KR0135516B1 - Process for the preparation of 3-phenylpyrrole derivatives - Google Patents

Abstract

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Description

Method for preparing 3-phenylpyrrole derivative

The present invention relates to a novel process for the preparation of 3-phenylpyrrole derivatives of the general formula (I).

이고, R₁및 R₂는 서로 독립적으로 수소, C₁-C₆알킬, C₁-C₆알콕시, C₁-C₆알킬티오, 니트로, 시아노, 할로겐 또는 C₁-C₆할로알킬이거나, 또는 R₁및 R₂는 함께 결합하여 메틸렌디옥시 또는 디플루오로메틸렌디옥시를 형성하며, R₃은 C₁-C₆알킬, C₁-C₆할로알킬, 페닐 또는 벤질 또는 각각 할로겐, 메틸, 메톡시 또는 메틸티오에 의해 치환된 페닐 또는 벤질이고, R₄는 수소, C₁-C₆알킬, C₁-C₆할로알킬, 페닐 또는 벤질 또는 각각 할로겐, 메틸, 메톡시 또는 메틸티오에 의해 치환된 페닐 또는 벤질이다.Wherein X is cyano, -CO-R ₃ , -CO-OR ₃ or

R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, nitro, cyano, halogen or C ₁ -C ₆ haloalkyl Or R ₁ and R ₂ join together to form methylenedioxy or difluoromethylenedioxy, and R ₃ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl or benzyl or halogen, respectively Phenyl or benzyl substituted by methyl, methoxy or methylthio, R ₄ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl or benzyl or halogen, methyl, methoxy or methylthio, respectively Phenyl or benzyl substituted by

Alkyl refers to straight or branched chain alkyl. Examples of suitable C ₁ -C ₆ alkyl radicals include the following. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, n-pentyl or pentyl isomers, hexyl or hexyl isomers, preferred alkyl radicals have up to 4 carbon atoms It contains.

Halogen as the halogen itself or as a residue of a substituent, as in halobenzyl, halophenyl or haloalkyl, means fluoro, chloro or bromo, preferably fluoro or chloro. Typical haloalkyls are chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrifluoroethyl , Pentafluoroethyl, 1,2,2-trifluoro-2-chloroethyl, 2,2,2-trifluoro-1, 1-dichloroethyl, pendichloroethyl, 3,3,3-tri Fluoropropyl, 2,3-dichloropropyl, 1,1, 2,3,3,3-hexyfluoropropyl, 1-chloropentyl, 1-chlorohexyl, in particular fluoromethyl, chloromethyl, difluoro Methyl or trifluoromethyl.

Examples of substituted benzyl and phenyl groups are as follows. 2-chlorophenyl, 3-crolophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,4,6-trichlorophenyl, 2,5 -Dichlorophenyl, 4-fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 2,4-dimethylphenyl, 4-trifluoromethylphenyl, 4-bromobenzyl, 4-methoxyphenyl, 2,4- Dimethoxyphenyl and 4-methylthiothiophenyl.

Typical alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy or four butoxy isomers, n-pentyloxy or isomers, n-hexyloxy or hexyloxy isomers, preferably methoxy, e. Oxy or isopropoxy.

Alkylthio is, for example, methylthio, ethylthio, n-propylthio, isopropylthio or four butylthio isomers, n-pentylthio or pentyldio isomers, n-hexylthio or hexylthio isomers, preferably methylthio .

3-phenylpyrrole derivatives of the general formula (I) in which R ₁ and R ₂ join together to form difluoromethylenedioxy and X is cyano, are disclosed as bactericides in EP-A-206 999.

3-phenylpyrrole derivatives of the general formula (I) wherein R ₁ and R ₂ independently of one another are hydrogen, halogen, methoxy or methylthio and X is cyano are intermediates in bactericide synthesis in EP-133 247. As it turns out.

EP-A-236 272 shows that compounds of formula (I) wherein R ₁ is 2-chloro, R ₂ is 3-chloro and X is cyano have excellent fungicidal activity.

