KR840001563B1 - Process for preparing 1-carbymayl-3-(3,5-dichlorophenyl)-hydantoins - Google Patents

Abstract

Title compds. (I; R1 = Ph radical, C1-4 alkyl radical; R2 = H, C1-4 alkyl radical) were prepd. by treating III with COCl2 in inactive organic solvent in the presence of acid receptors, and reaction with HNR1R2. Thus, phosgenation of 61.3g 3-(3, 5-dichlorophenyl)-hydantoin in PhCl and reaction with 14.7g isopropylamine gave 91.5% 1-isopropylcarbamoyl-3-(3, 5-dichlorophenyl) hydantoin

Description

Method for preparing 1-carbamoyl-3- (3,5-dichlorophenyl) -hydantoin derivative

The present invention provides a novel process for preparing N-substituted 1-carbamoyl-3- (3,5-dichlorophenyl) -hydantoin and a novel substance that can be used as a new intermediate in the preparation of this product, namely 1-chlorocarbonyl A method for preparing 3- (3,5-dichlorophenyl) -hydantoin.

Certain N-substituted 1-carbamoyl-3- (3,5-dichlorophenyl) -hydantoin are known as plant-protective products, in particular agricultural fungicides. This applies in particular to 1-isopropylcarbamoyl-3- (3,5-dichlorophenyl) -hydantoin, commonly referred to as iprodisilver, which forms the subject of French Patent Nos. 2,120,222 and 2,148,868. This compound can be prepared according to various methods.

The patent describes how 3- (3,5-dichlorophenyl) -hydantoin reacts with isopropylcarbamyl chloride, the latter of which occurs by condensation of phosgene with isopropylamine. However, this method is not sufficient for industrial scale yield. Nowadays, the development of the fungicides described above requires the development of a process which can produce them under much more economic conditions.

The present invention relates to a method which can satisfy these conditions. It relates in particular to a process of starting from the material of the following structural formula, 3- (3,5-dichlorophenyl) -hydantoin.

Wherein R ₁ is a phenyl radical or an alkyl radical having 1 to 4 carbon atoms, R ₂ is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, and the preparation method consists of two steps:

In the first step, phosgene is combined with 3- (3,5-dichlorofenyl) -hydantoin to produce 1-chlorocarbonyl-3- (3,5-dichlorophenyl) -hydantoin according to the following scheme. React in a solvent medium, preferably in the presence of an acid acceptor,

In a second step, the product of formula (II) is dissolved in an inert organic solvent in the presence of an acid acceptor according to the following scheme, wherein the primary or secondary amines are represented as defined above: HNR ₁ R ₂ , R ₁ and R ₂ And abuse).

The first step, called the phosgenation, is carried out using an excess of phosgene in terms of stoichiometry, in order to prevent the formation of urea from the condensation of the compound of formula (II) with the starting compound. This is preferred. However, unreacted phosgene should not be used in excessive amounts because it must be degassed at the end of the reaction.

The reaction is preferably carried out in excess of 5 to 100 mol%.

The first step is preferably carried out using at least stoichiometric amounts of the acid acceptor, in which case hydrochloric acid is the acid acceptor. As the receptor, a strong organic base or an inorganic base can be used.

Ferroorganic bases that can be used include tertiary amines such as trialkylamines (e.g. triethylamine) or pyridine such as pyridine and dimethylamino pyridine and the like. This organic base is advantageously used in approximately stoichiometric amounts.

Inorganicyl groups that can be used are alkali metal carbonates or alkali metal hydroxides, with carbonates in particular disodium carbonate being more preferred. This inorganic base may be used in stoichiometric amounts, but the excess amount is preferably up to 150%. The acid acceptor according to the invention is advantageously combined with an adjuvant. As an auxiliary agent, both an auxiliary base or a transfer agent can be used.

The auxiliary base formulated in an amount of 1 to 15%, preferably 5 to 10%, is an organic term of the same type as defined above, but different from the first. In particular, pyridine dimethylaminopyridine or triethylamine can be used for this purpose. Preferably, when the inorganic base, in particular the alkali metal carbonate is an acid acceptor, the transfer agent that can be used in combination with it may use an ammonium or phosphonium derivative or a sequestering agent, each compound being defined below. do.

