PL210000B1 - Method for production of tri-subsituted derivatives of 1,3,5-triazine - Google Patents

Description

The subject of the invention is a process for the preparation of trisubstituted 1,3,5-triazine derivatives of the general formula shown in the figure, where R1, R2 and R3 are chlorine, alkoxy, cycloalkoxy, substituted alkoxy, preferably methoxy, phenoxy, substituted phenoxy, with whereby if R1 and R2 are chlorine then R3 is the above-mentioned groups, and if R1 is chloro then R2 and R3 are the above-mentioned groups.

From the journal Chemische Berichte 36, 3195 (1903) there is known a method for the preparation of 2-chloro-4,6-disubstituted-1,3,5-triazines, which consists in treating cyanuric chloride with an appropriate alcohol in the presence of zinc. Due to the low yields and the use of metallic zinc, this method has not been widely used so far.

There is also a known method of producing 2,4-dichloro-6-monosubstituted-1,3,5-triazines and 2-chloro-4,6-disubstituted-1,3,5-triazines, which consists in the action of cyanuric chloride on alcohol in the presence of sodium bicarbonate used as a hydrogen chloride scavenger, at room or elevated temperature, with or without water and in the presence of a large excess of alcohol. This method is described in the following journals: Journal of American Chemical Society, 73, 2986 (1951), Journal of American Chemical Society 117, 5484 (1995), Recueil des Travaux Chimiques Pays-Bas, 97, 107 (1978), Synthetic Communications 26 , 3491 (1996), as well as in U.S. Patent Nos. 3,947,374 and 2,911,337 and in German Patent No. DE 2602216.

In all cases, the yields obtained were about 60-74%.

There is also known a method of producing mono- and disubstituted 1,3,5-triazine derivatives, in particular 2,4-dichloro-6-methoxy-1,3,5-triazine and 2-chloro-4,6-dimethoxy-1 , 3,5-triazines, using N, N-dimethylaniline as hydrogen chloride acceptor, described in Journal of Chemical Society (C) 1967, 466 and using collidine as hydrogen chloride acceptor, described in Bulletin of the Chemical Society of France , 1970, 606 and in the journal Recueil des Travaux Chimiques Pays-Bas, 78, 967, (1959).

However, all solutions based on the use of amines as a hydrogen chloride acceptor have the common disadvantage of the formation of colored, hard-to-remove by-products resulting from the degradation of amines, which make it difficult to clean the final product.

There is also a known method for the synthesis of 2-chloro-4,6-dimethoxy-1,3,5-triazine by treating cyanuric chloride with sodium methoxide at -30 ° C, described in the journal Pesticide Science 47, 103 (1996).

The Journal of Materials Chemistry 10, 867 (2000) describes the preparation of 2,4-dichloro-6-methoxy-1,3,5-triazine and 2-chloro-4,6-dimethoxy-1,3,5-triazine involving the action of cyanuric chloride with sodium methoxide at 0 ° C. Although the use of sodium methoxide promotes higher yields, the difficulties in handling this moisture-sensitive and chemically aggressive substrate reduce the usefulness of these methods. The process of substituting chlorine atoms in cyanuric chloride with sodium methoxide often leads to the formation of a difficult to separate mixture of the desired product, 2-chloro-4,6-dimethoxy-1,3,5-triazine with 2,4,6-trimethoxy-1,3,5 -triazine.

The Polish Journal of Chemistry 6, 837 (2000) describes a method for the preparation of 2,4-dichloro-6-phenoxy-1,3,5-triazine based on the action of phenol on cyanuric chloride in the presence of sodium hydroxide and water in CH2Cl2 at room temperature .

Synthetic Communications 15, 2153 (1994) describes the synthesis of mono- and disubstituted 1,3,5-triazines in which R1 or R1 = R2 = -CH3, -C2H5, -i-C3H7, -n-C5H11, -n -C8H17, CH2-C6H5, -C6H4-4-OCH3 by treating cyanuric chloride at room temperature with appropriate alcohols in the presence of K2CO3 and 18-crown-6 using aromatic hydrocarbons as a solvent. Reaction yields are 80 - 96%, but reaction times are very long, reaching 24 hours.

