CS273050B1 - Method of n,n-dicyaniacetamidine - Google Patents

Abstract

The preparation of sodium salt of N,N'-dicyanoacetamidine is performed in two reaction stages. In the first methyl-N-cyano-acetimidate is prepared by the reciprocal action of methylaminoacetate and cyanamide. In the second phase methyl-N-cyano-acetimidate reacts with a suspension of sodium salt of cyanoamidine in an environment of methanol causing the occurrence of N,N'-dicyanoacetamidine, which can be used for synthesis of pharmaceutical and herbicidal materials.<IMAGE>

Description

The invention relates to a process for the preparation of the sodium salt of dicyenoacetamidine of the formula I

CH,

Z ™ 'N - CN ¹ a

Na® - CD

The compound is an important reactive intermediate for the synthesis of substituted 1,3,5-trizine derivatives, which are useful in the preparation of herbicidal and pharmaceutical compounds of the sulfonylurea type.

N, N ^, -dicyanoamidines of formula IV

N - CN

3 - CN ( ^IV ) '

Na ⁺ (K ⁺ ) wherein R represents alkyl, aryl, alkylalkoxycarbonyl are prepared in several ways. The preparation of the substance I is described in the journal □. Org. Chem. 27 wherein the starting materials are ethyl acetimidate hydrochloride and cyanamide monosodium salt. The reaction is carried out in absolute ethanol under reflux for 27 h under a nitrogen atmosphere to remove the ammonia formed during the reaction. After completion of the reaction, the reaction mixture was cooled and filtered. The product is isolated from the filtrate by evaporation of ethanol and crystallization.

The disadvantage of this method is the long reaction time, the lower quality of the isolated product and the monosodium salt of cyanamide are introduced in dry form, requiring their separate preparation from NaOH and cyanamide, including energy-intensive aqueous isolation. The possibilities of the method are limited to lower alkyl imidates. The potassium salt of N, N-dicyanacatamidine can be obtained by reacting acetamidine hydrochloride with powdered KOH and cyanogen chloride in acetone at temperatures of -20 to -30 ° C. This method has a universal character but the disadvantage is the work with poisonous cyanogen cyanide, low working temperatures, demanding separation using high vacuum (133 to 206) Pa and the crude product usually requires further refining.

K. Robert Huffman and Fred C. Schaefer, '0. Org. Chem .: 28, 1816, (1963) use distilled ethyl N-cyanoacatiraidate for compounds of formula I, which is dissolved in the present anhydrous methanol, and then a free-flowing monosodium cyanamide salt (prepared from NaOH and cyanamide) is added and stirred for 1 h. the reaction mixture is maintained at 40 ° C. The product is separated by filtration, after vacuum distilling off the methanol and prorayti the filter cake with ethanol. This method is also of a universal nature and has numerous advantages compared to previous processes, a short reaction time, operating at normal temperatures and an isolated product of high purity. The disadvantage of this process is the use of distilled methyl-N-cyanoacetimidate, which is isolated by vacuum distillation, during its isolation at higher temperatures, with loss of isomerization of methyl-N-cyanoacatimidate to N-cyano-N-methylacetamide (Chapman's lock) and the like as in the first process, the monosodium cyanamide salt in dry form must be prepared and reacted.

We have now found that the sodium salt of N, N'-dicyanoacstimidine can be advantageously prepared with minimal effort in high yield and quality according to the present invention in two steps by first preparing methyl N-cyanoacetimidate by reacting cyanamide and methyliminoacetate hydrochloride in anhydrous methanol. at -5 to -45 ° C, which is separated from the reaction mixture in the form of a methanolic filtrate and after analytical determination of methyl-N-cyanoacatimidate and cyanomide content is transferred to a suspension of cyanemide monosodium salt prepared concurrently by reaction of cyanamide with methanolic sodium methoxide; the mixture is maintained at a temperature of 40 to 65 ° C. Isolation of the sodium salt of N, N'-cyanoacetimidine

CS 273 050 B1 is carried out after most of the methanol has been distilled off by filtering out a suspension of said salt.

The entire preparation of compound (I) is carried out in a single solvent, i.e. methanol, where the individual steps are connected and there is no need for refining of the intermediates or the final compound.

The actual synthesis of the compound (I) according to the invention is carried out by dissolving crystalline cyanamide in anhydrous methanol at normal temperature, then adding crystalline methyliminoacetate hydrochloride and stirring the resulting reaction mixture for 2-6 hours so that the temperature does not exceed 35 ° C. 25-30 ° C). During the reaction, a suspension of NH 4 Cl precipitates, which is filtered off after washing and washed with a small amount of fresh methanol.