Quaternary ammonium derivatives that can be used in the present invention preferably correspond to the following general structural formulas;

Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other, each of which is an alkyl radical having 1 to 20 carbon atoms, a cycloalkyl radical having 3 to 6 carbon atoms, and an alkenyl radical having 2 to 20 carbon atoms Or a substitution of 1 to 6 carbon atoms in the alkyl moiety represents an optional phenylalkyl radical, X represents a chlorine, bromine or fluorine atom or a SO ₄ , SO ₄ H, PO ₄ H ₂ or hydroxyl radical, 1 carbon atom Alkoxysulfonyl radicals of 4 to 4 (eg methoxysulfonyloxy or ethoxysulfonyloxy), alkanesulfonyloxy radicals of 1 to 4 carbon atoms (eg methanesulfonyloxy or ethanesulfonyloxy), arerensul Ponyoxyoxy radicals (e.g. benzenefonyloxy or p-toluenesulfonyloxy) or alkanoyloxyradicals (e.g. acetyloxy and propionyloxy) having 1 to 4 carbon atoms, n is the same number as the valence of X .

Good results are usually obtained by using mixtures of quaternary ammonium derivatives, such as those sold under the following trademarks, which are as follows:

Adogen 464: a mixture of methyltrialkylammonium having 8 to 10 carbon atoms in the alkyl moiety, and Cemulcat K 012: a mixture of dihydroxyethyldialkylammonium chloride having 16 to 18 carbon atoms in the alkyl moiety.

As the catalyst to be used, ammonium derivatives of the following structural formulas are preferable.

In the above formula, X and n have the same meaning as the above-mentioned structural formula, R ₅ is 1 to 4 carbon atoms such as ethyltributylammonium chloride, methbutylbutylammonium chloride, tetrabutyl ammonium chloride or tetrabutylammonium sulfate etc. Denotes an alkyl radical.

The phosphonium derivatives that can be used in the present invention preferably correspond to the following structural formula:

Wherein R ₁ ′, R ₂ ′, R ₃ ′ and R ₄ ′ are the same or different and each represents an alkyl radical having 2 to 8 carbon atoms and Y represents a chlorine or bromine atom.

The amount of this derivative can be varied within wide limits, ranging from 0.01 mole to 1 mole per equivalent of base material used. Indeed, for economic reasons phosphonium derivatives are used in amounts of 0.5 to 5 mole percent per mole of main reactant.

Alkali metal carbonates are preferably used in combination with metal ion sequestrants of the following structural formulas, which are known per se:

Wherein n is an integer greater than or equal to 0 and less than or equal to about 10, and R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other, and a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms R ₅ represents an alkyl and cycloalkyl radical having 1 to 12 carbon atoms, or a phenyl radical or a radical having _m between 1 and 12 -C _m H _2m -φ or C _m H _{2w + 1-} φ- .

R ₁ , R ₂ , R ₃ . Wherein R ₄ represents a hydrogen atom or methyl radical, R ₅ is preferably an alkyl radical having 1 to 4 carbon atoms having the same meaning as above, n is of the same meaning as above and at least 0 to 3 are preferred. Preference is given to using a metal ion disintegrant having

Examples of these compounds include:

Structure N- (CH _2- CH _2- H ₄ OC ₉₎ of _3-tris (3-oxa haeptil) -amine, the following structural formula N- (CH _2- CH _2- CH _2- O-CH ₃ O-CH ₃ ) _3, tris- (3,6-dioxa haeptil) -amine, the following structural formula _{N- (CH 2- CH 2- O-} CH 2- CH 2- O-CH 2- CH 2- O-CH 3) ₃ of Tris- (3,6,9-trioxadecyl) -amine, tris- (3,6-diox of structural formula N- (CH ₂ -CH ₂ -O ₂ -CH ₂ -OC ₂ -H ₅ ) ₃ Trioctyl) -amine, tris- (3,6,9-tree of formula N- (CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -OC ₂ -H ₅ ) ₃ Tris (3,6-dioxanonyl) -amine of oxoundecyl) -amine N- (CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -OC ₃ H ₇ ) ₃ , structure N- (CH _{2 - CH 2- O-CH 2- CH} 2- O-CH 2- CH 2- OC 3 H 7) ₃ of tris- (3,6,9- tree oxa-dodecyl) -amine, N- formula (CH _{2 -} O-CH _2- CH _2- CH _{2- 4} OC H _{9) 3} of tris- (3,6-dioxa-octyl) -amine and the formula _{N- (CH 2- CH 2- O-} CH 2- CH 2 _- O-CH _2- CH _{2- 4} OC H _{9) 3} tris (3,6,9- tree oxa tridecyl) has an amine or the like.