According to the method described in Tetrabedron letters (1972) 52, 5337-5340, in the presence of a strong base such as sodium hydride, cinnamonitrile of the general formula (III) is (p-tolylsulfonyl) methyl isoform of the general formula (IV) Cyclized by cyanide (TOSMIC) to 4-cyano-3-phenylpyrrole of formula (V):

Aside from the extremely low 35% yield on industrial scale synthesis, an important drawback of this method is that it can only be carried out with isolated and recrystallized (p-tolylsulfonyl) methyl isocyanide. However, since these compounds are susceptible to explosive decomposition at elevated temperatures, there is a very high safety risk in handling isolated and recrystallized (p-tolylsulfonyl) methyl isocyanide.

In addition, the method described above is expensive and complicated because of the complete anhydrous conditions necessary to conduct the reaction. Because of these shortcomings, this method is not suitable for the industrial production of 3-phenylpyrrole derivatives of general formula (I).

Japanese Laid-Open Patent Publication No. 61-30571 discloses 4-cyano of the following general formula (VI) by reacting (p-tolylsulfonyl) methyl isocyanide with cyanocinnimate of the following general formula (VII) in the presence of a base. A method for preparing 3-phenylpyrrole is described.

Wherein Z is halogen, alkyl, haloalkyl, alkylamino, alkoxy, nitro, cyano or methylenedioxy, n is 0 to 2 and R is hydrogen or alkyl.

Like the method described above, this method has the serious drawback that only (p-tolylsulfonyl) methyl isocyanide isolated, purified and recrystallized can be used to synthesize compounds of general formula (VI) in a satisfactory yield. As mentioned above, crystalline (p-tolylsulfonyl) methyl isocyanide is a thermally labile, prone to deflagration and is a potential source of danger when synthesized on an industrial scale because of the risk of severe explosion.

Recently, a novel process on an industrial scale has been found which allows the production of compounds of general formula (I) in a favorable yield in a non-hazardous and economically advantageous manner.

The novel process of the present invention for the preparation of 3-phenylpyrrole derivatives of formula (I) comprises: (a) phosphorooxy chloride and N- (p-tolylsulfonyl) methyl formamide in an inert solvent in the presence of an organic base; The reaction mixture was mixed with water, and then the aqueous phase of the resulting biphasic mixture was separated, and (b) an organic phase containing (p-tolylsulfonyl) methyl isocyanide in the presence of a base was Directly reacting with the compound of II).

Wherein X, R ₁ , R ₂ and R ₄ are as defined under formula (I), Y is -CO-NHR ₄ , -CO-R ₅ or -SR ₅ , and R ₅ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl or benzyl or phenyl or benzyl, each substituted by halogen, methyl, methoxy or methylthio.

Examples of suitable inert solvents are ring-opening or cyclic ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethoxymethane, 1,2-dimethoxyethane) or chloroalkanes (e.g. methylene Compounds or mixtures of compounds selected from chlorides, chloroform or carbon chlorides or ketones (e.g. acetone, methylethylketone, diethylketone, cyclohexanone, methylisopropylketone or methylisobutylketone) or lower carbonic acid Compounds selected from alkyl esters such as acetic acid methyl ester, acetic acid ethyl ester or propionic acid ethyl ester. Preferred solvents are tetrahydrofuran, dioxane, dimethoxymethane, acetic acid ethyl ester and 1,2-dimethoxyethane. Particularly preferred solvents are 1,2-dimethoxyethane and acetic acid ethyl ester.

Suitable organic bases for preparing (p-tolylsulfonyl) methyl isocyanide from N- (p-tolylsulfonyl) methyl formamide are, for example, quinoline, pyridine or diisopropylamine, preferably quinuclidin, N, N- dimethylaniline, dimethylaminopyridine, N- methylpyrrolidine or N, N, N ^{', N'} - tetramethylethylenediamine tertiary amines, most especially triethylamine or tri -n- propyl amine, such as tree Alkylamine. Triethylamine is particularly preferred.

Examples of suitable bases for the reaction of the compound of formula (II) with (p-tolylsulfonyl) methyl isocyanide include oxides, hydrides, hydroxides, carbonates, carboxylic acid salts or alcoholates, trialkyls of alkali or alkaline earth metals. Amine or pyridine base. Particularly suitable bases are sodium methylate, sodium ethylate, aqueous sodium hydroxide, aqueous potassium hydroxide, sodium hydroxide in methanol, potassium hydroxide in methanol, sodium carbonate or potassium carbonate. Particularly preferred bases are aqueous sodium hydroxide, sodium hydroxide in methanol, aqueous potassium hydroxide, potassium hydroxide in methanol and sodium methylate.

