RU2092478C1 - Method of preparing m-chlorodiphenyl methylurea - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: present invention describes method of preparing m-chlorodiphenyl methylurea. Reagent 1: m-chlorodiphenyl methane C₆H₅-CH(X)-C₆H₅, X is OH, OCOCH3, OCOCF₃, OSO₂Ph, NH₂, NH₂•HCl, NHCOH. Reagent 2: urea. Reaction conditions: in the presence of mineral acid selected from H₂SO₄, HCl and HClO₄ at reagent 1 to reagent 2 molar ratio of 1: (1.1-8.0):(0.01-1.5) at 40-160 C. EFFECT: more efficient preparation method. 2 cl, 3 tbl

Description

The invention relates to methods for producing a medicinal substance, namely meta-chlorodiphenylmethylurea, which is the original domestic anticonvulsant and is recommended by the USSR Pharmaceutical Committee for medical use as an antiepileptic drug called halodif [1]
The objective of the invention is to increase the yield of galodif and simplifying the method of its production.

X=-OH (I), -OCOCH₃(II), -OCOCF₃(III), -OSO₂Ph(IV), -NH₂(V), -NH₂•HCl(VI), -NHCOH(VII),
которое подвергают взаимодействию с мочевиной в присутствии минеральной кислоты при 40-160^oC при следующих молярных соотношениях реагентов: производное мета-хлордифенилметана мочевина минеральная кислота 1 (1,1-8,0) (0,01-1,5), соответственно.The problem is solved in that as a derivative of meta-chlorodiphenylmethane take compounds of General formula

X = -OH (I), -OCOCH ₃ (II), -OCOCF ₃ (III), -OSO ₂ Ph (IV), -NH ₂ (V), -NH ₂ • HCl (VI), -NHCOH (VII ),
which is reacted with urea in the presence of a mineral acid at 40-160 ^° C. at the following molar ratios of the reactants: meta-chlorodiphenylmethane derivative urea mineral acid 1 (1.1-8.0) (0.01-1.5), respectively.

 The invention proposed such technical solutions that allow you to use a number of other derivatives of meta-chlorodiphenylmethane as the starting organic substrate, and also use available and cheap urea as a derivative of carbamic acid in the presence of various mineral acids (sulfuric, perchloric and hydrochloric).

For the convenience of considering the invention and justifying the features of the production method, the initial organic substrates meta-chlorodiphenylmethane derivatives were divided into 2 groups, each of which was combined by a common mechanism of substrate condensation with a carbamic acid derivative urea:
Group 1 methachlorodiphenylcarbinol and its esters (substrates I-IV);
Group 2 amino derivatives of meta-chlorodiphenylmethane (substrates V-VII).

Анализ вышеприведенной схемы образования мета-хлордифенилметилмочевины показывает, что процесс конденсации субстратов I-IV с мочевиной требует создания обязательных кислотно-катализируемых условий проведения реакции.For the condensation of meta-chlorodiphenylcarbinol and its esters (substrates I-IY), the limiting stage is the generation of meta-chlorodiphenylmethyl carbocation. The formed meta-chlorodiphenylmethyl carbcation then attacks the nucleophilic urea pair and the subsequent proton emission step leads to the target product

Analysis of the above scheme for the formation of meta-chlorodiphenylmethylurea shows that the process of condensation of substrates I-IV with urea requires the creation of mandatory acid-catalyzed reaction conditions.

 The experimental data are given in table. 1 illustrate the effect of urea quality and the amount of acid catalyst on the yield of the target meta-chlorodiphenylmethylurea and on the time of its formation. As can be seen from these data, when the amount of urea is less than 3 mol per 1 mol of meta-chlorodiphenylcarbinol (Table 1, syntheses 1-2), along with the target product in significant quantities, a by-product is formed - 1,3-di / meta-chlorodiphenylmethyl / urea , which is the product of the interaction of the target meta-chlorodiphenylmethylurea with meta-chlorodiphenylmethyl carbocation. Consequently, a urea concentration of less than 3 mol per 1 mol of meta-chlorodiphenylcarbinol is clearly insufficient to suppress dimerization processes, i.e. side effects. The best yields of the target product are achieved with a urea flow rate of 4-8 mol per 1 mol of meta-chlorodiphenylcarbinol (Table 1, synthesis 4-8). An increase in the amount of urea in excess of 8 mol per 1 mol of carbinol is not advisable, because this does not lead to an adequate improvement in the positive effect (Table 1, synthesis 9).