의 트리스-(3,6-디옥사-4-메틸헵틸)-아민 및 구조식

의 트리스-(3,6-디옥사-2,4-디메틸헵틸)-아민도 예로 들수 있다.constitutional formula

Tris- (3,6-dioxa-4-methylheptyl) -amine of the formula

Tris- (3,6-dioxa-2,4-dimethylheptyl) -amine of is also exemplified.

The amount of these derivatives is about 0.5 to 15%, preferably 1 to 10% in molar ratio relative to the reactants.

Phosgenation is carried out in an inert organic solvent under reaction conditions. To facilitate the degassing of excess phosgene using relatively high boiling point solvents, especially aromatic solvents such as toluene or xylene, chlorinated aromatic solvents such as chlorobenzene, aliphatic solvents such as dodecane or chlorinated aliphatic solvents such as dichloroethane or trichloroethane It is preferable.

The phosgenation can be carried out at a temperature between 0 ° C. and the boiling point of the reaction medium. However, since the reaction is somewhat slow in nature, it is advantageous to promote it by heating to 60 to 130 ° C., preferably to reflux temperature. If the reaction is carried out at elevated temperatures, it is desirable to run in an autoclave under pressure up to 5 bar (absolute pressure).

In practice, solvent phosgene (preferably liquid phosgene) and starting hydantoin are introduced into the reactor.

Since hydantoin dissolves in very small amounts in the medium, a suspension is formed and, if appropriate, is heated to add an acid acceptor to facilitate the reaction.

It must be heated long enough to completely convert. The heating time was found to be suitable for 1 to 5 hours.

At the end of the reaction, there are two possible ways. One is to separate chlorocarbonyl, a weekly substance having the characteristics shown in the following examples.

The yield was found to be substantially quantitative.

Advantageously, however, when this method is used industrially, the organic solution of this intermediate can be used continuously in a second step, called the condensation step.

In any case, the medium must be cooled and excess phosgene must be degassed before the second stage begins.

The second step is much faster than the first, and is carried out at a temperature of 0 to 130 ° C., preferably 20 to 80 ° C.

The stoichiometric amounts of the amine and the acid acceptor are each introduced into chlorocarbonyl in the organic medium, the acid acceptor may be of the same type or amine itself (sometimes used twice in the reaction) as used in the first step, and also It may be an inorganic base.

The solvent is removed after cooling and washing in the acid medium to give the desired N-substituted derivatives with good yield of at least 90%.

The invention is illustrated by the following examples.

Example 1

First step: The following materials are subsequently introduced into a one-liter five-necked reactor equipped with a condenser, ie chlorobenzene (300 ml), followed by liquid phosgene (about 40 g, or 0.4 moles), Stopping stirring followed by 3- (3,5-dichlorophenyl) -hydantoin (61.3 g, or 0.25 mol).

The reactor is then heated to 75 ° C. for 1 hour and the liquid in the condenser is kept at a temperature where it can condense phosgene.

Triethylamine (25 g, ie 0.25 mole) is introduced into the reactor and cooled to about 30 ° C. for 10 to 15 minutes.

The temperature is maintained at 130 ° C. for 3 hours and 30 minutes, and the liquid in the condenser keeps the temperature at which the solvent can be condensed and dehydrogenated.

Second step: After cooling the medium obtained in the first step to 35 ° C., isopropylamine (14.7 g. Or 0.25 moles) and then triethylamine (25 g or 0.25 moles) are introduced at 15 minute intervals.

The medium is heated to 75 ° C. for 20 minutes and then cooled at 20 ° C. 5% strength sulfuric acid (300 ml) is introduced and the resulting mixture is vigorously stirred for 30 minutes.

The aqueous phase is separated by tilting, and then the chlorobenzene phase is washed with distilled water. The chlorobenzene layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 80 g of a material having a melting point of 130 ° C. containing 91.5% of 1-isopropylcarbamoyl-3- (3,5-dichlorophenyl) -hydantoin are obtained, that is, 97% yield.

Example 2

The first step procedure of Example 1 is carried out except that the intermediate is separated at the end of the reaction. A white solid at melting point 202 ° C. with the following percentage composition is obtained.

Infrared spectroscopy analysis shows the presence of bands at 1830-1820, 1760 and 1720 cm ⁻¹ , which are characteristic of carbonyl groups, being 1-chlorocarbonyl-3- (3,5-dichlorophenyl) -hydantoin.

