NO844953L - PROCEDURE FOR PREPARING SUBSTITUTED CONAZOLIN-2.4 (1H.3H) -DION. - Google Patents

Description

The present invention relates to a new process for the preparation of substituted quinazoline-2.4(1H.3H)-dione of the general formula I

where R stands for hydrogen, lower alkyl, unsaturated lower alkyl, substituted lower alkyl or aralkyl, and

1*2 stands for an optionally substituted aryl residue

under conditions of phase-transfer catalysis.

Preferably, the method according to the invention is carried out for

to prepare compounds of the general formula I, wherein

R.j stands for hydrogen, lower alkyl groups of 1 to 6 carbon atoms, lower alkenyl groups of 3 to 5 carbon atoms, propargyl, cyclopropyl, cyclopropylmethyl, haloethyl, trihalogenethyl, acetoxyethyl, alkoxyalkyl groups of 2 to 4 carbon atoms, lower hydroxyalkyl groups of 2 to 3 carbon atoms, hydroxyethoxyethyl, ethoxycarbonylmethyl or benzyl, and

R2 stands for a phenyl radical, which can be substituted by nitro- or halogenated-preferably fluorinated-lower alkyl groups, preferably the CF₂ group, alkylthio or alkoxy groups with up to 3 C atoms.

Particularly preferred is the preparation of 1-(3-nitrophenyl)-3-ethylquinazoline-2,4(1H,3H)-dione by the method according to the invention.

There are already known methods for preparing compounds of the general formula I. One method consists in reacting substituted anthranilic acid amide with suitable carboxylic acid derivatives (see DE-OS 2 459 090). In this method, the anthranilic acid amide is first allowed to react with alkali metals or sodium amide, hydride or alcoholate in an absolute solvent. This is difficult for large-scale production. The product is then reacted with suitable carbonic acid derivatives. As a rule, these must be used in an excess corresponding to several times the molar amount in order to achieve a good yield. This known method is consequently not economical. Furthermore, the surplus of reagents must be processed or disposed of in an environmentally neutral form. This constitutes a further disadvantage of the method.

Surprisingly, it was now found that compounds of the general formula I can be prepared by

Reaction of compounds of the general formula II, where

R 1 and R 2 have the meanings given in connection with

the general formula I,

with stoichiometric amounts, or optionally a small excess, of compounds of the general formula III, where R3 is halogen, preferably chlorine or bromine, and

R4 is halogen, alkoxy or aryloxy, preferably chlorine

or ethoxy,

in the presence of an aqueous base and a suitable organic solvent which is practically immiscible with water, under

mild conditions, and when working under the conditions of phase transfer catalysis (see, among others, Angew. Chem. 8_9, 521

(1977)), in high yield.

According to the invention, a solvent which is practically not miscible with water means a non-polar, aprotic solvent, such as e.g. halogenated or aromatic hydrocarbons. Dichloromethane and toluene have proven to be particularly suitable. Anthranilic acid derivatives of the general formula II are dissolved in this solvent. After adding a phase transfer catalyst, react with a suitable base and<1>the two-phase mixture is stirred vigorously for a few minutes.

As phase transfer catalysts, e.g. tetraalkylammonium-, tetraalkylphosphonium-, tetraalkylarsonium-

or trialkylsulfonium salts, crown ether, cryptate, polyethylene glycol and ethers thereof; tetraalkylammonium salts, especially tetrabutylammonium hydrogensulphate have proven to be particularly beneficial. Preferred bases are alkali hydroxides, a 50% by weight aqueous caustic soda is particularly suitable.

The reaction mixture is then reacted with compounds of

the general formula III, where

R^ and R^ have the meaning stated above - preferred is chloroformic acid ester, especially ethyl ester or phosgene, which is dissolved in a suitable solvent.

The solvent used for III can be the same as, or different from, the solvent used for II, however it must also be as much as possible, non-polar, aprotic and practically immiscible with water. Here too, dichloromethane and toluene have proven to be particularly suitable. The addition of III can be done all at once or in several portions,

in some cases, the addition of more than one mole of III per

mol II be required; preferred is a profit of 5%-20%. The reaction is carried out under strong stirring with a magnetic stirrer

for a period of 10 minutes to 2 hours, preferably for 30-

40 minutes at temperatures between approx. 10 - 35°C, preferably at room temperature. Room temperature here means temperatures between approx. 18°C and 25°C. After completion of the reaction, the reaction mixture is diluted with water and the organic solvent used, the organic phase is separated, washed with water, dried, evaporated and the residue is purified in a suitable manner, preferably by crystallization or chromatography.

The present invention is explained in more detail with the help of the following examples:

Example 1

A solution of 712.5 mg (2.5 mmol) of 2-(3-nitrophenylamino)-benzoic acid ethylamide in 7.5 ml of dichloromethane was reacted at room temperature with 4 2.4 mg (0.125 mmol) of tetrabutylammonium hydrogen sulfate and 2.5 ml of 50 % aqueous NaOH, and the mixture was vigorously stirred for 5 minutes. Then, over the course of 10 minutes and with vigorous stirring, 2.6 25 ml of a 1 M solution of chloroformic acid ethyl ester in dichloromethane was added dropwise to the reaction mixture, and stirring was continued for 30 minutes. It was diluted with 15 ml of each of the compounds water and dichloromethane, the organic phase was separated, the aqueous phase was extracted with a further 5 ml of dichloromethane and the combined organic phases were washed with 15 ml of water. To remove polar impurities, the organic phase was treated with 4 g of "silica gel 60", filtered, the silica gel precipitate was washed with 80 ml of dichloromethane and the combined filtrate was evaporated in vacuo. By stirring the evaporated residue in ether, 641 mg (82.5% of theoretical yield) of 1-(3-nitrophenyl)-3-ethylquinazoline-2.4(1H.3H)-dione with freezing point 187 - 88°C was obtained.