A process for the preparation of trisubstituted 1,3,5-triazine derivatives of the general formula shown in the figure, wherein R1, R2 and R3 are as defined above, which consists in treating cyanuric chloride with an alcohol at room temperature or boiling the reaction mixture, ensuring the disappearance of the starting materials and of intermediates in the presence of a hydrogen chloride acceptor, according to the invention, is characterized in that the reaction is carried out in a multiphase system resulting from adding a solvent or a mixture of solvents sparingly soluble in water to the reaction mixture. Halogenated aliphatic hydrocarbons, preferably chloroform, dichloromethane, dichloroethane, aromatic hydrocarbons, substituted aromatic hydrocarbons, preferably toluene, benzene, chlorobenzene, are used as solvents that are difficult to dissolve in water. Hydrogen chloride acceptors are alkali or alkaline earth metal hydrogencarbonates, alkali or alkaline earth metal carbonates or mixtures thereof, preferably sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or mixtures thereof.

By the method of the invention, substituted 1,3,5-triazine derivatives are obtained with a yield of 81-96% and a purity of over 98%, with a lower consumption of substrates than in the known methods, with the use of low aggressive substances as hydrogen chloride acceptors, preventing the color of the product. final. The 2-chloro-4,6-dimethoxy-1,3,5-triazine obtained by the process according to the invention is used as a vigorously acting condensing reagent, useful in the synthesis of amides, peptides, carboxylic acid esters, carboxylic acid anhydrides. 2-Chloro-4,6-dimethoxy-1,3,5-triazine can be easily converted by the action of tertiary amines into quaternary triazinylammonium salts which, like the parent compound, find use as condensing reagents. Due to the mild conditions of the condensation reaction taking place with the participation of 2-chloro-4,6-dimethoxy-1,3,5-triazine and the effective procedures for removing impurities, it is often used in the synthesis of products with a complex structure, including products for the pharmaceutical industry. 2-Chloro-4,6-dimethoxy-1,3,5-triazine is also used in the production of herbicides, bleaches, antioxidants, and polymer improvers.

The process of the invention is illustrated by the following examples.

P r z x l a d I.

To a vigorously stirred suspension of 600 g of sodium bicarbonate in 600 ml of methanol was added 1000 ml of dichloromethane and then, in portions, 1000 g of cyanuric chloride. After the addition of the cyanuric chloride was complete, stirring was continued for 30 minutes until the cyanuric chloride had disappeared. The reaction mixture volume was then doubled by dilution with water, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and again with water, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was crystallized from hexane.

After filtration and drying, 925 g of 2,4-dichloro-6-methoxy-1,3,5-triazine was obtained in the form of a white, crystalline solid, mp 88-90 ° C, which was 95% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.141 (s, 3H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-190 ° C, 6 ° C / min): Rt = 3.015 purity:> 99%.

P r z x l a d II

To a vigorously stirred suspension of 100 g of sodium bicarbonate and 184 g of cyanuric chloride in 500 ml of toluene was added 100 g of phenol in portions at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, stirring was continued for 30 minutes until no cyanuric chloride was found. After completion of the reaction, the mixture was diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium hydrogen carbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from toluene.

After filtration and drying, 220 g of 2-chloro-4,6-diphenoxy-1,3,5-triazine were obtained in the form of a white, crystalline solid, m.p. 112-113 ° C, which was 91% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 7.02-7.65 (m, 5H) [ppm].

¹³ C-NMR (250 MHz; CDCl 3): δ = 120.91; 126.94; 129.93; 151.05; 171.03; 173.02 [ppm].

P r x l a d III

To a vigorously stirred suspension of 15 g of potassium bicarbonate in 10 ml of cyclopentanol was added 10 ml of chloroform followed by portions of 18.5 g of cyanuric chloride at such a rate that the temperature of the mixture did not exceed 20-25 ° C. After the addition was complete, stirring was continued for 180 minutes and heated to reflux until no cyanuric chloride was present. After the cyanuric chloride had disappeared, the mixture was diluted with water as in Example 1, then stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium hydrogen carbonate solution and then with water, dried over anhydrous magnesium sulfate, then the solvent was evaporated and the residue was distilled under reduced pressure, collecting the fraction bp 130 ° C / p = 773 Pa.

PL 210,000 B1

21 g of 2-chloro-4,6-dicyclopentyloxy-1,3,5-triazine were obtained in the form of a colorless oil, which was 90% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 1.94-2.01 (m, 8H); 5.33 (qu, 1H) [ppm].

¹³ C-NMR (250 MHz; DMSO): δ = 21.73; 32.58; 84.24; 170-172 [ppm].