 In the developed method for producing meta-chlorodiphenylmethylurea from substrates I-IV and urea, mineral acid has a two-fold role: to generate a meta-chlorodiphenylmethyl cation through intermediate protonation of substrates I-IV, on the one hand, and for binding the nucleophile released from condensation from substrates I- IV, on the other hand. The experimental data are given in table. 2, substantiate the molar amounts of the acid catalyst using sulfuric acid as an example. In the absence of sulfuric acid, the reaction of meta-chlorodiphenylcarbinol with urea does not take place (Table 1, synthesis 10), and the formation of the target meta-chlorodiphenylmethylurea in appreciable quantities begins to occur at 0.005 mol of sulfuric acid per 1 mol of carbinol (synthesis 11). For the successful condensation of meta-chlorodiphenylcarbinol with urea, the following molar ratios between carbinol and sulfuric acid are optimal: 1 (0.01-0.5) (Table 1, synthesis 13-16).

 An increase in the amount of sulfuric acid in excess of 0.5 mol per 1 mol of methachlorodiphenylcarbinol is undesirable, since this leads to a decrease in the yield of the target product due to the progressive course of side processes (Table 1, synthesis 17, 18). It was found that the condensation of meta-chlorodiphenylcarbinol acetate (substrate II) with urea can successfully proceed in the presence of perchloric acid instead of sulfuric at the following molar ratios of the reagents: meta-chlorodiphenylcarbinol acetate acetate urea perchloric acid 1 5 0.05 (90) (see examples of specific performance experiment).

It was found that for the successful process of condensation of meta-chlorodiphenylcarbinol with urea in the presence of sulfuric acid, a significant role belongs to the temperature factor (Table 2), which mainly affects the intensification of the process. At temperatures of 30-50 ^o C (table. 2, syntheses 1-3) for 6-7 hours, the target meta-chlorodiphenylmethylurea from a mixture of unreacted reagents by fractional crystallization can be removed only with a yield of 25-51. A favorable temperature range for the condensation of meta-chlorodiphenylcarbinol with urea in the presence of sulfuric acid accounts for 60-110 ^o C (table. 2, synthesis 4-10). With an increase in the reaction temperature above 110 ^° C, there is a tendency to thicken the reaction mass due to an increase in the content in the mixture of the side hardly soluble 1,3-di / meta-chlorodiphenylmethyl / urea (Table 2, syntheses 11, 12). Therefore, the yield of the target product is reduced. In addition, an increase in temperature above 110 ^o C leads to the dissociation of urea, as evidenced by the formation of urethane meta-chlorodiphenylcarbinol, which is the product of the interaction of meta-chlorodiphenylcarbinol, which is the product of the interaction of meta-chlorodiphenylcarbinol with isocyanic acid. It was found that meta-chlorodiphenylcarbinol trifluoroacetate (substrate III) and meta-chlorodiphenylcarbinol phenylsulfonate (substrate IV) are condensed with urea in the presence of sulfuric acid in acetic acid at lower temperatures of 40-50 ^° C than with condensation of meta-chlorodiphenylcarbinol (substrate I )

 It was found that the process of condensation of meta-chlorodiphenylcarbinol with urea in the presence of sulfuric acid occurs either in acetic or trifluoroacetic acids, or in the absence of a solvent (Table 3). Condensation of meta-chlorodiphenylcarbinol with urea in the presence of sulfuric acid does not occur in common solvents such as benzene, toluene, hexane, ethanol, propanol-2, methyl ethyl ketone, carbon tetrachloride and dimethylformamide. Obviously, acetic acid and trifluoroacetic acid, being organic acids, serve as an additional proton donor and thereby favor the formation of the target meta-chlorodiphenylmethylurea.

 When using meta-chlorodiphenylcarbinols and their esters (substrates I-IV) as derivatives of meta-chlorodiphenylmethane, the reaction progress and preliminary identification were carried out by TLC analysis on Silufol UV-254 plates (eluent-benzene: ethanol 8: 2, staining under UV light and subsequent processing of the plate with Ehrlich reagent).

На примере мета-хлордифенилметиламина (субстрат V) было установлено, что образование мета-хлордифенилметилмочевины в заметных количествах в присутствии концентрированной соляной кислоты начинается уже при 100^oC, но высокие выходы галодифа достигаются лишь со 110^oC (табл. 4, синтезы 1-3). Дальнейшее увеличение температуры конденсации, вплоть до 160^oC, заметно ускоряет процесс образования целевого продукта и увеличивает его выход (табл. 4, синтезы 4-9). Увеличение температуры конденсации мета-хлордифенилметиламина с мочевиной свыше 160^oC приводит к падению выхода мета-хлордифенилметиламина, а при температурах 180-190^oC преимущественно происходит димеризация целевого продукта, т. е. образуется 1,3-ди/мета-хлордифенилметил/мочевина (табл. 4, синтезы 11-13).Thus, the condensation of meta-chlorodiphenylcarbinol and its esters (substrates II-IV) with urea in the presence of mineral acids at a temperature of 40-110 ^o C leads to the formation of meta-chlorodiphenylmethylurea (halodif) with a yield of 95
The use of amino derivatives of meta-chlorodiphenylmethane (substrates V-VII) as an organic substrate for condensation with a urea carbamic acid derivative already requires different process conditions than the condensation of urea with meta-chlorodiphenylcarbinol and its esters (substrates I-IV). In essence, the formation of the target meta-chlorodiphenylmethylurea based on substrates V-VII is the result of the interaction of amino derivatives of meta-chlorodiphenylmethane (V-VII) with isocyanic acid, and the limiting stage in this case is the process of dissociation of urea to isocyanic acid and ammonia. It is known that urea undergoes thermal dissociation along the route discussed above at a temperature of more than 133 ^o C, however, the introduction of additives of mineral acid and water in the reaction mixture in some cases stimulates the dissociation of urea:

Using meta-chlorodiphenylmethylamine (substrate V) as an example, it was found that the formation of meta-chlorodiphenylmethylurea in appreciable amounts in the presence of concentrated hydrochloric acid begins already at 100 ^° C, but high yields of halodif are achieved only at 110 ^° C (Table 4, synthesis 1- 3). A further increase in the condensation temperature, up to 160 ^o C, significantly accelerates the process of formation of the target product and increases its yield (table. 4, syntheses 4-9). An increase in the condensation temperature of meta-chlorodiphenylmethylamine with urea above 160 ^o C leads to a drop in the yield of meta-chlorodiphenylmethylamine, and at temperatures of 180-190 ^o C, the target product is mainly dimerized, i.e., 1,3-di / meta-chlorodiphenylmethyl / urea is formed (table. 4, syntheses 11-13).

The examples are given in table. 4 (syntheses 4-6), indicate that under the claimed conditions, the dissociation of urea to isocyanic acid occurs at substantially low temperatures. The decrease in urea dissociation temperature is obviously due to the catalytic activity of hydrochloric acid. The experimental argument is supported by the experimental fact that, in the absence of hydrochloric acid, the formation of meta-chlorodiphenylmethylurea is not observed even at 120 ^o C (Table 5, syntheses 1-3) and only at 130 ^o C for 19 h the target product is formed with a yield of 44 (table. 5, synthesis 4). The experimental data are given in table. 5, justify the necessary and sufficient amount of hydrochloric acid. When the amounts of hydrochloric acid are less than 0.08 mol per 1 mol of meta-chlorodiphenylmethane (syntheses 5, 6), the duration of the process of condensation with urea increases. The target product with a good yield is formed when the amounts of hydrochloric acid are 0.08-1.5 mol per 1 mol of meta-chlorodiphenylmethane (Table 5, syntheses 7-13), and an excess of hydrochloric acid over 1.5 mol affects the yield of meta-chlorodiphenylmethylurea due to the formation of its dimer (Table 5, syntheses 14, 15). In addition, for the developed method of obtaining a significant role is given to compliance with molar amounts of urea (table. 5). So, for example, at equimolar ratios of methachlorodiphenylmethylamine and urea (synthesis 16), the process of obtaining 1,3-di / meta-chlorodiphenylmethyl / urea is mainly realized. It was experimentally found that, with the ratios of meta-chlorodiphenylmethylamine and urea 1 (3-7), the best yields of meta-chlorodiphenylmethylurea are achieved (Table 5, syntheses 12, 19-21).

 It was shown that the found optimal quantitative ratios of the reagents and the preferred reaction temperature of meta-chlorodiphenylmethylamine with urea in hydrochloric acid (Table 5, synthesis 12) are quite acceptable for the preparation of meta-chlorodiphenylurea from meta-chlorodiphenylmethylamine hydrochloride (substrate VI) and from meta-chlorodiphenylmethylformide (substrate VII), and in this case the target product was obtained with a yield of 94 and 90, respectively.

 When using amino derivatives of meta-chlorodiphenylmethane (V-VII) as an organic substrate, the reaction progress and identification of the target product were monitored by TLC analysis on Silufol-UV-254 plates (eluent benzene: ethanol 8: 2, stains under UV light and subsequent processing of the plate with Erlich reagent).

Thus, it was found that the condensation of amino derivatives of meta-chlorodiphenylmethane (substrates V-VII) with urea in the presence of hydrochloric acid at 110-160 ^o C leads to the formation of meta-chlorodiphenylmethylurea (halodif) with a yield of up to 94%
Thus, such methods for producing meta-chlorodiphenylurea (halodif) are not known, from which it would follow that the process of condensation of a meta-chlorodiphenylmethane derivative (I-VIII) with a carbamic acid derivative, which is used as urea, in a solvent in the presence of mineral acid 40-160 ^o C would lead to the formation of meta-chlorodiphenylmethylurea in high yield (up to 95%).