Example 2

By using cetyltrimethylammonium bromide instead of tetrabutylammonium hydrogen sulphate, 50% of the theoretical yield of the product with a freezing point of 187 - 88°C was obtained by the same method as in example 1.

Example 3

By using benzyltributylammonium bromide instead of tetrabutylammonium hydrogensulphate, 72% of the theoretical yield of the product with a freezing point of 187 - 88°C was obtained by the same method as in example 1.

Example 4

A solution of 2.85 g (10 mmol) of 2-(3-nitrophenylamino)-benzoic acid ethylamide in 30 ml of dichloromethane was reacted at room temperature with 169 mg (0.5 mmol) of tetrabutylammonium hydrogen sulfate and 10 ml of 50% aqueous caustic soda, and stirred vigorously in 30 minutes. After adding 7.5 ml of a solution containing 146 g of phosgene per liter of toluene (11 mmol), it was stirred for 15 minutes and the further processing was carried out according to the method described in example 1.

Yield: 2.4 g (77.2% of theoretical yield) of 1-(3-nitro-phenyl)-3-ethylquinazoline-2.4(1H.3H)-dione with freezing point 185 - 188°C.

Claims (10)

1. Process for the preparation of substituted quinazoline-2.4(1H.3H)-dione of the general formula I where R.j stands for hydrogen, lower alkyl, unsaturated alkyl, substituted lower alkyl or aralkyl, and R2 stands for an optionally substituted aryl residue, characterized in that the preparation takes place under conditions of phase transfer catalysis. 2. Process according to claim 1, characterized in that R 1 stands for hydrogen, alkyl with 1 to 6 C atoms, preferably with 1 to 4 C atoms; unsaturated alkyl of 3 to 5 carbon atoms, preferably propargyl; cyclopropyl, cyclopropylmethyl, haloethyl, trihalogenethyl, acetoxyethyl; alkoxyalkyl groups of 2 to 4 carbon atoms; hydroxyalkyl groups with 2 to 3 C atoms, preferably hydroxyethoxyethyl; ethoxycarbonylmethyl or benzyl, and R2 stands for a phenyl residue which can be substituted by nitro- halogenated - preferably fluorinated - lower alkyl groups, preferably with 1 to 4 C atoms, particularly preferred are the trifluoromethyl group, alkylthio or alkoxy groups. » 3. Process for the preparation of 1-(3-nitrophenyl)-3-ethylquinazoline-2.4(1H.3H)-dione of the formula characterized in that the preparation takes place under conditions for phase transfer catalysis. 4. Process for the preparation of substituted quinazoline-2.4(1H.3H)-dione according to one or more of claims 1 to 3, characterized by employing compounds of the general formula II where R 1 stands for hydrogen, lower alkyl, unsaturated lower alkyl, substituted lower alkyl or aralkyl, and R2 stands for an optionally /substituted aryl residue, with approximately stoichiometric amounts of compounds of general formula III where 3 is halogen, preferably chlorine or bromine, and R. is halogen, preferably chlorine or bromine or alkoxy or aryloxy, in the presence of an aqueous base and an organic solvent which is practically immiscible with water, in the presence of a phase transfer catalyst and under vigorous stirring. 5. Process for the production of substituted quinazoline-2.4(1H.3H)-dione according to one or more of claims 1 to 4, characterized in that the reaction is carried out in a non-polar, aprotic solvent, and using a phase transfer catalyst and alkali hydroxide. 6. Method according to claim 4 or 5, characterized in that one or more of the group consisting of halogenated or aromatic hydrocarbons, preferably dichloromethane and/or toluene, is used as a solvent which is practically not miscible with water; as phase transfer catalyst one or more compounds from the group consisting of tetraalkylammonium, tetraalkylphosphonium, tetraalkylarsonium, trialkylsulfonium salts, crown ether, cryptate, polyethylene glycol and ethers thereof, preferably tetraalkylammonium salts, particularly preferred tetrabutylammonium hydrogen sulfate. 7. Process according to one or more of claims 4 to 6, characterized by adding the compounds of formula III in an excess of up to 25 mol%, preferably 5-20 mol%, to compound II. 8. Method according to one or more of claims 4 to 7, characterized in that the reaction is carried out under vigorous stirring at temperatures between approx. 10°C and approx. 35°C, preferably at room temperature. 9. Method according to one or more of claims 4 to 8, characterized in that the aqueous base uses approx. 50% by weight aqueous caustic soda. 10. Method according to one or more of claims 4 to 9, characterized in that the reaction of compounds of the general formula II with compounds of the general formula III is carried out by vigorous mixing at temperatures between 10 and 35°C; with an excess of compound III of from 5 to 20 mol% in the presence of dichloromethane and/or toluene; tetraalkylammonium salts, preferably tetrabutylammonium hydrogensulphate and an approx. 50% aqueous caustic soda.