In the combined methanolic filtrates, the content of methyl N-cyanoacetimidate and cyanamide (optionally dissolved NH4Cl) is determined by gas chromatography or titration. Based on the determined methyl N-cyanoacetimidate content, particularly less than an equimolar amount of cyanamide in methanol is dissolved, which is neutralized with a slight excess of sodium methanolate (molar ratio of sodium methanolate / methyl N-cyanoacetimidate = &gt; 1.03 max) and the methanolic suspension formed. The monosodium salt of cyanamide is heated to 40-45 ° C. Then the suspension is monosodium. The cyanamide salts in methanol release a methanolic solution of methyl N-cyanoacetimidate with stirring, and the reaction mixture is stirred at a temperature of about 40 ° C to about 50 ° C.

3.5 hours. After the above time, the reaction mixture is concentrated under reduced pressure to a thick paste, cooled to normal temperature, and then the N, N-cyanoacetamide sodium salt suspension is filtered off and washed with methanol and the product paste is dried in an oven. The recovered methanol is recirculated to the production process.

The advantage of this process is the technological and energy-intensive use of advantageously the sequence of subsequent reactions to achieve a qualitatively higher yield of the sodium salt of N (N'-dicyanoacetamidine.) Analysis of the methyl N-cyanoacetimidate content in methanolic solution is routine for a laboratory equipped with a gas chromatograph. only by volumetric analysis.

The following example illustrates an embodiment of the invention.

An example of a reactor equipped with a stirrer, reflux condenser, thermometer, and nitrogen inlet was charged with 2030 ml of anhydrous methanol (0.04% HgO) and 588.56 g (14 moles) of crystalline cyanamide (99%). with stirring, 1,533.7 g of mathylacetimidate hydrochloride (14 mol) was added. The resulting reaction mixture was rinsed to normal temperature and then at 30 to 35 ° C for a total reaction time of about 5 h. Then the reaction mixture was cooled to 25 ° C and the ammonium chloride suspension was filtered off, washed with 2 x 470 ml methanol and always exhausted sharply. After drying, 555 g of ammonium chloride (87.5% of theory) and 3740 ml (3330 g) of methanol-methyl-N-cyanoacetimidate solution were obtained, which contained 34.7% by weight of ammonium chloride. methyl N-cyanoacetimidate; 4.4 wt. methyl acetate; 0.5 wt. toluene; 0.1 wt. acetamide;

L 3.1 wt. cyanamide; 1.8 wt. % ammonium chloride and less than 0.05 wt. N-cyanoacetamidine. The yield of methyl N-cyanoacetimidate was 84.13% of theory. By liquid and gas chromatography analysis, about 2.5 to 3 wt. 2-amino-4-methoxy-6-methyl-1,3,5-triazine.

Note: Depending on the quality of the methyl acetimidate hydrochloride, the yield of N-cyanoacetimidate was 84-88% of theory.

The same reactor was charged with 204.3 g methanol, 96.52 g cyanamide and 612.1 g

22.5% sodium methoxide and the mixture was heated at 40-45 ° C for 2 h. Thereafter, the reaction mixture containing the suspension of cyanamide monosodium salt was cooled to 25-30 ° C and then treated with 700 g of a 34.7% solution of methyl N-cyanoacetimidate in methanol. The reaction mixture was kept for 3.5 h at a temperature of 40 to 45 ^D C. The sodium salt of N, N ^# -dikyanoacetamidinu was isolated from the reaction mixture after most of the methanol removed by vacuum distillation after filtration and washing with 2 x 50 ml methanol and dried to obtain about 290 g of compound (I)

CS 273 050 Bl

m.p. Mp = 246-250 ° C.

P

A process for producing sodium salt

Claims (2)

NN ^from dicyanoacetamidine of formula I JT-CN CH -C _Ω \ -GN (I) from methyliminoacetate and sodium cyanamide in anhydrous methanol, characterized in that it is carried out in two steps, whereas in the first reaction step methyliminoacetate hydrochloride of formula II is treated JSH.HC1 CH ₃ - (ii) ^x o-ch ₃ cyanamide at -5 to + 45 ° C in anhydrous methanol and the reaction product formed by a methanolic suspension containing methyl-N-cyanoacetimidate of formula III N-CN CH, -C (III) 3 \ After separating the solid NH 4 Cl in the second reaction step, O-CH ₃ is treated with a suspension of sodium cyanamide in methanol, the mixture is allowed to react at 20 to 65 ° C and the resulting product is separated mechanically. 2. A process according to claim 1, wherein the sodium cyanamide is prepared in situ by reacting the cyanamide with a methanolic solution of sodium methoxide.