In a preferred embodiment of the process according to the invention, the compound of formula (II) is added to a solution of (p-tolylsulfonyl) methyl isocyanide followed by the addition of a base to the reaction mixture.

In the reaction of (p-tolylsulfonyl) methyl isocyanide with the compound of formula (II), the base is usually added in an amount of 2 to 3 moles, preferably 2 to 2.4 moles per mole of the compound of formula (II). The reaction of the (p-tolylsulfonyl) methyl isocyanide and the general formula (II) compound is carried out at -25 ° to + 25 ° C. in general, and a preferable temperature range is -10 to + 10 ° C.

Compounds of formula (II) and (p-tolylsulfonyl) methyl isocyanide are conveniently used in equimolar amounts or in excess of 10 to 20 mole percent of compounds of formula (II). It is especially preferable to use it in equimolar amount.

If an alkyl ester of a ketone or lower carbonic acid is used as the inert solvent in step (a), it is advantageous to add an aqueous solution of the base to the organic phase and then separate the aqueous phase from the mixture before carrying out step (b).

Suitable bases for this variant are, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate, but in particular sodium hydroxide and sodium carbonate. As the inert solvent of this modification method, ethyl acetate is particularly suitable.

A particularly preferred embodiment of the process according to the invention is to react N- (p-tolylsulfonyl) methyl formamide in 1,2-dimethoxyethane with phosphorooxy chloride in the presence of triethylamine and react the reaction mixture. After mixing with 0.5 to 0.7 times the volume of water, the aqueous phase is separated from the resulting two-phase reaction mixture, and the organic phase containing (p-tolylsulfonyl) methyl isocyanide in the presence of a base is converted to general formula (II). Directly reacting with a compound of Formula 1).

In a more preferred embodiment of the process according to the invention, the reaction mixture obtained from the reaction of porooxy chloride with N- (p-tolylsulfonyl) methyl formamide using dioxane as the inert solvent is 0.2 to 0.35 times the volume. Mixing with water.

Another variant of the invention employs a reaction mixture obtained from the reaction of N- (p-tolylsulfonyl) methyl formamide with phosphorooxy chloride using tetrihydrofuran as a solvent and a volume of 0.3 to 0.8 times the volume of water. It involves mixing.

Another variant of the invention provides a reaction mixture obtained from the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide using dimethoxyketan as an inert solvent and having a volume of 0.3-1.2 volumes of water. And mixing with.

In an embodiment of the method according to the invention described above, Y is —CO—NHR ₄ or —CO—R ₅ , R ₄ is hydrogen or methyl, R ₅ is methyl or phenyl and R ₁ and R ₂ are independent of each other To hydrogen or chloro or together form methylenedioxy or difluoromethylenedioxy, wherein X is cyano, -CO-R ₃ or -CO-OR ₃ and R ₃ is methyl It is preferable to use.

The process according to the invention makes it possible to prepare compounds of formula (I) in good yields and in a simple manner.

A particular advantage of the process according to the invention is that it is not necessary to isolate (p-tolylsulfonyl) methyl isocyanide obtained as an intermediate from the reaction medium and to purify it for reaction with the compound of formula (II). none. The risk of stability in the isolation and refining of (p-tolylsulfonyl) methyl isocyanide, in which the dried crystalline product may explode, is completely excluded from the process of the present invention. In addition to being not an expensive way of carrying out the reaction under anhydrous conditions, it should be mentioned in particular that the method according to the invention makes handling of (p-tolylsulfonyl) methyl isocyanide extremely simple, with at least a safeguard than conventional methods. do.

Another advantage of the process according to the invention is that when water is added, the reaction mixture separates into two phases-an organic phase containing the preferred intermediate and an aqueous phase containing by-products. The intermediates after the disadvantages of the two phases are thus obtained directly in the form of a solution in the solvent used.

The following examples illustrate the method of the invention in more detail.

