SU1452477A3 - Method of producing 3,4,5-trimethoxybenzonitrile - Google Patents

Abstract

A process for the preparation of 3,4,5-trimethoxy-benzonitrile from 3,4,5-trimethoxy-benzoic acid comprises reacting 3,4,5-trimethoxy-benzoic acid with urea and sulfaminic acid and thereafter isolating the 3,4,5-trimethoxy-benzonitrile thus obtained. The sulfaminic acid may be formed in situ from urea and chlorosulfonic acid. 3,4,5-trimethoxy-benzonitrile is a known valuable intermediate useful in the chemical industry, particularly in the pharmaceutical industry. The process is readily and economically feasible on the industrial scale and provides high yields.

Description

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This invention relates to an improved process for the preparation of 3,4,5-trimethoxyben onitrile. 3,4,5-Tri-.methoxybenzonitrile is a known intermediate that is used in the chemical industry, especially in the pharmaceutical industry. This intermediate product is used in the preparation of tO 2,4-diamino-5- (3,4,5-trimethoxybenzyl) -pyrimidine (trimethoprim bacterial agent and sulfonamide potentiator).

3,4,5-Trimethoxybenzonitrile is also changed to produce 3,4,5-trimethoxybenzaldehyde, the latter being a hard-to-reach derivative. This compound is most often obtained from 3,4,5-trimethoxybenzonite-20 reel,

In order to obtain 3,4,5-trimethoxybenzonitrile, several methods of preparation are known.

According to one group of these methods, 3,4,5-trimethoxybenzoic acid is used as the starting material.

According to one method, 3,4,5-trimethoxybenzoic acid introduces

with 3,4,5-trimethoxybenzoyl chloride, interacting with thionyl chloride by reacting with ammonium hydroxide, is converted into the amide of 3,4,5-trimethoxybenzoic acid, and the latter compound is converted into the target 3 by dehydration with phosphorus oxychloride. , 4,5-trimethoxybenzonitrile (I.Org.Chem 24, 1387, 1959). 40

This method is associated with various disadvantages. Synthesis consists of three stages of the process and intermediate products must be isolated. The formation of ds of an acid chloride, carried out with the help of thionyl chloride, is a very corrosive process, which, during operation, causes hardware difficulties. The overall yield of the three stages (based on - 3,4,5-trimethoxybenzoic acid) is relatively moderate.

According to another method, 3,4,5-trimethoxybenzoic acid is heated with an equal amount of lead rhodanide.

The disadvantage of this method is that the lead compound used is very toxic, and hydrogen sulfide is released during the conversion process. This method is unsuitable for industrial purposes due to environmental and health problems (Berichte, 38, 3635, 1905).

According to the following method (Be-richte of the German Pharmaceutical Society, 277, 221-233, 1934), 3.4, 5-trimethoxybenzoic acid is heated with lead thiocyanate at 200 C.

The disadvantages of this method are identical to the disadvantages of this method. The toxic properties of lead compounds exclude the applicability of this method in industry. In the cited literary sources, it is not covered in 3.

According to another group of methods for producing 3,4,5-trimethoxybenzonitrile, 3,4,5-trimethoxybenzaldehyde is used as the starting material. According to one method, 3.4, 5-trimethoxybenzaldehyde is converted to the corresponding oxime and the thus obtained 3,4,5-trimethoxybenzaldoxime is heated at boiling with a 10-fold amount of acetic anhydride. Heating in acetic anhydride is a water sensitive and corrosive process. In addition, difficulties arise in the selection of material that is expensive for the construction of structures. This literary source does not report any output (Berichte, 41, 506.1921). According to other methods (T.Am.Chem.Ro, 83,2203, 1961; Osterr Chemiker Zeitung, 63, 6, 177-182 1962), 3,4,5-trimethoxybenzaldehyde in glacial acetic acid is introduced as a medium with nitropropane and diammonium hydrogen phosphate. The yield of 3,4,5-trimethoxybenzonitrile is 74%. The reaction mixture is refluxed for a long time (16 hours). .

The disadvantages of this method are that the reaction medium from glacial acetic acid is very corrosive, and nitropropane is extremely explosive and difficult to handle.

In addition to these drawbacks, the method derived from 3,4,5-trimethoxybenzaldehyde 1 3,4,5-trimethoxybenzopitrnl obtained is also unprofitable in industry because 3, A, 5-trimethoxanebenealdehyde is a very difficult-to-use starting material. 3,4,5-Trnmethoxybenonitrile can be produced commercially from 3,4,5-trimethoxybenzoic acid profitably. However, due to the described drawbacks in operation, the known methods cannot be carried out cost-effectively and favorably.

