DD252374A1 - PROCESS FOR THE PREPARATION OF 2-AMINO-4-ALKOXY-6-ALKYL-1,3,5-TRIAZINENE - Google Patents

Abstract

The process according to the invention relates to the preparation of 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines which can be used as intermediates for herbicidal active ingredients, pharmaceuticals or optical brighteners. According to the invention, the triazines are prepared by reacting dicyandiamide with corresponding alcohols with or without the addition of further solvents and copper (II) salts in a first process step to carbamimidoyl-O-alkylisourea copper complexes and subsequently in the second process step with carboxylic anhydrides or mixtures of these and Carboxylic acids are cyclized. This process allows the exclusion of by-products or by-products and a high purity of the target products.

Description

Field of application of the invention

The invention relates to a simple two-step process for the preparation of 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines, which are important intermediates for herbicidal N-benzenesulfonyl-N '- (1,3,5-triazine). 2-yl) ureas are. They are also suitable for the production of pharmaceuticals or optical brighteners.

Characteristic of the known state of the art

It is known that 2-amino-4-alkoxy-6'alkyl-i, 3,5-triazines by reaction of N-cyano-alkylimidsäurealkylestem with cyanamide, amidine -, guanidine, OvAlkylisoharnstoff- or S-alkylisothiourea salts are accessible under acid- or base-catalyzed ring closure (Ü.Org.Chern: 28 [1963] 1816; DE-PS 3411202; EP 84224; GB-PS 2110692; Heterocycles 20 [1983] 463). This synthesis process is characterized by a high präparatiyen effort, low yields and formation of by-products. In addition, a technical use of Alkylcarbonsäureorthoestern and other accessible only on a laboratory scale chemicals out of the question.

Grignardization and alcoholysis of cyanuric chloride lead to the formation of poorly separable product mixtures in a subsequent aminolysis only in low yields and technically non-relevant process steps, such as ether extractions, to the corresponding triazines (DE-PS 2412955, GB-PS 1067695, CH-PS 384584, HeIv. Chim. Acta 33 [1950] 1365; Austr. J. Chem. 27 [1974] 2627).

Furthermore, it is known to prepare 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines by reaction of carbamimidoyl-O-alkylisourea salts with acylating agents (DE-PS 1220431 or FR-PS 1380818; DE-PS 3324800; J. Pharmac Soc. [Japan] 95 [1975] 499; Chem. Pharm. Bull. [Japan] 16 [1968] 474). For this purpose, it is necessary to recover the readily soluble and partially thermally labile carbamimidoyl-O-alkylisohamstoffsalze using hydrogen sulfide from the corresponding copper salt complexes. If copper acetate complexes are used as starting materials, they must additionally be converted into sparingly soluble copper hydrogen sulfate or hydrochloride complexes and then hydrogen sulphide into the corresponding copper-free urea salts (J. Ind. Chem. Soc. 36 [1959] 499; Nippon Kagaku Zasshi 82 [1961] 1672). Only these react with Acylierungsmittelnschlussring to the desired Ami notriazinen, before or during the reaction, in particular when using bifunctional Ci building blocks (DD-PS 212643), the Isourea salts must be additionally converted by means of alkali metal hydroxide or alkali metal oxide in the thermally labile free bases. The yield-reducing conversion into various copper salts, the subsequent release to copper-free salts using toxicologically unobjectionable hydrogen sulfide and thus accumulation of unusable copper sulfide, the additional use of acid acceptors to release the corresponding carbamimidoyl-O-alkylisoureas, often low yields in the cyclization step and long reaction times For economic and toxicological reasons, this multi-stage process does not make much sense for a technical application.

Object of the invention

The object of the invention is to find a technically simple, shortened process for the preparation of 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines, which allows the reaction without formation of by-pass or To lead waste products at the same time high purity of Zieiproduktes.

