HU202503B - Process for producing 2-amino-1,3,5-thiazines - Google Patents

Abstract

According to the present invention, the carboxylic acid amine of formula (I), wherein R is a straight or branched alkyl group having 1 to 4 carbon atoms, R1 is a C1-4 straight chain alkyl or benzyl group, is reacted with (EB). N, N -imidido-dithiocyanic acid ester, wherein R, R 3 are each independently C 1 -C 8 straight or branched alkyl, C 2-4 alkenyl 2 nyl or phenyl (C 1 -C 4 alkyl). - and an alcohol of formula R1-OH - R1 in the above-mentioned solvent or an excess of R1-OH at a temperature of 0-80 ° C, preferably 5-40 ° C. The molar ratio (1.21.8) to the compound of formula (I), formula (I), and R1-OH is (1) (at least 10. C = N-CN * phenyl-0H3SO3) (III) Scope of the description: 4 pages, Figure 1 EN 202 503 A -1-

Description

The present invention relates to a process for the preparation of 2-amino-1,3,5-triazine derivatives of formula (I) wherein R 1 is C 4 straight or branched alkyl, R ^{11 is} C 1-4 alkyl or benzyl.

According to the invention, the carboxylic acid amidine is reacted with an N-cyanamidodithioic acid ester and an alcohol.

The compounds of formula I are important intermediates in the manufacture of pesticides and pharmaceuticals. A particularly important product is 2-amino-4-methyl-6-methoxy-1,3,5-triazine, which is an intermediate of the high-efficiency, superselective sulfonylurea herbicide family.

Several methods have been developed for the synthesis of compounds of formula (I). Thus, it is known from Fraction 1 380 818 that, for example, 2-amino-4-alkyl-6-methoxy-1,3,5-triazine was prepared by the ring closure reaction of carboxylic acid chloride and guanyl-O-methylisocarbamide. The process yields the aforementioned compound from intermediates that are difficult to prepare and in extremely low yields in an industrially unavailable manner.

A 3,154,547. U.S. Pat. For example, 2-amino-4-methyl-6-methoxy-1,3,5-triazine can be prepared by the reaction of O-methylisocarbamide and N-cyanoacetamide in 45% yield. However, this method is not applicable on an industrial scale either because of the poor yield or because of the relative instability of O-methylisocarbamide.

However, the yields obtained from the N-cyanoacetamidine ester and sodium hydrogen cyanamide (J. Org. Chem. 1816 (1963)) are improved. 2-amino-4-methyl-6-methoxy-1,3,5-triazine can be prepared in 65% yield. However, this does not result in an industrial scale process either.

U.S. Pat. No. 3,154,547 discloses a more advanced version of the processes disclosed in U.S. Patent No. 3,441,202, which may be commercially available, with excellent yields. An important recognition of this process is that the N-cyano-imidoester can be reacted in excellent yields with O-alkylisocarbamides and S-alkylisothioureas, guanidine and amidines, if these reagents, from their organic or inorganic salts immediately before the reaction, in a reaction mixture with a base, preferably an alkali alcoholate, in an alcoholic solution. This solution avoids unwanted side reactions and causes yields 95.4-99.4% for 2-amino-4-methyl-6-methoxy-1,3,5-triazine. Although this process can be implemented on a factory scale, it also has disadvantages. Thus, the most important compound, in the synthesis of 2-amino-4-methyl-6-methoxy-1,3,5-triazine, is liberated from O-methylisocarbamide sulfate with methanolic sodium methylate solution by external cooling with complete exclusion of air humidity. the relatively unstable O-methylisocarbamide is added followed by additional external cooling of the N-cyanoacetamidoethyl ester and the reaction mixture is stirred for 42 hours at room temperature and the precipitate precipitated is carefully washed with water to remove the sodium sulfate. The industrial implementation of the process has the disadvantage of having to work in an anhydrous medium, using external cooling, long reaction times, and the relatively large amount of water required to wash out the sodium sulfate formed during the recovery.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the processes described so far and to provide a process which is readily obtainable in an industrially feasible manner and provides a product of sufficient purity.

In order to achieve this goal, starting from the starting materials used in the prior art processes, we start from new raw materials which are well industrially manufactured.

