetrahydrofuranyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, pyrazolyl methyl, furanylmethyl, thienyl methyl or thiazolyl methyl.

The starting materials of the general formula (II) have not been disclosed in the literature; they are novel substances and also form the subject of the present invention.

Novel 1-amino-6-hydroxy-3-phenyl-dihydro-1, 4(1H, 3H) -pyrimidinedione derivatives of general formula (II) are prepared by reacting 3-phenyl-2H-1, 3-oxazine-2, 4- (3H) -dione derivatives of general formula (III)

Wherein

R¹，R²，R³，R⁴And R⁵The definition is as above-mentioned,

with hydrazine, hydrazine hydrate or acid adducts of hydrazine, such as hydrazine acetate, hydrazine hydrochloride or hydrazine sulfate, preferably hydrazine hydrate,

optionally in the presence of reaction auxiliaries and/or diluents, such as acetic acid or propionic acid, at temperatures of from-30 ℃ to +100 ℃, preferably from-10 ℃ to +80 ℃.

3-phenyl-2H-1, 3-oxazine-2, 4(3H) -dione derivatives of the general formulｃA (III) are known and/or can be prepared by processes known per se (cf. EP-A-371240, EP-A-638563, WO-A-98/27057, WO-A-98/27067, WO-A-98/27068).

The process of the present invention for preparing 1-amino-3-phenyl-uracil derivatives (1-amino-3-phenyl-2, 4(1H, 3H) -pyrimidinedione derivatives) of the general formula (I) is carried out by using a dehydrating agent. The dehydrating agents used herein are conventional dehydrating materials. Preferred dehydrating agents are: carbodiimides, such as dicyclohexylcarbodiimide; orthoesters, such as trimethyl orthoformate or triethyl orthoformate; acids, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid; anhydrides, such as acetic anhydride, propionic anhydride; phosphorus (V) -oxide or sulfur trioxide; acid chlorides such as phosgene, oxalyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus (V) -chloride (phosphorus (V) -chloride), diethyl chlorophosphate, acetyl chloride, trimethylsilylchloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, or Lewis acids such as boron trifluoride or aluminum trichloride.

Thionyl chloride is particularly preferred as a dehydrating agent in the process of the present invention.

The process of the invention for the preparation of 1-amino-3-phenyl-uracil-derivatives of the general formula (I) (1-amino-3-phenyl-2, 4(1H, 3H) -pyrimidinedione derivatives) is carried out by using one or more reaction auxiliaries. Reaction auxiliaries which are useful in carrying out the process of the invention are all customary inorganic or organic bases. Preference is given to using alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogen carbonates, hydrides, hydroxides or alkanolates, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or calcium hydrogen carbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium or potassium methanolates, ethanolates, n-or iso-propanolates, n-, iso-, sec-or tert-butanolates; and basic organic nitrogen compounds, for example trimethylamine, triethylamine, tripropylamine, tributylamine, ethyl-diisopropylamine, N-dimethyl-cyclohexylamine, dicyclohexylamine, ethyl-dicyclohexylamine, N-dimethyl-aniline, N-dimethyl-benzylamine, 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, N-ethyl-piperidine, N-methyl-morpholine, n-ethyl-morpholine, 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).

The basic organic nitrogen compounds mentioned above, in particular pyridine, are very particularly preferred as reaction assistants in the process of the present invention.

The process of the present invention for the preparation of 1-amino-3-phenyl-uracil-derivatives of the general formula (I) (1-amino-3-phenyl-2, 4(1H, 3H) -pyrimidinedione derivatives) is carried out by using one or more diluents. Diluents which are useful in carrying out the process of the invention are all customary inert, organic solvents. Preferably, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons can be used, such as, for example, gasoline, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride; ethers, such as diethyl ether, isopropyl 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 n-or isobutyronitrile; amides, such as N, N-dimethyl-formamide, N-diethyl-formamide, N-dipropyl-formamide, N-dibutyl-formamide, N-dimethylacetamide, N-methyl-formanilide, N-methyl-pyrrolidone or hexamethyl-phosphorous triamide; esters, such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide.

Very particular preference is given to using aprotic polar solvents, such as methyl-isobutyl-ketone, acetonitrile, propionitrile or N-or isobutyronitrile, N-dimethyl-formamide or N, N-dimethyl-acetamide, as diluent in the process according to the invention.