P r x l a d IV.

To a vigorously stirred suspension of 1000 g of sodium bicarbonate in 1000 ml of methanol was added 1000 ml of chloroform and then, in portions, 1000 g of cyanuric chloride at such a rate that the temperature of the reaction mixture did not exceed 25-30 ° C. After the addition of the cyanuric chloride was complete, the mixture was heated to reflux for 30 minutes until no more 2,4-dichloro-6-methoxy-1,3,5-triazine was carried out. The mixture was then cooled to room temperature, doubled in volume by dilution with water, then stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then twice more with water, then dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was crystallized from hexane.

After filtration and drying, 876 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine was obtained in the form of a white, crystalline solid, m.p. 65-67 ° C, which was 92% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.09 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.107, purity> 99%.

P r z k ł a d V.

To a vigorously stirred suspension of 1000 g of sodium bicarbonate in 1000 ml of methanol was added 1000 ml of dichloromethane and then, in portions of 1000 g of cyanuric chloride at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 120 minutes until the 2,4-dichloro-6-methoxy-1,3,5-triazine disappeared. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, then the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 771 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, m.p. 66-67 ° C, which was 81% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.03 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.068 purity:> 99%.

P r x l a d VI.

To a vigorously stirred suspension of 1000 g of potassium bicarbonate in 1000 ml of methanol was added 1000 ml of a 1: 1 volume ratio of chloroform and dichloromethane, and then 1000 g of cyanuric chloride was added portionwise at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 90 minutes until no more 2,4-dichloro-6-methoxy-1,3,5-triazine was carried out. The mixture was then cooled to room temperature, diluted with water as in Example 1, then stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium hydrogen carbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 828 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, mp 63-65 ° C, which was 87% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.06 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.102 purity:> 99%.

Example VII.

To a vigorously stirred suspension of 1000 g of sodium bicarbonate in 1000 ml of methanol was added 800 ml of toluene, and then, in portions, 1000 g of cyanuric chloride at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated

It takes 45 minutes to boil until the 2,4-dichloro-6-methoxy-1,3,5-triazine has disappeared. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 893 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, m.p. 66-68 ° C, which was a 94% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.11 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.95 purity:> 99%.

P r x l a d VIII.

To a vigorously stirred suspension of 1000 g of potassium bicarbonate in 1000 ml of methanol was added 1000 ml of chloroform, and then 1000 g of cyanuric chloride portionwise at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 30 minutes until no more 2,4-dichloro-6-methoxy-1,3,5-triazine was carried out. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 850 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, m.p. 64-66 ° C, which was a 90% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.11 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° / min): Rt = 4.151 purity:> 99%.

P r x l a d IX.

To a vigorously stirred suspension of 800 g of sodium bicarbonate and 200 g of potassium bicarbonate in 1000 ml of methanol was added 1000 ml of chloroform, and then, in portions, 1000 g of cyanuric chloride at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 30 minutes until no more 2,4-dichloro-6-methoxy-1,3,5-triazine was carried out. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 875 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, m.p. 65-67 ° C, which was 92% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.07 (s, 6H) [ppm].

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.111 purity:> 99%.

P r z k ł a d X.

To a vigorously stirred suspension of 320 g of sodium carbonate in 500 ml of methanol was added 500 ml of chloroform, and then 500 g of cyanuric chloride batchwise at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 60 minutes until no more 2,4-dichloro-6-methoxy-1,3,5-triazine was carried out. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from hexane.

After filtration and drying, 515 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, mp 62-65 ° C, which was 91% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 4.11 (s, 6H) [ppm].

PL 210,000 B1

GC (Schimadzu G.C.-14A; OV1701 column; temperature 130-210 ° C, 6 ° C / min): Rt = 4.107 purity:> 99%.

P r z k ł a d Xl.

To a vigorously stirred suspension of 1000 g of sodium bicarbonate in 1000 ml of ethanol was added 1000 ml of chloroform and then, in portions, 1000 g of cyanuric chloride at such a rate that the temperature of the reaction mixture did not exceed 25-30 ° C. After the addition of cyanuric chloride was complete, the mixture was heated to reflux for 30 minutes until no more 2,4-dichloro-6-ethoxy-1,3,5-triazine was allowed to proceed. The mixture was then cooled to room temperature, doubled in volume by dilution with water, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom, and the residue was crystallized from hexane. After filtration and drying, 996 g of 2-chloro-4,6-diethoxy-1,3,5-triazine were obtained in the form of a white, crystalline solid, m.p. 41-42 ° C, representing a 90% yield.