The aim of the invention is to simplify the process and develop a cost-effective 3,4,5-trimethoxybenzonitrile process starting from 3,4,5-trimethoxybenzoic acid.

The subject of the invention is a process for the preparation of 3,4,5-trimethoxybenzonitrile from 3,4,5-trimethoxybenzoic acid, characterized in that 3,4,5-trimethoxybenzoic acid is reacted with urea and sulfamic acid and then The resulting 3,4,5-tri methoxybenzonitrile is isolated at the indicated ratio of reactants, temperature and treatment of the reaction mass.

The invention is based on the fact that if 3,4,5-trimethoxy benzoic acid is reacted with urea and sulfamic acid, 3,4,5-trimethoxy benzonitrile is obtained with a good yield at a single stage of the process.

According to the SOE method, sulfamic acid can be used either by itself or it can be formed in situ in the reaction mixture.

The proposed method is carried out in the following ratio of reagents, namely, based on 1 mol of 3,4,5-tr methoxybenzoic acid, 2 mol of urea and 2.0-2.5 mol of sulfamic acid are used. The reaction can take place at 190-200 ° C; preferably at a temperature of about. The reaction takes place in a few hours; reaction time is 3-5 hours.

It is preferable to add a solvent boiling above 200 ° C as a diluent to the reaction mixture. For this purpose, dialkylene glycol monomer or dialkyl ethers (e.g., distilenglycol dimethyl ether or diethylene1 glycol diethyl ether), I-JIH-coli (e.g., propylene glycol), glycol ethers or aromatic hydrocarbons (e.g. decalin) can be used. . Diethylene glycol monomethyl ether is most preferred.

According to another embodiment of the proposed method

0 sulfamic acid is obtained

in situ by reacting urea with chlorosulfonic acid. The interaction of urea with chlorosulfonic acid can be carried out

5 when heated, at a temperature of about 100 ° C. 3,4,5-Trimethoxybenzoic acid is added at the end of the gas evolution. The reaction is carried out at 190-200 ° C, preferably at a temperature of about 200 ° C. In this case, based on 1 mol of 3,4,5-trimethoxybenzoic acid, 3.0 mol of urea and 1.8 mol of chlorosulfonic acid are used.

5 The reaction mixture can be treated in various ways.

According to one method, the reaction mixture is poured into water and basified with an aqueous solution of a base.

0 (for example, using an aqueous solution of an alkali metal hydroxide). Inorganic salts and unreacted 3,4,5-trimethoxybenzoic acid are transferred to the aqueous phase, and the precipitated 3,4,5-trimethoxybenzonitrile can be separated by filtration or centrifugation.

According to another method 3,4,5, - trimethoxybenzonitrile is extracted

0 with a suitable solvent (for example, toluene) and the extract is evaporated.

Example 1. A mixture of 125 kg (0.59 kmol) of 3,4,5-trimethoxybenzoic acid, 71 kg (1.18 kmol) of urine and 144 kg (1.48 kmol) of sulfamic acid is melted at 140 ° C, after which the temperature is raised to 190 ° C. The reaction mixture is stirred at this temperature for 2 hours. After the addition of 90 liters of diethylene glycol monomethyl ether, the temperature rises again to 190 ° C and the reaction mixture is stirred for the next 2 hours at this temperature.

The reaction mixture is poured into 1000 liters of water, after which the slurry, which is slightly heated, is cooled to 20 ° C. After the addition of 670 kg of a 25% aqueous solution of sodium hydroxide

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inorganic salts and unreacted 3,4,5-trimethoxybenzoic acid are transferred to the aqueous phase. The suspension is centrifuged. 95 kg of 3,4,5-trimethoxybenzonitrile melting at 90 ° C is obtained. The yield is 83.5%. After recrystallization from methanol, 76.5 kg of 3,4,5-trimethoxybenzonitrile are obtained. Yield 67.22%. M.p. 94 ° C.

The mother liquor obtained after centrifugation is cooled to 40-45 ° C and the pH is adjusted to 1 by addition of concentrated hydrochloric acid. The resulting suspension is cooled until the liberated 3,4,5-trimethoxybenzoic acid is washed with water until the acid is completely free. 50 kg of 3,4,5-trimethoxybenzoic acid wet after centrifugation are obtained. This product is suspended in 200 liters of water. To the suspension is added, until a 25 L aqueous solution of ammonium hydroxide is dissolved. The insoluble material is removed by centrifugation, and in the filtrate by adding concentrated hydrochloric acid the pH value is set to 1. The precipitated 3,4,5-trimethoxy benzoic acid is centrifuged, washed with water until acid is removed and dried. The separated 3,4,5-trimethoxybenzoic acid (25 kg) is recycled to the process for the preparation of 3.4, 5-trimethoxybenzonitrile. In terms of the reacted 3,4,5-trimethoxybenzoic acid, the selectivity of 3,4,5-trimethoxybenzonitrile is 84.0% (recrystallized 3,4,5-trimethoxybenzonitrile).