Production Example

Example P1 4-Siino-3- (2,3-dichlorophenyl) pyrrole

(a) Preparation of (p-tolylsulfonyl) methyl isocyanide solution

41.5 g (0.27 mol) of phosphorooxy chloride was added to a solution consisting of 55.5 g (0.26 mol) of N- (p-tolylsulfonyl) methyl formamide, 124 g of triethylamine, and 155 g of 1,2-dimethoxyethane at 0 ° C. Dropwise added over 2 to 3 hours. The reaction mixture is stirred at 0 ° C. for 1 h and then mixed with 220 ml of water while cooling. After raising the temperature of the reaction mixture to + 20 ° C., the lower aqueous phase of the resulting biphasic mixture was separated to give (p-tolylsulfo) in 1,2-dimethoxyethane containing 23.2% by weight (72% of theory) of the product. 157 g of a solution of nil) methyl isocyanide are obtained.

(b) While stirring, 48.3 g of (alpha) -cyano-2,3-dichlorocinnamid is added to 157 g of (p-tolylsulfonyl) methyl isocyanide solutions prepared according to (a). After cooling the reaction mixture to 0 ° C., 53.3 g (0.4 mol) of 30% aqueous sodium hydroxide is added dropwise over 2 hours with stirring. Stirring is continued at 0 ° C. for 2 hours and then 200 g of water is added. The reaction solution is concentrated at + 70 ° C./200 mbar and the product is isolated by filtration after addition of 300 g of water at room temperature. Washing the filter residue with 80 g of toluene and drying under vacuum yielded 44.9 g (97% of theory) of 4-cyano-3- (2,3-dichlorophenyl) pyrrole, melting at 149 ° C.

Example P2: 4-Siino-3- (2,3-methylenedioxyphenyl) pyrrole

While stirring, 24.9 g of α-cyano-2,3-methylenedioxycinimide was added to 96.9 g of a 23.2 wt% solution of (p-tolylsulfonyl) methyl isocyanide prepared according to Example P1 (a). do. Then 41.4 g of a 30% solution of sodium methylate in methanol is added dropwise over 2 hours. The mixture is stirred for 30 minutes, then 300 ml of water is added dropwise and the product is isolated by filtration. Washing the filter residue with toluene and drying under vacuum yielded 21 g (86.5% of theory) of 4-cyano-3- (2,3-methylenedioxyphenyl) pyrrole, melting at 206-208 ° C.

Example P3 4-Methylcarbonyl-3- (2,3-dichlorophenyl) pyrrole

To 65 g of a 23.2 wt% solution of (p-tolylsulfonyl) methyl isocyanide prepared according to Example P1 (a) at 0 ° C., while stirring, 1,1-di (methylcarbonyl) -2- (2, 20 g of 3-dichlorophenyl) ethene are added. Then 28.1 g of a 30% solution of sodium methylate in methanol are added dropwise over 3 hours. The mixture is stirred at + 10 ° C. for 60 minutes before 170 ml of water is added dropwise and the product is isolated by filtration. The filtered residue was recrystallized from a methanol / ethanol 1: 1 mixture, dried under vacuum and melted at 192-194 ° C., 8.3 g of 4-methylcarbonyl-3- (2,3-di-chlorophenyl) phenyl (50 of theory). %) Is obtained.

Example P4 4-Siino-3- (4-chlorophenyl) pyrrole

While stirring, 28.8 g of α-cyano-4-chlorocinnamid is added to 117.4 g of a 23.2 wt% solution of (p-tolylsulfonyl) methyl isocyanide prepared according to Example P1 (a) at 0 ° C. . Then 50.4 g of a 30% solution of sodium methylate in methanol are added dropwise over 3 hours at + 5 ° C. The mixture is stirred for 2 hours and 70 ml of water are added. 50 ml of the solvent mixture is removed by concentrating the reaction mixture at 50 ° C. under vacuum. After addition of 140 ml of water, the reaction mixture is filtered and the filter residue is washed with 30 ml of toluene. Recrystallization of the filter residue dried from toluene yielded 25.4 g (89.5% of theory) of 4-cyano-3- (4-chlorophenyl) pyrrole, melting at 147-148 ° C.