Explanation of the essence of the invention

The object of the invention is to develop a two-step process with high yields. This object is achieved in that dicyandiamide with appropriate alcohols with or without the addition of further solvents, for. As dimethylformamide, dimethyl or diethyl glycol and copper-II salts in a known per se first step to carbamimidoyl-O-alkylisourea copper salt complexes implemented, and these in the subsequent second reaction step according to the invention with at least the stoichiometric amount of carboxylic anhydrides or mixtures thereof and carboxylic acids to 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines in which R ¹ and R ^{2 are the} same or different and substituted and / or unsubstituted alkyl radicals having 1 to 6 carbon atoms for R ¹ and 1 to 4 carbon atoms for R ² are cyclized according to the following scheme.

NH

NH

OR ¹ ^

₀ .

(R ² COO).

, or R '

R ¹ OH

₁ Cuac ₂ o. Cu (R ² COO)

The copper (II) salts used in the first process step can, for. Example, copper chloride, nitrate, sulfate, acetate or carbonate.

In the reaction of the second reaction step, either the corresponding anhydride and the acid equivalent formed in the reaction may form the reaction medium, or a certain amount of a carboxylic acid having a chain length of 1 to 3 carbon atoms, preferably acetic or formic acid, or a high boiling polar solvent , such as dimethylformamide, dimethyl or diethyl glycol, too. The reaction mixtures are heated to boiling under atmospheric pressure or in vacuo, although very reactive anhydrides do not give a second acylation at the amino group of the triazines. After the reaction is distilled off from the optionally excessively used acid anhydride or any solvent added in vacuo. If anhydride is used excessively, the anhydride acid mixture obtained by distilling off can be used for the reaction up to three times without loss of yield. Depending on the pk _s value of the acid used, either the copper salt of this acid or copper acetate is recovered. After cooling, the reaction products are partly precipitated as crystalline masses or are obtained by concentration to complete dryness. By stirring with water or, if appropriate, prior ethyl acetate extraction, the aminotriazines precipitate as white solids and are pure enough for further reactions. The copper salts contained in the aqueous solution are recovered by concentration in vacuo for re-complex formation.

The advantage of the invention consists in a simple two-step synthesis of 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines in high yield and good purity. As starting materials technically easily accessible compounds are used, which are brought to the reaction without technical effort. By short reaction times, higher yields, clean reaction products, a clear reaction course without occurrence of by-products, almost complete recovery of the copper salts used and their reuse, elimination of the previously necessary transfer of copper acetate complexes into other copper complexes and their yield-reducing release to the corresponding carbamimidoyl-0- Alkylisohamstoffsalzen or free bases and thus avoiding the use of hydrogen sulfide and attack of copper sulfide, the inventive method is superior to the known from the prior art method. The invention is illustrated by, but not limited to, the following examples.

embodiments

Example 1 Preparation of 2-amino-4-alkoxy-6-methyl-1,3,5-triazines

Step 1: carbamimidoyl-O-alkylisourea copper salt acetate complexes

2mol (168g) dicyandiamide and 0.975mol (195g) finely powdered copper acetate are intimately mixed, with 600-75OmI corresponding alcohol and stirred for 3-4h. heated refluxing in a heating bath. After about 1 hour, the color changes from green-blue to violet and the reaction mass becomes visibly firmer. The mixture is allowed to cool well in the refrigerator, the precipitated crystals are filtered off with suction and further reaction product is obtained by vacuum distillation of the alcoholic solution.

If the reaction products obtained by concentration are still smeared, it is mixed with 200 ml of water, stirred well and again concentrated to dryness in vacuo.

The copper complexes show no melting point and can be used without further purification for further reactions.

Table 1: Carbamimidoyl-O-alkylisourea-copper acetate complexes

R ¹ 'Molecular Formula Molecular Weight Yield in%

CH ₃ C ₁₀ H ₂₀ N ₈ O ₆ Cu 411.5 95 C ₂ H ₅ 'C ₁₂ H ₂₄ N ₈ O ₆ Cu. 439.5 95 C ₃ H ₇ C ₁₄ H ₂₈ N ₈ O ₆ Cu 467.5 '89 C ₄ H ₉ C ₁₆ H ₃₂ N ₈ O ₆ Cu 495.5' 84 JC ₄ H ₉ C ₁₆ H ₃₂ N ₈ O ₆ Cu 495 ^ 5 88