EXAMPLE 2 A mixture of 396 g (6.6 mol) of urea, 639 g (6.59 mol of sulfamic acid, and 700 g (3.30 mol) of 3,4,5-trimethoxybenzoic acid is heated at 190 ° C in for 4 hours, the reaction mixture is cooled to room temperature and 1.5 l of water, 5 l of toluene, and 100 g of potassium carbonate are added.The 3,4,5-trimethoxybenzonitrile forms a toluene phase and the reaction mixture is heated for 20 minutes and cooled to room temperature. After adding the ammonium hydroxide saturation solution and 25 g of bone char, the solution is filtered and the filtrate is distributed between

776

organic and aqueous phase. The toluene layer is concentrated under reduced pressure. The residue is dissolved in 1.5 l of acetone and 25 i of bone carbon is added. The mixture is heated and filtered. Under stirring, the filtrate is poured into water, the precipitated product is filtered off and dried. 510 g of 3,4,5-trimethoxybenzonitrile are obtained. Output 80% -. M.p.

93 C.

The pH of the aqueous filtrate is adjusted to 1 with concentrated hydrochloric acid. The mixture was allowed to stand, the precipitated product was filtered, washed with water until neutral and dried. Thus, the resulting 3,4,5-trimethoxybenzoic acid (35 g} is returned to the production of 3,4,5-trimethoxybenzonitrile. The selectivity to 3,4,5-trimethoxybenzoic acid, which was reacted to 3,4,5-trimethoxybenzoic acid, is 84 3%.

Example To 18, Og (0.3 mol of urea, while stirring and cooling with water at a temperature below 50 ° C, 20.4 g (0.18 mol) of chlorosulfonic acid are added dropwise. The mixture is heated to 100 ° C and after the end of the gas evolution is stirred at this After addition of 21.2 g (0.10 mol) of 3,4,5-trimethoxybenzoic acid, the reaction mixture is stirred for 4 hours at 190-, cooled to room temperature, and 100 ml of 10% is added. sodium hydroxide solution. The resulting suspension is filtered, the product on the filter is washed with water and dried. 15 g of 3,4,5-t are obtained. imetoksibenzonitrila. The yield was 77.7%. T.pl.92 C. Recrystallization from methanol gave 12.5 g melting at trimetoksibenzonitrila-3,4,5, yield was 64.7%.

The 3,4,5-trimethoxybenzoic acid contained in the filtrate is regenerated by the method described in Example 1 in an amount of 4.5 g. The 3,4,5-Trimethoxybenzonitrile selective for 3,4,5-trimethoxy benzoic acid, calculated for the reacted 3,4,5-trimethoxy benzoic acid, is 82.2 %

The proposed method is carried out in one stage to obtain the desired

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product with a yield of 6 / 4,7-80%. This does not require the use of toxic: lead compounds, in the process of conversion of which hydrogen sulfide is released, as a result of which the environmental and health problems arise under the conditions of the known method (in this case, the yield in the prototype is not indicated).

Claims (5)

1. A method for preparing 3,4,5-trimethyroxybenzonitrile from 3,4,5-trimethoxy-benzoic acid at elevated temperature, characterized in that, in order to simplify the process, 3,4,5-trimethoxybenzoic acid is reacted with urine - wine and sulfamic acid at a molar ratio of 1: 2: 2-2,5, respectively, and a temperature of 190-200 ° C, followed by treatment of the reaction mixture with an aqueous solution of the base, separation of the target product and treatment of the aqueous solution obtained target product acid with the release of unreacted 3,4,5-trimethoxybenzoic acid, which is recycled.  2. Method pop.1, which differs in the fact that sulphamic acid obtained in situ from chlorosulfonic acid and urea, taken at a molar ratio of 1.8: 3 per mole of 3.4 , 5-trimethoxybenzoic acid. 3. Method POP1, characterized in that the process is conducted in a medium of diethylene glycol monomethyl ether. 4. Method POP1, characterized in that the separation of the target product is carried out by filtration or centrifugation. 5. Method Pop. 1, differing from the fact that the treatment with an aqueous solution of a base is carried out in the presence of toluene to obtain, with this, a toluene extract, from which the desired product is isolated by evaporation.