Example P5 4-methoxycarbonyl-3- (2,3-dichlorophenyl) pyrrole

While stirring, 20 g of methyl α-methylcarbonyl-2,3-dichlorocininamate was added to a 22 wt% solution of (p-tolylsulfonyl) methyl isocyanide prepared according to Example P1 (a) at 0 ° C. Add. Then 26.3 g of a 30% solution of sodium methylate in methanol are added dropwise over 2 hours. The mixture is stirred for 2 hours and then 35 ml of water is added dropwise. The reaction mixture is concentrated at 50 ° C. under vacuum. After further 70 ml of water is added, the reaction mixture is concentrated once again under vacuum and then filtered. Toluene washing of the filtration residue and recrystallization from ethanol yielded 10.8 g (58% of theory) of 4-methoxycarbonyl-3- (2,3-dichlorophenyl) pyrrole, melting at 200-210 ° C.

Example P6 4-Siino-3- (2,3-dichlorophenyl) pyrrole

(a) In a solution consisting of 59.6 g (0.28 mol) of N- (p-tolylsulfonyl) methyl formamide, 134 g of triethylamine and 168 g of tetrahydrofuran at -5 ° C, 44.5 g of phosphorooxy tricoolide was added. Add dropwise for 2 hours. After 1 h of stirring at 0 ° C., the reaction mixture is added dropwise to 300 ml of water. During this drop, the temperature is raised to + 20 ° C. The lower aqueous phase of the resulting biphasic mixture is separated to give 198 g of a solution of (p-tolylsulfonyl) methyl isocyanide in tetrahydrofuran containing 33 g of product.

(b) While stirring, 46.9 g of α-cyano-2,3-dichlorocinnamid is added to 198 g of (p-tolylsulfonyl) methyl isocyanide prepared according to (a). The reaction mixture is cooled to + 5 ° C. and then 43.6 g of a 50% solution of potassium hydroxide is added dropwise over 90 minutes with stirring. The mixture is stirred for 2 hours and then 80 ml of water is added. 50 ml of the solvent mixture is removed by evaporation. After 150 ml more water is added, the reaction mixture is concentrated once more and filtered. The filter residue was washed with toluene and recrystallized from methanol to give 34.2 g (85% of theory) of 4-cyano-3- (2,3-dichlorophenyl) pyrrole, melting at 146-148 ° C.

Example P7 4-Siino-3- (2,3-dichlorophenyl) pyrrole

(a) Preparation of (p-tolylsulfonyl) methyl isocyanide solution

31.5 g of phosphorooxy chloride was added dropwise to the solution consisting of 43 g (0.2 mol) of N- (p-tolylsulfonyl) methyl formamide, 92.1 g of triethylamine and 145 g of acetic acid ethyl ester at 0 to 5 ° C. The reaction mixture is stirred for 0-5 ° C. for 30 minutes and then mixed with 150 ml of water. Stirring at + 20 ° C. for 10 min is followed by separation of the aqueous phase. Add 100 mL of aqueous IN sodium hydroxide and stir for 10 minutes. The aqueous phase is separated and then the organic phase is washed with 50 ml of water to give 150 g of a solution of (p-tolylsulfonyl) methyl isocyanide in acetic acid ethyl ester containing 31 g of product.

(b) While stirring, 38.6 g of α-cyano-2,3-dichlorocinnamid is added to 150 g of (p-tolylsulfonyl) methyl isocyanide prepared according to (a). The reaction mixture is cooled to 0 ° C. and 63.2 g of 30% sodium methylate is added dropwise to methanol over 3 hours with stirring. 100 ml of water are added and stirring is continued for 15 minutes before the aqueous phase is separated. After addition of water the solvent is removed completely at 50-60 ° C. under reduced pressure. The remaining suspension is cooled to room temperature and the product is different by filtration. Washing the filter residue with 200 ml of toluene and drying gave 31 g (82% of theory) of 4-cyano-3- (2,3-dichlorophenyl) pyrrole, melting at 148 ° C.

Example P8 4-Siino-3- (2,3-difluoromethylenedioxy) pyrrole

(a) Preparation of (p-tolylsulfonyl) methyl isocyanide solution

In a solution consisting of 42.6 g (0.2 mol) of N- (p-tolylsulfonyl) methyl formamide, 96 g of triethylamine and 160 g of acetic acid ethyl ester at 0 to 5 DEG C, 31.8 g (0.208 mol) of phosphorooxy chloride was added to the solution. Add dropwise for 2 hours. The reaction mixture is stirred at 0-5 ° C. for 1 hour and then mixed with 150 ml of water. The temperature of the reaction mixture is raised to + 20 ° C. and the lower aqueous phase is separated. Add 100 ml of 10% aqueous sodium carbonate and continue stirring for 10 minutes. The aqueous phase is then separated to give 210 g of a solution of (p-tolylsulfonyl) methyl isocyanide in acetic acid ethyl ester containing 33.2 g (85% of theory) of the product.