Step 2: 2-Amino-4-alkoxy-6-methyl-1,3,5-triazines

5 mmol (2.05 g) of carbamimidoyl-O-alkylisourea-copper acetate complex are refluxed with 4-5 ml of acetic anhydride for 5 min. Under reflux. The reaction solution is freed of the excess acetic anhydride in vacuo, refluxed with 20 ml of methanol or ethanol for 30 min and concentrated again. The crystalline or viscous masses are stirred with 10 ml of water, whereby the triazine separates as a white solid. The resulting triazines are filtered off, washed with water and optionally recrystallized.

Table 2: 2-Amino-4-alkoxy-6-methyl-1,3,5-triazines

R ¹ R ² F ⁰ C yield analysis Ber./Gef. N (umkrist. off) % C H 39,98 CH ₃ CH ₃ 256-257 ^{a |} 81-96 42.85 5.75 40,00 (10-20% igerHAc) 42.79 5.69 36.34 C ₂ H ₅ CH ₃ 173.5 to 175 71 46.74 6.54 36,45 (Toluene) - 46.78 6.59 33,31 C ₃ H ₇ CH ₃ 154-155 95 49,98 7.19 33.43 (EtOH / H ₂ O) 49.72 6.98 30.75 C ₄ H ₉ CH ₃ 124.5-126 ^b) 61 52.73 7.75 30.72 (EtOH / H ₂ O) 52.81 7.71 30.75 JC ₄ H ₉ CH ₃ 130.5 to 132 66 52.73 7.75 30.68 (EtOH / H ₂ O) 52.91 7.67

a) ¹ H-NMR (DMSO-d ₆ / CDCl ₃ ); 6 in ppm: 2.42 CH ₃ ; 4.02 OCH ₃ ; 7.45 NH ₂

b) ¹ H-NMR (CDCl ₃ ); δ in ppm:

2.31 CH ₃ ; 4.27 OCH ₂ ; 1.61 CH ₂ ; 1.42 CH ₂ ; 0.90 CH ₃ ; 6.21 NH ₂

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

Stage 1: as in Example 1

Step 2: 2-Amino-4-methoxy-6-methyl-1,3,5-triazine

0.5mol (205g) of carbamirnidoyl-O-methylisourea-Kupferacetatkornplex are heated in 450-50OmI acetic anhydride with stirring for 10-15min to reflux, whereby everything goes into solution and the color changes from pink to dark blue to green. It is cooled, the triazine and the copper acetate largely precipitate, sucks and the filtrate concentrated in vacuo. The distilled acetic anhydride can be used again without loss of yield for 1-2 further approaches. Both residues are combined and refluxed with 200-30OmI methanol for 30 min with stirring. After cooling, the crystalline mass is filtered off with suction and the methanolic solution is concentrated to dryness in vacuo. Both resulting reaction masses are stirred into 500 ml of water at 80 ° C, whereby the temperature drops to 50-60 ⁰ C, the copper acetate goes into solution and the triazine remains as a white solid. If the triazine still contains traces of traces of copper acetate, it is redistributed in 300 ml of 80 ⁰ C hot water, cooled, filtered off with suction and washed with water.

Yield: 114-134g (81-96%)

F = 249-252 ⁰ C

Example 3 Preparation of 2-amino-4-alkoxy-6-chloromethyl (dichloromethyl) -1,3,5-triazines Stage 1: as in Example 1

Step 2: 2-Amino-4-alkoxy-6-chloromethyl (dichloromethyl) -1,3,5-triazine

5 mmol of carbamimidoyl-O-alkylisourea-copper acetate complex are mixed with 0.0165-0.02 mol of chloro or dichloroacetic anhydride, intimately mixed and in the case of 2-amino-4-alkoxy-6-chloromethyl-1,3,5- triazines in an oil bath of 130 ° C-140 ° C 1-2min or in the case of dichloromethyl in an oil bath of 110-120 ⁰ C 3-5min to "heated to complete liquefaction in a vacuum reflux.