The results of the analysis of the obtained product were as follows:

Combustion analysis for the formula C7H10ClN3O2;

Calculated:% C 41.29; % H 4.95; % Cl 17.41; % N 20.64.

Found:% C 41.38; % H 4.90; % Cl 17.39; % N 20.84.

P r x l a d XII.

To a vigorously stirred suspension of 20 g of sodium bicarbonate in 20 ml of cyclopentanol was added 20 ml of chloroform, and then 18.5 g of cyanuric chloride portionwise at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 120 minutes until the 2,4-dichloro-6-cyclopentyloxy-1,3,5-triazine was gone. The mixture was then cooled to room temperature, diluted with water as in Example 1, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was distilled under reduced pressure, collecting the fraction bp 140 ° C / p = 800 Pa.

26.1 g of 2-chloro-4,6-dicyclopentyloxy-1,3,5-triazine were obtained in the form of a colorless oil, which was 91% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 1.92-2.31 (m, 16H); 5.59 (qu, 2H) [ppm].

P r x l a d XIII.

50 ml of toluene was added to a vigorously stirred suspension of 25 g of sodium bicarbonate and 23.5 g of phenol, followed by portions of 18.5 g of cyanuric chloride at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 90 minutes until the 2,4-dichloro-6-phenoxy-1,3,5-triazine disappeared. The mixture was then cooled to room temperature, diluted with water as in Example 1, then stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, then the solvent was evaporated and the residue was crystallized from cyclohexane.

After filtration and drying, 27 g of 2-chloro-4,6-diphenoxy-1,3,5-triazine were obtained in the form of a white crystalline solid, mp 122-124 ° C, which was a 90% yield.

The results of the analysis of the obtained product were as follows:

¹ H-NMR (250 MHz; CDCl 3): δ = 7.12-7.16 (m, 4H); 7.26-7.30 (m, 2H); 7.37-7.40 (m, 4H) [ppm].

FAB-MS: 300 (M + H ⁺ ).

P r z k ł a d XIV.

To a vigorously stirred suspension of 25 g of sodium bicarbonate and 33.4 g of 4-nitrophenol in 50 ml of toluene was added 18.5 g of cyanuric chloride in portions at such a rate that the temperature of the mixture did not exceed 25-30 ° C. After the addition was complete, the mixture was heated to reflux for 120 minutes until the 2,4-dichloro-6- (4-chlorophenoxy) -1,3,5-triazine disappeared. The mixture was then cooled to room temperature, diluted with water, stirred for 3 minutes, and finally the aqueous layer was separated. The organic layer was washed with 1% sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from cyclohexane.

PL 210,000 B1

After filtration and drying, 8 g of 2-chloro-4,6-di- (4-nitrophenoxy) -1,3,5-triazine were obtained as a light yellow crystalline solid, m.p. 141-144 ° C (69% yield).

Claims (3)

A method for the preparation of trisubstituted 1,3,5-triazine derivatives of the general formula shown in the figure, wherein R1, R2 and R3 are chloro, alkoxy, cycloalkoxy, substituted alkoxy, preferably methoxy, phenoxy, substituted phenoxy, with whereby if R1 and R2 are chlorine then R3 is the above-mentioned groups, and if R1 is chlorine then R2 and R3 are the above-mentioned groups, consisting in the action of alcohol on cyanuric chloride at room temperature or the boiling of the reaction mixture ensuring the disappearance of the starting materials and products intermediate, in the presence of a hydrogen chloride acceptor, characterized in that the reaction is carried out in a multiphase system, resulting from adding a solvent or a mixture of solvents sparingly soluble in water to the reaction mixture, where alkali or alkaline earth metal bicarbonates, carbonates are used as hydrogen chloride acceptors alkali or alkaline earth metals or mixtures thereof, preferably sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or mixtures thereof. 2. The method according to p. The process of claim 1, characterized in that halogenated aliphatic hydrocarbons, preferably chloroform, dichloromethane, dichloroethane are used as sparingly soluble solvents in water. 3. The method according to p. The process of claim 1, characterized in that aromatic hydrocarbons, substituted aromatic hydrocarbons, preferably toluene, benzene, and chlorobenzene are used as the sparingly soluble solvents in water.