When carrying out the process according to the invention for preparing the compounds of the formula (I), the reaction temperatures can be varied within a relatively wide range. The working temperature is generally from-30 ℃ to +180 ℃, preferably from-10 ℃ to +150 ℃, more preferably from 0 ℃ to 100 ℃.

The process of the invention is generally carried out at atmospheric pressure. However, it may be carried out under elevated pressure, or under reduced pressure as long as the volatile component is not used.

For carrying out the process according to the invention, in general from 0.2 to 2Mol, preferably from 0.5 to 1.5Mol, of dehydrating agent are used per mole of 1-amino-6-hydroxy-3-phenyl-dihydro-2, 4(1H, 3H) pyrimidinedione derivative of the formula (II).

In a preferred embodiment of the process according to the invention, the amino-6-hydroxy-3-phenyl-dihydro-2, 4(1H, 3H) pyrimidinedione derivative of the formula (II) is initially charged in a suitable diluent and the dehydrating agent and the reaction auxiliary are slowly metered in. The reaction mixture is then stirred (optionally under elevated pressure) until the end of the reaction. The work-up was carried out by conventional methods (reference preparation).

The 1-amino-3-phenyl-uracil derivatives of the formulｃA (I) can be used as herbicides for weed control (cf. EP-A-648749, WO-A-94/04511, WO-A-95/29168, WO-A-96/35679).

Preparation examples

Example 1

25.5g (97.5%, 56.7mMol) of N- [5- (3-amino-4-hydroxy-2, 6-dioxo-4-trifluoromethyltetrahydro-1 (2H) -pyrimidinyl) -2-cyano-4-fluoro-phenyl ] -ethanesulfonamide are initially introduced into 100ml of N-butyronitrile and 224mg (2.8mMol) of pyridine are added at room temperature (approx. 20 ℃). To the suspension was added dropwise 33.7g of thionyl chloride. A small amount of gas evolved and the reaction mixture turned yellow. After about 1 minute, a clear solution formed, after about 5 minutes turbidity appeared and after about 10 minutes a large amount of precipitate formed. The mixture was heated at reflux temperature and stirring was continued for 30 minutes with substantial gas evolution above about 60 ℃. After cooling to room temperature, the mixture is diluted with 50ml of n-butyronitrile, 100ml of ice-water are added, the phases are separated and the organic phase is washed 3 times with a small amount of water, dried over sodium sulfate and filtered. The solvent in the filtrate was carefully distilled off under reduced pressure.

22.6g (94%, determined by 19F NMR, 89% of theory) of N- [5- (3-amino-2, 6-dioxo-4-trifluoromethyl-3, 6-dihydro-1 (2H) -pyrimidinyl) -2-cyano-4-fluoro-phenyl ] -ethanesulfonamide are obtained, which have a melting point of 190 ℃.

Starting materials of the formula (II)

Example (II-1)

60.7g (99.3%, 150mMol) of N- [ 2-cyano-5- (2, 4-dioxo-6-trifluoromethyl-2H-1, 3-oxazin-3 (4H) -yl) -4-fluoro-phenyl ] -ethanesulfonamide are initially introduced into 300ml of propionic acid, and 9,0g of hydrazine hydrate (99%, 178mMol) are added with stirring at room temperature (approx. 20 ℃). The mixture (suspension) was heated to about 30 ℃ and the suspension was stirred at this temperature for 5 hours while the color turned light. The mixture was cooled to 15 ℃ and filtered with suction, and the filtered residue was stirred with a spatula on a suction filter and washed several times with isopropanol and sucked to dryness. The light yellow filter cake was first dried under air and then dried overnight in a desiccator with potassium hydroxide.

41g (94.9%, 60% of theory) of N- [5- (3-amino-4-hydroxy-2, 6-dioxo-4-trifluoromethyl-tetrahydro-1 (2H) -pyrimidinyl) -2-cyano-4-fluoro-phenyl ] -ethanesulfonamide are obtained, which have a melting point of 182 deg.C (decomposition).