The resulting dark blue solution is refluxed with 20 ml of methanol or 20 ml of 50% methanol for 30 min and concentrated to dryness in vacuo.

The 2-amino-4-ethoxy-6-chloromethyl-1,3,5-triazine already crystallizes on cooling the methanolic solution. The crystalline-viscous masses are stirred with 20-30 ml of water, which separates the triazine within 1-3 min as a white solid. The 2-amino-4-methoxy (ethoxy) -6-chloromethyl-1,3,5-triazine and the 2-amino-4-methoxy-6-dichloromethyl-1,3,5-triazine may optionally also immediately by addition Recrystallized from 15 ml of water from the copper salt solution.

The other triazines are processed further without further purification or optionally recrystallized.

R ² F / ° C yield analysis - 4 - 252 374 (umkrist. off) % C CH ₂ Cl 163 to 164.5 99 34.39 Ber./Gef. (EtOH / H ₂ O) 34.44 H N Table 3: 2-Amino-4-alkoxy-6-chloromethyl (dichloromethyl) -1,3,5-triazines CH ₂ C! 143-145 53 38.21 4.04 32,09 R ¹ (H ₂ O) , 38,34 4.09 • 32.11 CH ₂ Ci 119-122 94 41.49 4.81 29.70 CH ₃ (Et0H / H ₂ 0) 41.66 4.93 29.56 CH ₂ Cl 108.5 to 111 60 44.35 5.47 27.65 C2H5 (EtOH / H ₂ O) 44.41 5.49 27.72 CH ₂ Cl 107.5 to 109.5 73 44.35 6.05 25.85 C ₃ H ₇ (EtOH / H ₂ O) 44.28 6.09 25.94 CHCI ₂ 108.5-110.5 ³¹ 53 28.73 6.05 25.85 C4H9 (EtOH / H ₂ O) 28.55 6.12 25.78 CHCI ₂ 118-120 36 32.31 2.89 '26.80 iC ₄ H ₉ (EtOH / H ₂ O) 32.46 2.86 27.02 CHCI ₂ 90-92 59 35.46 3.62 25.12 CH ₃ (EtOH / H ₂ O) 35.51 3.62 25.24 CHCI ₂ 99.5-101 ^bl 58 38.26 4.25 23.63 C ₂ H ₅ (EtOH / H ₂ O) 38,30 4.24 23.64 CHCI ₂ 108-110 75 38.26 4.82 22.31 C ₃ H ₇ (EtOH / H ₂ O) 38.28 4.69 22.29 4.82 22.31 C4H9 4.74 22.30 1-C ₄ Hg

6.34 CH; 3.97 OCH ₃ ; 6.34 and 6.79 2x NH

b) ¹ H-NMR (CDCl ₃ ); δ in ppm:

6.34 CH; 4.36 OCH ₂ ; 1.66 CH ₂ ; 1.44 CH ₂ ; 0.95 CH ₃ ; 6.05 and 6.72 2x NH

Example 4 Preparation of 2-amino-4-methoxy-6-chloromethyl-1,3,5-triazine Step 1: as in example 1

Step 2: 2-Amino-4-methoxy-6-chloromethyl-1,3,5-triazine

0.05 mol (20,58g) carbamimidoyl-O-methylisourea kupferacetatkomplex be Mito, 15 mol (25.7 g) of chloroacetic anhydride, optionally with stirring in an oil bath of 120-130 ⁰ C at 12-15mm vacuum 5-7min to boiling under reflux heated. The green, oily residue is mixed with 100-120 ml of water, heated again to boiling, filtered, the precipitated after cooling triazine filtered off with suction and washed with water. Concentration of the aqueous solution recovers the corresponding copper acetate for further reactions. If necessary, the resulting triazine can be recrystallized from 5-10% ethanol

 Yield: 14-16g (80-91%). F = 163-164.5 ° C

Example 5 Preparation of 2-amino-4-alkoxy-6-trichloromethyl-1,3,5-triazines Stage 1: as in Example 1

Step 2: 2-Amino-4-alkoxy-6-trichloromethyl-1,3,5-triazines ·

0.015 mol (4.6 g) of trichloroacetic anhydride are added to 5 mmol of carbamimidoyl-O-alkyl isohamstoff-copper acetate complex, immediately placed in an oil bath preheated to 170-180 ° C and refluxed for 3-5 min under a vacuum of 15-20mm the solid copper complex converts to a blue to green viscous mass, which solidifies after a short time. Then it is mixed with 20 ml of methanol or 50% methanol, heated again for 30 min to boiling and concentrated in vacuo.