In the process of the invention, the 2-amino-1,3,5-triazines of formula (I) are prepared by reacting the carboxylic acid amidine of formula (Π), wherein R is the former, with the formula (etű). With N-cyano-amido-dithiocarboxylic acid esters - wherein R ^z and R ³ are independently C 1-8 straight or branched alkyl, phenyl (C 1-4 alkyl), C 2-4 alkenyl, and an alcohol of the formula R ¹ -OH, wherein R ¹ is as defined above, in the presence or absence of an inert solvent at a temperature of 0-80 ° C, preferably 5040 ° C. The resulting target product is isolated by filtration, washing and drying in known manner

The starting carboxylic acid amidine (Π), its organic or inorganic salt, preferably its hydrochloride, is liberated in an inert solvent or an R ¹ -OH alcohol, using an organic or inorganic base, preferably an alkali alcoholate.

A solution of the filtered solution of carboxylic acid amide H in which R is as above is reacted with N-cyanoimidodithiocarboxylic acid ester III and at least 10 times the stoichiometric amount of R ¹ -OH. on with vigorous stirring. The by-products of the R ² SH and R ³ SH mercaptans, where R ² and R ³ are the former, preferably methyl, are removed by continuous air supply.

The target product precipitated from the reaction mixture after stirring for 0.5-4 hours, usually for 2 hours, is usually obtained, for example, by filtration and evaporation.

Namely, in the process of the invention is that the OI) carboxylic acid amidine of the formula with an organic or inorganic salt of alcohol R ¹ OH and (ΙΠ) of N-cyano-imidoditioszénsav ester of formula - R ^1, R ² and R ³ represents liberating the former, in the presence or absence of the solvent, in the presence of an organic or inorganic base, preferably sodium alcoholate, potassium alcohol, sodium hydroxide, potassium hydroxide R ¹⁰ OH, with stirring, and upon completion of the reaction the target product is filtered off, washed with water, desalted and dried. The reaction temperature is 5-30 ° C, preferably

-2HU 202503A

10-20'C.

The solvent used in the process of the invention is the alcohol R-OH itself, but other inert solvents may also be used, such as: aromatic hydrocarbons: benzene, toluene, xylene; aliphatic hydrocarbons: hexane, octane; halogenated aliphatic hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, etc., as well as dioxane, acetone, methylethylketone, dimethylformamide, acetonitrile, dimethylsulfoxide.

In the process of the present invention, it is generally sufficient to select the molar ratio of the three reaction components so that the molar ratio of carboxylic acid amidine (Π), N-cyano-imidodithiothioic acid ester (H1) and alcohol (R-OH) is 1.2. -l, 8): l: Must be at least 10.

A preferred embodiment of the process of the present invention is the use of carboxylic acid amidine hydrochloride as the starting material, which is suspended in an alcohol of formula R'-OH, liberated with an equivalent amount of potassium OR ¹ base and filtered to remove the free potassium chloride. To the filtrate was added N-cyano-imidodithio carbonate ester dissolved in R-OH alcohol at 25 ° C, 1: 1.5 molar ratio, stirred for 2 hours at this temperature, the precipitated crystalline target product was filtered off and dried. 99% pure product is obtained.

The invention is illustrated by the following examples.

Example 7

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

To a solution of 6.96 g (0.12 mole) of acetamidine in 100 ml of acetonitrile was added 32 g (1 mole) of methanol at room temperature and 14.6 g (0.1 mole) of N was added to the resulting homogeneous solution with vigorous stirring. 50 ml of acetonitrile solution of cyano-imidodithiocarboxylic acid dimethyl ester.

After the addition, the reaction mixture was stirred for an additional two hours at 20 ° C. The precipitated product was filtered off, washed with 50 ml of acetone and air dried.

Weight of product: 10.15 g (72.5%). 249251 'C.

Example 2

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

To a solution of 6.96 g (0.12 mol) of acetamidine in 100 ml of methanol under vigorous stirring at 25 ° C in small portions for 2 hours was 14.6 g (0.1 mol) of crystalline N-cyanimidodithioic acid dimethyl ester was added. After the addition was complete, the reaction mixture was stirred for another 2 hours at 20 ° C, and the precipitated crystalline 2-amino-4-methyl-6-methoxy-1,3,5-triazine was filtered off, washed with 50 ml of acetone. Dry at 25 ° C.