After concentration of the mother liquor, the residue still contains 35.5% N- [5- (3-amino-4-hydroxy-2, 6-dioxo-4-trifluoromethyl-tetrahydro-1 (2H) -pyrimidinyl) -2-cyano-4-fluoro-phenyl ] -ethanesulfonamide according to HPLC-analysis (further 23% relative to the theoretical yield). Therefore, the total yield was 83%.

Claims (13)

1. A process for the preparation of a compound of formula (I),

wherein

R¹Is hydrogen, cyano, nitro or halogen,

R²is cyano, nitro, halogen or in each case optionally substituted alkyl or alkoxy,

R³is hydrogen, hydroxy, mercapto, amino, hydroxylaminoHydrazino, halogen, or a group-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them is that the first one is,

wherein

Q is O, S, SO or SO₂，

Q¹And Q²Each independently of the other being oxygen or sulfur and

R⁶is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl radical,

R⁴is hydrogen, halogen or optionally substituted alkyl, and

R⁵is a fluorine-and/or chlorine-substituted alkyl group,

characterized by the fact that it is prepared by reacting a compound of the general formula (II)

Wherein

R¹，R²，R³，R⁴And R⁵The definition is as above-mentioned,

with a dehydrating agent at a temperature of-30 ℃ to +180 ℃.

2. The process as claimed in claim 1, characterized in that a compound of the formula (II) is reacted, where

R¹Is hydrogen, cyano, nitro, fluorine, chlorine or bromine,

R²is cyano, nitro, fluorine, chlorine, bromine or each of which is optionally fluorine-andor a chloro-substituted alkyl or alkoxy group having 1 to 4 carbon atoms,

R³is hydrogen, hydroxy, mercapto, amino, hydroxylamino, halogen, or is a radical-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them is that the first one is,

wherein

Q is O, S, SO or SO₂，

Q¹And Q²Each independently of the other being oxygen or sulfur and

R⁶is optionally cyano-, halogen-, C₁-C₄-alkoxy-, C₁-C₄-alkylthio-, C₁-C₄-alkyl-carbonyl-, C₁-C₄-alkoxycarbonyl-or C₁-C₄-alkylaminocarbonyl-substituted alkyl of 1 to 6 carbon atoms,

or each of which is optionally cyano-, carboxy-, halogen-, C₁-C₄-alkylcarbonyl-, C₁-C₄-alkoxycarbonyl-or C₁-C₄-alkylaminocarbonyl-substituted alkenyl or alkynyl groups having 2 to 6 carbon atoms respectively,

or each of which is optionally cyano-, carboxy-, halogen-, C₁-C₄-alkylcarbonyl-or C₁-C₄-alkoxycarbonyl-substituted cycloalkyl or cycloalkylalkyl, each having 3 to 6 carbon atoms in the cycloalkyl group and optionally 1 to 4 carbon atoms in the alkyl moiety,

or each of which is optionally substituted by hydroxy-, mercapto-, amino-, cyano-, carboxy-, carbamoyl-Thiocarbamoyl-, C₁-C₄-alkyl radical, C₁-C₄-haloalkyl radical, C₁-C₄-alkoxy radical, C₁-C₄-haloalkoxy-, C₁-C₄-alkylthio-, C₁-C₄-haloalkylthio-, C₁-C₄-alkylsulfinyl-, C₁-C₄-alkylsulfonyl-, C₁-C₄-alkylamino-and/or dimethylamino-mono-to trisubstituted aryl or arylalkyl, each having 6 or 10 carbon atoms in the aryl group and optionally 1 to 4 carbon atoms in the alkyl moiety,

or in each case optionally substituted by hydroxy-, mercapto-, amino-, cyano-, carboxy-, carbamoyl-, thiocarbamoyl-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-, C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, C₁-C₄-alkylthio-, C₁-C₄-haloalkylthio-, C₁-C₄-alkylsulfinyl-, C₁-C₄-alkylsulfonyl-, C₁-C₄-alkylamino-and/or dimethylamino-mono-to trisubstituted heterocyclyl or heterocyclylalkyl having 2 to 6 carbon atoms and 1 to 3 nitrogen atoms and/or 1 or 2 oxygen atoms and/or one sulfur atom in the heterocyclyl and optionally having 1 to 4 carbon atoms in the alkyl moiety,

R⁴is hydrogen, fluorine, chlorine, bromine or alkyl having 1 to 6 carbon atoms which is in each case optionally fluorine-and/or chlorine-substituted,

R⁵is a fluorine-and/or chlorine-substituted alkyl group of 1 to 6 carbon atoms.