Example 1. In a three-necked flask equipped with a stirrer, reflux condenser and dropping funnel, 2.18 g (0.01 mol) of meta-chlorodiphenylcarbinol, 3 g (0.05 mol) of urea, 10 ml of glacial acetic acid and 0.2 ml of sulfuric acid. The reaction mixture is heated to 80 ^o C and maintained at this temperature for 4 hours. After the completion of the reaction, the mixture is cooled, treated with a 15-soda solution to pH 7. The resulting precipitate is filtered off, washed with warm water, recrystallized from ethanol and 2.47 g are obtained meta-chlorodiphenylmethylurea, which is 95 per meta-chlorodiphenylcarbinol.

Example 2. Meta-chlorodiphenylmethylurea is obtained in a yield of 92 from 0.01 mol of meta-chlorodiphenylcarbinol acetate, 0.05 mol of urea in 10 ml of glacial acetic acid in the presence of 0.2 ml of perchloric acid for 5 hours at 80 ^° C, isolated and purified in a similar manner example 1.

Example 3. Meta-chlorodiphenylmethylurea is obtained with a yield of 93 from 0.01 mol of meta-chlorodiphenylcarbinoltoifluoroacetate, 0.05 mol of urea in 10 ml of trifluoroacetic acid in the presence of 0.2 ml of sulfuric acid for 4 hours at 40 ^° C., isolated and purified analogously to the example 1.

Example 4. Meta-chlorodiphenylmethylurea is obtained in a yield of 92 from 0.01 mol of meta-chlorodiphenylcarbinolbenzenesulfonate, 0.05 mol of urea in 10 ml of glacial acetic acid in the presence of 0.2 ml of sulfuric acid for 4 hours at 50 ^° C., isolated and purified analogously example 1.

Example 5. In a three-necked flask equipped with a stirrer, a reverse ring and a dropping funnel, 3.6 g (0.06 mol) of urea, 10 ml of water are charged and 2.18 (0.01 mol) of meta-chlorodiphenylmethylamine is added to the mixture and 0.004 mol of hydrochloric acid, ρ 1.18). The temperature of the reaction mixture was raised to 130 ^° C. over 1 hour, 0.003 mol of hydrochloric acid was added to the mixture at this temperature, and the reaction mixture was kept at 130 ^° C. for 4 hours. After the completion of the reaction, the mixture was cooled, the precipitate formed was filtered off, washed with warm water and a soda solution. to pH 7, recrystallized from ethanol to give 2.44 g of meta-chlorodiphenylmethylurea, which is 94 based on meta-chlorodiphenylmethane.

Example 6. Meta-chlorodiphenylmethylurea is obtained with a yield of 95 from 0.01 mol of meta-chlorodiphenylmethylamine hydrochloride, 0.06 mol of urea in 10 ml of water in the presence of 0.007 mol of hydrochloric acid at 130 ^° C. for 5 hours, isolated and purified analogously to Example 5.

Example 7. Meta-chlorodiphenylmethylurea is obtained in 93% yield from 0.01 mol of meta-chlorodiphenylmethylformamide, 0.006 mol of urea in 10 ml of water in the presence of 0.007 mol of hydrochloric acid at 130 ^° C. for 6 hours, isolated and purified analogously to Example 5.

Physico-chemical characteristics of meta-chlorodiphenylmethylurea:
T. pl. 135-137 ^o C.

Found, C, 64.49; H 5.19; N, 10.83. C ₁₄ H ₁₃ N ₂ ClO.

 Calculated, C 64.61; H 5.00; N, 10.76.

IR spectrum (n, liquid paraffin, cm ^-1 ): 1665 (C = C), 3280 (NH), 3325, 3415 (NH ₂ ).

NMR ¹³ C spectrum (d DMSO, ppm): 56.10 (CH), 157.54 (C = 0).

Claims (2)

1. The method of obtaining m-chlorodiphenylmethylurea, characterized in that the condensation of the derivative of m-chlorodiphenylmethane of the General formula

where X is —OH, —OSOCH ₃ , —OSOCF ₃ , —OSO ₂ Ph, —NH ₂ , —NH ₂ , —HCl, —NHSON
with urea in the presence of a mineral acid selected from the range of H ₂ SO ₄ , HCl, HclO ₂ , at 40 160 ^o With the following molar ratios of the reactants: derivative of m-chlorodiphenylmethane urea mineral acid 1 1.1 8.0 0.01 1, 5.  2. The method according to claim 1, characterized in that in the case of using m-chlorodiphenylmethylcarbinol, the process is conducted in the presence of acetic or trifluoroacetic acid or a mixture of acetic acid and acetic anhydride.

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