In the case of the methoxy derivative is stirred with 20 ml of water, whereby the triazine crystallized after some time.

All other compounds are boiled with 10 ml of ethyl acetate, filtered, the ethyl acetate removed from the filtrate and the resulting oily residue air dried. Both residues are triturated with water, whereby the ethoxy derivative is obtained in low yield as a crystalline substance.

Table 4: 2-Amino-4-alkoxy-6-trichloromethyl-1,3,5-triazines

R ¹ R ² F / ° C yield analysis Ber./Gef. N (umkrist. off) % C H 23,01 CH ₃ CCI ₃ 183-185, 5 ^al 45 24,66 2.07 23.28 (EtOH / H ₂ O) 24,89 2.09 21.76 C ₂ H ₅ CCI ₃ 97-99.5 23 27,98 2.74 21.82 (EtOH / H ₂ O) 28,02 2.77 20.63 C ₃ H ₇ CCI ₃ oily-viscous 27 30.96 3.34 19.62 C4H9 CCI ₃ oily-viscous 33 33.65 3.88 19.62 JC ₄ H ₉ CCI ₃ öiig-viscous 29 33.65 3.88

a) ¹ H-NMR (CDCl ₃ ); δΊη ppm: 4.04 OCH ₃ ; 6.16 NH ₂

Example 6 Preparation of 2-amino-4-alkoxy-6-trifluoromethyl-1,3,5-triazines

Stage 1: as in Example 1

Step 2: 2-Amino-4-alkoxy-6-trifluoromethyl-1,3,5-triazines

5mmol of carbamimidoyl-O-alkylisourea-copper acetate complex is poured over with 0.02mol (3.5-4ml) of trifluoroacetic anhydride while cooling. Under exothermic reaction, dissolution and color change from dark blue to green. The mixture is refluxed for 5 minutes and then allowed to cool. The reaction mixture is concentrated to dryness, refluxed with 15-2OmI methanol for 0.5-1 hr. And then concentrated in vacuo. The partially crystalline mass is stirred with 15 ml of water, whereby the triazine precipitates as a white solid from the copper salt solution.

Table 5: 2-Amino-4-alkoxy-6-trifluoromethyl-1,3,5-triazines

R ¹ R ² CF ₃ F / ° C yield analysis Ber./Gef. N (umkrist. off) % C H 28.86 CH ₃ CF ₃ CF ₃ 163 to 165.5 62 30.94 2.59 28,88 (MeOH / H ₂ O) 30.96 2.63 26.92 C2H5 CF ₃ CF ₃ 126 to 127.5 53 34.62 3.38 26,86 (MeOH / H ₂ O) • 34.70 3.42 25.22 C ₃ H ₇ 102.5 to 103 74 37.84 4.08 25.24 (MeOH / H ₂ O) 37.93 4.04 23.72 C4H9 93-94 57 40.68 4.69 23.81 (MeOH / H ₂ O) 40.63 4.61 23.72 JC ₄ Hg 102.5-104 ^bl 47 40.68 4.69 23.88 (Dioxane / H ₂ O) 40.59 4.58

a) ¹ H-NMR (CDCl ₃ ); δ in ppm:

4.46 OCH ₂ ; 1.39 CH ₃ ; 6.16 and 7.05 2x NH

b) ¹ H NMR (CDCl ₃ ) JaInPPm:

4:19 OCH ₂ ; 2.11 CH; 1.02CH ₃ ; 6.11 and 6.99 2x NH

Example 7 Preparation of 2-amino-4-alkoxy-6-ethyl-1,3,5-triazines

Stage 1: as in Example 1

Step 2: 2-Amino-4-alkoxy-6-ethyl-1,3,5-triazines

Smmol carbamimidoyl-O-alkylisourea copper complex are Mito, 025mol (3.5 g) of propionic anhydride in the case derMethoxy-undEthoxyverbindung 1-3 min at 130-135 ⁰ C until complete dissolution brought to the reaction and 5 minutes at this temperature, with good water-jet vacuum , or the other compounds for 1-2min under normal pressure to boiling. The excess anhydride is distilled off in vacuo, the reaction mass with 20 ml of ethanol and heated again for 30 min under reflux. After distilling off the alcohol, the blue-green, viscous residue is boiled three times with 20 ml of ethyl acetate, the insoluble residue is discarded and the ethyl acetate solution is concentrated in vacuo. The resulting residue is triturated with 10-2OmI of water, whereby copper acetate goes into solution and the triazine precipitates as a solid.

Table 6: 2-Amino-4-alkoxy-6-ethyl-1,3,5-triazines

R ¹ R ² F / ° C yield analysis Ber./Gef. N (umkrist. off) % C H 36.34 CH ₃ C2H5 152.5 to 153 94 46,75 6.54 36.31 (H ₂ O) 46,80 6.55 33,31 C ₂ H ₅ C ₂ H ₅ 99-100.5 53 49,98 7.19 33.37 (H ₂ O) 50.03 7.14 30.75 C ₃ H ₇ C ₂ H ₅ 86.5-88 ^a) 77 52.73 7.74 30.64 (EtOH / H ₂ O) 52.96 7.57 28.55 C4H9 C ₂ H ₅ 76 to 77.5 31 55.08 8.22 28.46 (EtOH / H ₂ O) 55,95 8.17 28.55 iC ₄ H ₉ C2H ₅ 89 to 90.5 36 55.08 8.22 28.55 (EtOH / H ₂ O). '54.98 8.13

a) ¹ H-NMR (CDCl ₃ ); δ in ppm:

4.25 OCH ₂ ; 1.74CH ₂ ; 0.96 CH ₃ ; 2.57 CH ₂ ; 1.22 CH ₃ ; 6.14 NH ₂

Example 8 Preparation of 2-amino-4-methoxy-6-ethyl-1,3,5-triazine

Stage 1: as in Example 1

Step 2: 2-Amino-4-methoxy-6-ethyl-1,3,5-triazine

0.05 mol (20,58g) carbamimidoyl-O-methyl-isourea-copper complex are mit0,25mol (33g) of propionic anhydride and the mixture to a uniform blue color, which can not turn into its green, heated in an oil bath at 130-135 ⁰ C 5min and then refluxed for a further 5 minutes at 12-15 mm to complete the reaction. The excess anhydride is stripped off in vacuo, the resulting reaction mass heated again refluxing with 120 ml of ethanol for 30 min and concentrated in vacuo. The blue solid is mixed with 130-150 ml of water, boiled everything, filtered and allowed to cool. The precipitated triazine is filtered off with suction, triturated or washed with 50 ml of water.

Optionally, one can recrystallize from water or xylene.

Yield: 11.5-14.5 g (75-94%)

F = 152.5-153.5 ⁰ C

Claims (2)

1. A process for the preparation of 2-amino-4-alkoxy-6-alkyl-1,3,5-triazines of the general formula _t OR ¹ in which R ¹ and R ^{2 are the} same or different and are substituted and / or unsubstituted alkyl radicals having 1 to 6 carbon atoms for R ¹ and 1 to 4 carbon atoms for R ² , characterized in that dicyandiamide with corresponding alcohols with or converted to carbamimidoyl-O-alkylisohamstoff-copper complexes in a known first step in a conventional per se, without the addition of further solvents and copper-II salts, worked up and then cyclized in the 2nd step with at least the stoichiometric amount of carboxylic anhydrides or with mixtures of these and carboxylic acids become. 2. The method according to item 1, characterized in that are used as the solvent dimethylformamide or dimethyl orDiethylglykol.