3. The process as claimed in claim 1, characterized in that the compounds of the formula (II), in which

R¹Is a compound of hydrogen, fluorine or chlorine,

R²is cyano, fluoro, chloro, bromo, methyl or trifluoromethyl,

R³is hydroxy, mercapto, amino, fluorine, chlorine, bromineOr is a radical-R⁶，-Q-R⁶，-NH-R⁶，-NH-O-R⁶，-NH-SO₂-R⁶，-N(SO₂-R⁶)₂，-CQ¹-R⁶，-CQ¹-Q²-R⁶，-CQ¹-NH-R⁶，-Q²-CQ¹-R⁶，-NH-CQ¹-R⁶，-N(SO₂-R⁶)(CQ¹-R⁶)，-Q²-CQ¹-Q²-R⁶，-NH-CQ¹-Q²-R⁶or-Q²-CQ¹-NH-R⁶One of them is that the first one is,

wherein the content of the first and second substances,

q is O, S, SO or SO₂，

Q¹And Q²Each independently of the others being oxygen or sulphur and,

R⁶is methyl, ethyl, n-or i-propyl, n-, i-or s-butyl, each optionally substituted by cyano-, fluoro-, chloro-, methoxy-, ethoxy-, methylthio-, ethylthio-, acetyl-, propionyl-, methoxycarbonyl-, ethoxycarbonyl-, methylaminocarbonyl-or ethylaminocarbonyl,

or propenyl, butenyl, propynyl or butynyl each optionally substituted by cyano, carboxy, fluoro, chloro, bromo, acetyl, propionyl, n-or isobutyryl, methoxycarbonyl, ethoxycarbonyl, n-or isopropoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-or isopropylaminocarbonyl,

or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl each optionally substituted by cyano, carboxy, fluoro, chloro, bromo, acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl,

or phenyl, benzyl or phenylethyl each optionally mono-to trisubstituted by hydroxyl, mercapto, amino, cyano, carboxyl, carbamoyl, thiocarbamoyl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, ethylthio, difluoromethylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, methylamino, ethylamino and/or dimethylamino,

or in each case optionally substituted by hydroxyl, mercapto-, amino-, cyano-, carboxyl-, 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-, methylsulfonyl-, ethylsulfonyl-, methylamino-, ethylamino-and/or dimethylamino-mono-or disubstituted heterocyclyl or heterocyclylalkyl selected from oxiranyl, oxetanyl, furyl, tetrahydrofuranyl, dioxolanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, triazinyl, pyrazolylmethyl, furylmethyl, thienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridylmethyl, pyrimidinylmethyl,

R⁴is hydrogen, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl,

R⁵is trifluoromethyl, chlorodifluoromethyl, fluorodichloromethyl or pentafluoroethyl.

4. A compound of formula (II)

Wherein

R¹，R²，R³，R⁴And R⁵As defined in any one of claims 1 to 3.

5. Process for the preparation of compounds of the formula (II) according to claim 4, characterized in that compounds of the formula (III)

Wherein

R¹，R²，R³，R⁴And R⁵As defined in any one of claims 1 to 3

With hydrazine, hydrazine hydrate or acid adducts of hydrazine at temperatures of-30 ℃ to +100 ℃.

6. The process of claim 1, characterized in that the reaction is carried out in the presence of one or more reaction assistants.

7. The process according to claim 1 or 6, characterized in that the reaction is carried out in the presence of one or more diluents.

8. A process as claimed in claim 1, 6 or 7, wherein the dehydrating agent used is a carbodiimide, an orthoester, an acid, an anhydride, an acid chloride or a Lewis acid.

9. A process according to claim 1 or 6 to 8, characterized in that the dehydrating agent used is thionyl chloride.

10. The process as claimed in any of claims 6 to 9, characterized in that the reaction assistants used are basic organic nitrogen compounds.

11. A process according to claim 10, characterized in that the reaction auxiliary used is pyridine.

12. A process according to claim 7, characterized in that the diluent used is an aprotic polar solvent.

13. The process of claim 1, characterized in that the reaction is carried out at a temperature of-10 ℃ to +150 ℃.