(b) 42.8 g (0.17 mol) of α-cyano-2,3-difluoromethylene-dioxycinnamid to 210 g of (p-tolylsulfonyl) methyl isocyanide solution prepared according to (a) while stirring Add). The reaction mixture is cooled to 0-5 [deg.] C. and then 45.8% (0.204 mol) of 35% potassium hydroxide in methanol is added dropwise over 1 hour with stirring. Stir at +20 for 1 hour. The preparation can be continued by one of the following methods.

Method 1: 120 ml of acetic acid ethyl ester / methanol mixture is removed by distillation at 65-70 ° C. After adding 300 ml of methanol, 170 ml of solvent was evaporated to concentrate the reaction mixture once again. After addition of 90 ml of water, the reaction mixture is filtered. The filter residue is washed with a methanol / water mixture to give 35.8 g (85% of theory) of 4-cyano-3- (2,3-difluoromethylenedioxyphenyl) pyrrole that melts at 190 to 195 ° C. .

Method 2: 120 ml of acetic acid ethyl ester / methanol mixture is removed by kind at 65 to 70 ° C. After the addition of 120 ml of methanol the reaction mixture is once again concentrated by evaporation. 120 ml of methanol are added and the reaction mixture is filtered. The filter residue is washed with a methanol / water mixture to give 34.3 g (83% of theory) of 4-cyano-3- (2,3-difluoro-methylenedioxy) pyrrole that melts at 190 to 195 ° C. .

Method 3: 200 ml of water is added and the aqueous phase is separated and 120 ml of acetic acid ethyl ester is removed by distillation. The reaction mixture is once again concentrated by adding 300 ml of methanol to the residue and then evaporating 170 ml of solvent. After 90 ml of water is added, the reaction mixture is filtered. Wash the filtration residue with methanol / water mixture to give 34.3 g (83% of theory) of 4-cyano-3- (2,3-difluoromethylenedioxyphenyl) pyrrole which melts at 190 to 195 ° C. .

Claims (26)

(a) reacting phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide in an inert solvent in the presence of an organic base, mixing the reaction solution with water and separating the aqueous phase of the resulting two-phase mixture And (b) directly reacting an organic phase containing (p-tolylsulfonyl) methyl isocyanide in the presence of a base with a compound of formula (II): Process for the preparation of phenylpyrrole derivatives.