Product weight: 12.5 g (89.3%). Mp: 251-253'C.

Example 3

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

To a solution of 10.44 g (0.18 mol) of acetamidine in 75 g of methanol is added a solution of 14.6 g (0.1 mol) of N-cyanimidodithioic acid ester in 75 g of methanol at room temperature over 3 hours. After stirring for a further two hours at 20 ° C, the resulting 2-amino-4-methyl-6-methoxy-1,3,5-triazine was filtered off, washed with 50 ml of acetone and dried at room temperature. Product weight: 13.36 g (95.4%).

Similarly to the methanolic mother liquor, 8.76 g (0.6 mole) of a solution of N-cyanoimidodithiocarboxylic acid ester in 50 ml of methanol is obtained, whereby another product is obtained. Product weight: 7.68 g (91.51%).

Yield is based on the N-cyano-imidodithioic acid ester.

Example 4

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

To a solution of 14.6 g (0.1 mol) of N-cyanoimidodithiocarboxylic acid dimethyl ester and 15.12 g (0.16 mol) of acetamidine hydrochloride in 120 ml of methanol is added a solution of 9.92 g in 50 ml of methanol under vigorous stirring. g (0.16 mol) of potassium hydroxide. The reaction mixture was stirred for 4 hours at 20 ° C and the mixture of product and potassium chloride formed was filtered off. The inorganic salt was washed with water (2 x 50 mL) and the residue was washed with acetone (2 x 25 mL) to give 99% pure 2-amino-4-methyl-o-methoxy-1,3,5-triazine. Product weight: 13 g (92.851%). M.p .: 251-253 'C.

Example 5

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

A solution of 22.2 g (0.1 mole) of N-cyanimidido-dithiocarboxylic acid benzyl methyl ester in 50 ml of methanol is added at 25 ° C over 2 hours to a solution of 15.2 g (0.16 mole) of acetamidine in 100 g of methanol. followed by stirring at 20'C for an additional three hours. The precipitated crystalline 2-amino-4-methyl-6-methoxy-1,3,5-triazine was filtered off, washed with 50 ml of acetone and dried.

Product weight: 11.9 g (85%). Mp: 248250'C.

Example 6

Preparation of 2-amino-4-methyl-6-methoxy-1,3,5-triazine

A solution of 8.94 g (0.03 mole) of dibenzyl N-cyano imidodithiocarboxylate in 50 ml of methanol is added over 2 hours to a solution of 2.1 g (0.036 mole) of acetamidine in 25 ml of methanol, then stirred at this temperature for a further 2 hours. The precipitated product was washed with 10 ml of acetone to give 2 amino-4-methyl-6-methoxy-1,3,5-triazine in 96% purity. Product weight: 2.9 g (69%). Mp: 247250'C.

Example 7

A solution of 2-amino-4-ethyl-6-methyl-1,3,5-triazine dimethyl ester of N-cyanoimidodithioic acid (0.05 mol) in ethanol (75 ml) was added at 4.64 g at 25 ° C. (0.08 mol) acetamidine in 50 g ethanol

The solution was raised to 70 ° C and stirred at this temperature for 6 hours, then 70 ml of ethanol was distilled off and the solution was cooled to 25 ° C and allowed to stand overnight. The following day, the crystalline precipitated 2-amino-4-ethyl-6-methyl-1,3,5-triazine was filtered off, washed with 10 ml of acetone and dried. Melting point: 179-180 ° C. Weight: 5.1 g (681%).

Example 8

2-Amino-4-benzyloxy-6-methyl-1,3,5-triazine To a solution of 8.7 g (0.15 mol) of acetamidine in 75 ml of benzyl alcohol was added 14.6 g (0.1 mol) of N-cyanide. dimethyl ester of imidodithioic acid in small portions at 25 ° C. The temperature of the reaction mixture was raised to 80 ° C and stirred at this temperature for a further 6 hours. The solution was cooled to 25 ° C and ether (100 mL) was added. The precipitated 2-amino-4-benzyloxy-6-methyl-1,3,5-triazine is filtered off, washed with 10 ml of ether and dried. Melting point: 183-184 ° C. Weight: 14.6 g (64.8%).