EXAMPLES 3-7

In the second step, the method of Example 1 is carried out except that each of the same amount of ethylamine, n-propylamine, aniline and dimethylamine is substituted for isopropylamine.

Yields and melting points of the products are shown in the following table.

Example 8 Use of Isopropylamine as the Acid Receptor.

A solution of isopropylamine (3.6 g, or 0.06 mole) of chlorobenzene (29 ml) was obtained from 1-chlorocarbonyl-3- (3,5-dichlorophenyl) -hydantoin of chlorobenzene (80 ml) obtained in Example 2. (9.2 g, 0.03 mol) Introduce into the suspension for 20 minutes and maintain the temperature at up to 30 ° C.

After stirring for 1 hour, chlorobenzene (150 ml) is added. The organic solution is washed with 3.6% strength aqueous hydrochloric acid solution (100 ml). The mixture was concentrated and concentrated under reduced pressure to obtain 9.9 g of 1-isopropylcarbamoyl-3- (3,5-dichlorophenyl) -hydantoin as a solid material having a melting point of 135 ° C.

EXAMPLES 9-13

Organotilyl group (1 mol, excess if appropriate) is a mixture of 3- (3,5-dichlorophenyl) -hydantoyl (1 mol) and phosgene (1.5 mol) of chlorobenzene (1100 ml) (prepared in advance) Is introduced into the suspension.

The reaction medium is then heated for some time. In one of the experiments, phosgenation is carried out in a pressure of about 3 bar and in a pressure sole. The resulting chlorocarbonyl is separated. This is used for the condensation reaction as described in Example 1.

The yields of various conditions and intermediates of phosgenation and carbonyl and 1-isopropyl-3- (3,5-dichlorophenyl) -hydantoin are reported in the following table.

Example 14

a. Phosgenation

3- (3,5-dichlorophenyl) -hydantoin (1 mol), disodium carbonate (2 mol), dimethylaminopyridine (0.09 mol) and chlorobenzene (1100 ml) at 20 ° C. into a reactor equipped with a condenser Introduce.

Then phosgene (2 moles) is introduced.

The reaction mixture is heated at 80 ° C. for 1 hour 30 minutes and then to 150 ° C. for the same time. The inorganic material is filtered off at high temperature (110 ° C.) and the cake is washed with hot chlorobenzene (130 ° C.) (2 × 50 ml).

This yields 1-chlorocarbonyl-3- (3,5-dichlorophenyl) -hydantoin in 94% yield.

b. Condensation

This is done according to the method of Example 1 (second step).

Under this condition, 1-isopropylcarbamoyl-3- (3,5-dichlorophenyl) -hydantoin is obtained at a yield of 92%.

Example 15

a. Phosgenation

3- (3,5-dichlorophenyl) -hydantoin (1 mole), disodium carbonate (2.5 moles) and tetrabutylammonium bisulfate (0.036 moles) are introduced into a reactor with a condenser.

The phosgene (4 moles) is introduced and then the semi-melt mixture is heated to 80 ° C. for 1 hour and 30 minutes and then again at 105 ° C. for the same time. The total amount of inorganic material suspended on the filter is removed by filtration at high temperature (about 110 ℃) and the cake is washed with 130 ℃ chlorobenzene (2 x 50 ml).

b. Condensation

This is carried out according to the method of Example 1 (second step). The product is separated by washing with acidic and neutral chlorobenzene solution and then evaporating the solvent.

Under this condition, a product containing 94% of 1-isopropylcarbamoyl-3- (3,5-dichlorophenyl) -hydantoin in a yield of 92% is obtained.

Repeating this experiment with 0.036 mol 0.018. Of carbonate in phosgenation yielded 80% yield of 1-isopropyl carbamoyl3- (3,5-dichlorophenyl) -hydantoin.

Claims (1)

3- (3,5-dichlorophenyl) -hydantoin of the following general formula (III) is reacted with phosgene in an inert organic solvent medium in the presence of an acid acceptor to yield 1-chlorocarbonyl-3- of the general formula (II) (3,5-dichlorophenyl) -hydantoin is prepared and the product is reacted with a primary or secondary amine of the general formula HNR ₁ R ₂ in an inert organic solvent medium in the presence of an acid acceptor. Process for the preparation of the compound of I).

(Wherein R ₁ is phenyl radical or alkyl radical having 1 to 4 carbon atoms and R ₂ is hydrogen atom or alkyl radical having 1 to 4 carbon atoms).