Wherein X is cyano, -CO-R ₃ , -CO-OR ₃ or

R ₁ and R ₂ are independently of each other hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, nitro, cyano, halogen or C ₁ -C ₆ haloalkyl Or R ₁ and R ₂ join together to form methylenedioxy or difluoromethylenedioxy, and R ₃ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl or benzyl or halogen, methyl, respectively Is phenyl or benzyl substituted by methoxy or methylthio, R ₄ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl or benzyl or halogen, methyl, methoxy or methylthio, respectively Is phenyl or benzyl, Y is -CO-NHR ₄ , -CO-R ₅ or -SR ₅ , and R ₅ is C ₁ -C ₆ alkyl, C ₁ -C | ₆ haloalkyl, phenyl or benzyl or phenyl or benzyl, each substituted by halogen, methyl, methoxy or methyldio. The process of claim 1 comprising (a) adding a compound of formula (II) to a solution of (p-tolylsulfonyl) methyl isocyanide and (b) adding a base to the reaction mixture. The process of claim 1 comprising adding 2-3 moles of base per mole of compound of formula (II) to the reaction of the compound of formula (II) with (p-tolylsulfonyl) methyl isocyanide. The compound of claim 1, wherein R ₁ and R ₂ are independently of each other hydrogen, halogen, methoxy or methylthio or combine together to form methyllandioxy or difluoromethylenedioxy, and R ₃ and R ₅ are mutually Independently C ₁ -C ₄ alkyl or C ₁ -C | ₄ haloalkyl, R ₄ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl, and Y is —CO-NHR ₄ or —CO-R ₅ . The process according to claim 1, wherein the compound of formula (II) is used in an excess of 10 to 20 mol% relative to the amount of (p-tolylsulfonyl) methyl isocyanide. The method according to claim 1, wherein (p-tolylsulfonyl) methyl isocyanide and the compound of formula (II) are used in an equimolar amount. The process of claim 1 wherein the inert solvent is a compound or mixture of compounds selected from ring-opened or cyclic ethers, chloroalkanes, ketones or alkyl esters of lower carbonic acid. The method of claim 1 wherein the inert solvent is a compound or mixture of compounds selected from ring-opened or cyclic ethers or chloroalkanes. The process according to claim 1, wherein tertiary amine is used as the base in the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide. The oxide, hydride, hydroxide, carbonate, carboxylate or alcohol of an alkali metal or alkaline earth metal as a base in the reaction of a compound of formula (II) with a solution of (p-tolylsulfonyl) methyl isocyanide Processes using late, trialkylamine or pyridine bases. The process according to claim 1, wherein the compound of formula (II) is reacted with (p-tolylsulfonyl) methyl isocyanide at -25 to + 25 ° C. The process according to claim 1, wherein (p-tolylsulfonyl) methyl isocyanide and the compound of general formula (II) are reacted at -10 to + 10 ° C. The method of claim 10 wherein the base is sodium methylate, sodium ethylate, aqueous sodium hydroxide, aqueous potassium hydroxide, sodium carbonate or potassium carbonate. The process according to claim 10, wherein 2 to 2.4 moles of base are used per mole of compound of formula (II). 10. The method of claim 9, wherein the base is triethylamine. The process according to claim 1, wherein the inert solvent is dimethoxymethane, 1,2-dimethoxyethane, diethyl ether, diisopropylether, tetrahydrofuran, dioxane, methylene chloride, chloroform, carbon tetrachloride or ethyl acetate. The method of claim 1 wherein the inert solvent is dimethoxymethane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform or carbon tetrachloride. The process according to claim 1, wherein the inert solvent is dimethoxymethane, 1,2-dimethoxyethane, tetrahydrofuran, dioxane or acetic acid ethyl ester. The method of claim 1 wherein the inert solvent is dimethoxymethane, 1,2-dimethoxyethane, tetrahydrofuran or dioxane. The reaction mixture of claim 1, wherein the inert solvent is 1,2-dimethoxyethane and the reaction mixture obtained after the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide is prepared in a volume of 0.5 to 0.7 times the volume of water. How to mix with. The process according to claim 1, wherein the inert solvent is dioxane and the reaction mixture obtained after the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide is mixed with 0.2 to 0.35 times the volume of water. The process of claim 1, wherein the inert solvent is tetrahydrofuran and the reaction mixture obtained from the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide is mixed with 0.3 to 0.8 times the volume of water. . The process of claim 1 wherein the inert solvent is dimethoxymethane and the reaction mixture obtained from the reaction of phosphorooxy chloride with N- (p-tolylsulfonyl) methyl formamide is mixed with 0.3 to 1.2 times the volume of water. . _2. Methylenedioxy or difluoromethylenedi according to claim 1, wherein X is cyano, -CO-OR ₃ or -CO-R ₃ , and R ₁ and R ₂ are independently of each other hydrogen, chlorine or are bonded together Forms oxy, R ₃ is methyl, Y is —CO—NHR ₄ or —CO—R ₅ , and R | ₄ is hydrogen or methyl and R ₅ is methyl or phenyl. The reaction mixture according to claim 1, wherein (a) phosphorooxy chloride and N- (p-tolylsulfonyl) methyl formamide in 1,2-dimethoxyethane are reacted in the presence of triethylamine, and the reaction mixture is 0.55 to 0.6. The aqueous phase is separated from the resulting two phase reaction mixture after mixing with twice the volume of water, and (b) the presence of 2 to 2.4 moles of aqueous sodium hydroxide relative to the compound of formula (II) at -10 to + 10 ° C. And reacting an organic phase containing (p-tolylsulfonyl) methyl isocyanide under an equimolar amount of the general formula (II) compound with respect to (p-tolylsulfonyl) methyl isocyanide. The method of claim 22 comprising adding a compound of formula (II) to a (p-tolylsulfonyl) methyl isocyanide solution and (b) adding aqueous sodium hydroxide to the reaction mixture.