Example 9

2-Amino-4-isopropoxy-6-methyl-1,3,5-triazine A solution of 7.3 g (0.05 mol) of dimethyl ester of N-cyano-iminodithioic acid in 75 ml of isopropanol was added at 25 ° C. To a solution of 4.64 g (0.08 mol) of acetamidine in 75 ml of isopropanol was added, the temperature was raised to 70 ° C and stirred at this temperature for 8 hours, then 100 ml of isopropanol was distilled off under reduced pressure to 25 ° C. heat it and leave it to stand overnight. The next day, the crystalline precipitated 2-amino-4-isopropoxy-6-methyl-1,3,5-triazine was filtered off, washed with 10 ml of acetone and dried.

Melting point: 168-70 ° C. Weight: 1.56 g (311%).

Example 10

2-Amino-4-methyl-6-methoxy-1,3,5-triazine A solution of 5.16 g (0.03 mol) of allyl methyl N-cyanoiminothiothiocarboxylate in 50 ml of methanol for 2 hours, To a solution of 1 g (0.036 mol) of acetamidine in 25 ml of methanol was added at 25 ° C and stirred at this temperature for a further 2 hours. The precipitated product is filtered off, washed with 10 ml of acetone and dried. Weight: 2.64 g (63%).

Example 11

2-Amino-4-methyl-6-methoxy-1,3,5-triazine A solution of 5.64 g (0.03 mol) of N-cyano iminodithiocarboxylic acid methyl sec-butyl ester in 50 ml of methanol was added over 2 hours. A solution of acetamidine (2.1 g, 0.036 mol) in methanol (25 ml) was added at 25 ° C and stirred at this temperature for a further 2 hours. The precipitated product is filtered off, washed with 10 ml of acetone and dried. Melting point: 2513'C. Weight: 2.39 g (571%).

The main advantages of the invention are:

The process of the present invention allows the industrial preparation of 2-amino-1,3,5-triazines used as pesticide intermediates in commonly used chemical equipment, in high purity, in good yield, with commercially available and easy to use starting materials, with favorable temperature intervals and appropriate reaction times.

The obtained target products can be used without further purification for the production of pesticides.

Claims (2)

PATENT CLAIMS A process for the preparation of 2-amino-1,3,5-triazines of the formula I wherein R is a linear or branched alkyl group, R is a linear alkyl of 1-4 carbon atoms, or benzyl 25, by reaction of a carboxylic acid imidine, an N-cyano-imidodithioic acid ester and an alcohol, wherein a carboxylic acid amidine of formula (Π) wherein R is as defined above is reacted with an N30 cyanide of formula (ΙΠ) with an imidodithioic acid ester, wherein R, R ³ are independently C 1-8 straight or branched alkyl, C 2-4 alkenyl or phenyl (C 1-4 alkyl) - and R-OH 35 alcohol - wherein R ¹ is as defined above - or an (Π) karbonsavamidin formula a hydrochloride - wherein R is as defined above, is reacted with a (Π) of N-cyano-imido ditioszénsavészterrel formula: - wherein R ² , R ³ are as defined above for an alcohol of the formula -R ¹ -OH where R ¹ is as defined above, and for an organic or inorganic base, preferably an alkali alcoholate, in an inert solvent or for an excess of R * -OH alcohol 0-80 'C hőmérsékle45 ten - preferably 5 to 40 ° C - while maintaining the carboxylic acid amidine of the formula (Π) of (ΙΠ) of N-cyano-imido szénsavészter formula I and the molar ratio of alcohol ^Rf -OH (1.2 -1.8): 1: at least 10, then the precipitated 2-amino-1,3,550 triazine of the formula (I) is obtained by filtration, washing and evaporation in known manner. 2. A process according to claim 1, wherein the 1.8: 1: 10 molar solution of acetamidine, N-cyanimidodithioic acid ester and methanol is used. After stirring at room temperature for 55 minutes, the precipitated 2 amino-4-methyl-6-methoxy-1,3,5-triazine was filtered, washed, and dried.