NL8403885A - PROCESS FOR THE PREPARATION OF 3,4,5-TRIMETHOXY-BENZONITRIL. - Google Patents

Description

NL 32504-Kp / cs

Process for the preparation of 3,4,5-trimethoxy-benzonitrile. _

The invention relates to a new and improved process for the preparation of 3,4,5-trimethoxy-benzonitrile.

3,4,5-trimethoxy-benzonitrile is a known intermediate product for the chemical industry - in particular the pharmaceutical industry - which compound can be used, for example, for the preparation of 2,4-diamino-5— [3,4 .5 - trimethoxy-benzyl} -pyrimidine [trimethoprim], a known antibacterial and sulfonamide potentiating agent. 3,4,5-tri-10-methoxy-benzonitrile is also useful for the preparation of 3,4,5-trimethoxy-benzaldehyde, which compound is widely used in the chemical industry. The said 3.4.5-trimethoxy-benzaldehyde is a difficult to obtain compound and is often prepared from 3,4,5-trimethoxy-benzonitrile.

Various methods are known for the preparation of 3,4,5-trimethoxy-benzonitrile. According to some of those methods, 3,4,5-trimethoxy-benzoic acid is used as the starting material. According to a known method, 3,4,5-trimethoxy-benzoic acid is reacted with thionyl chloride, the 3,4,5-trimethoxy-benzoyl chloride thus obtained is converted into 3,4,5-trimethoxy-benzoic acid amide by treatment with ammonium hydroxide and the resulting amide is dehydrated with phosphorus oxychloride to yield 3,4,5-trimethoxy-benzonitrile / J. Org. Chem. 24, 387 25 (1959) 7. The drawback of the known method is that it comprises three steps, in addition, the intermediates have to be isolated. The acid chloride forming step requires the use of thionyl chloride, which is highly corrosive and causes problems in the selection of the construction materials in industrial scale production. The total yield of the three steps is rather moderate. In another method, 3,4,5-trimethoxy-benzoic acid is converted to 3,4,5-trimethoxy-benzonitrile by heating with an equal.

amount of lead rhodanide. The drawback of this method is that the lead compound used is very toxic and that hydrogen sulphide escapes during the method. This method is unsuitable for industrial scale production because of 1403885; -2- environmental pollution and health hazard / Berichte 38, 3635 /. According to yet another method / Berichte der deut-. schen pharmazeutischen Gesellschaft 277, 221-233 (1934) 7 3,4,5-trimethoxy-benzoic acid is heated with lead thiocyanate 5 at 200 ° C. This method has the same drawbacks as the previous method and is also unsuitable for industrial scale production due to the use of highly toxic lead compounds. No yields are reported in the literature mentioned.

Another large group of methods for the preparation of 3,4,5-trimethoxy-benzonitrile uses 3,4,5-trimethoxy-benzaldehyde as starting material.

According to one method, 3,4,5-trimethoxy-benzaldehyde is converted into the corresponding oxime, after which the 3,4,5-trimethoxy-benzaldoxime thus obtained is heated to boiling with a tenfold excess of acetic anhydride. The drawback of this method is that the heating in acetic anhydride is a very corroding operation in addition to a high sensitivity to water; this means that when preparing on an industrial scale, the choice of the structural material encounters great problems and is moreover expensive. No yields are reported / Berichte 41_, 1921 / · According to other literature · / J. Am. Chem. Soc. H3, 2203 (1961); osterr. Chemiker. Zeitung 6-3 (6), 177-182 (1962]) / 3,4,5-trimethoxy-25-benzaldehyde is reacted with nitropropane and diammonium hydrogen phosphate in glacial acetic acid as medium to yield 3.4.5-trimethoxy-benzonitrile with a yield of 74% The reaction is carried out by refluxing for a long period (16 hours). The disadvantage of this method is that the glacial acetic acid medium is very aggressive and corrosive, while the nitropropane is a very explosive hazardous material, which is difficult to handle.

In summary, it can be stated that in addition to the above-mentioned drawbacks, the preparation of 3,4,5-trimethoxy-benzonitrile starting from 3,4,5-trimethoxy-benzaldehyde is uneconomical on an industrial scale for reasons that 3,4,5-trimethoxy - benzaldehyde is a difficult to obtain material. The economical preparation of 3,4,5-trimethoxy-benzonitrile on an industrial scale can be carried out using 3,4,5-trimethoxy-benzoic acid as a starting material.

8403835 * - 3 -

However, the known procedures using 3,4,5-trimethoxy-benzoic acid as a starting material are unsuitable for industrial scale preparation because of the disadvantages set forth above.

It is an object of the present invention to overcome the disadvantages of the known methods and to develop an economic industrial scale process for the preparation of 3,4,5-trimethoxy-benzonitrile starting from 3,4,5-trimethoxy -benzoic acid.

The invention provides a process for the preparation of 3,4,5-trimethoxy-benzonitrile from 3,4,5-trimethoxy-benzoic acid, characterized in that 3,4,5-trimethoxy-benzoic acid is reacted with urea and sulfamic acid, followed by isolation of the 3,4,5-trimethoxy-benzonitrile thus obtained.

The invention is based on the recognition that upon conversion of 3,4,5-trimethoxy-benzoic acid with urea and sulfamic acid, the desired 3,4,5-trimethoxy-benzonitrile is obtained in one step at a good yield.

Sulfamic acid can either be used as such or prepared in situ in the reaction mixture.

In one embodiment of the invention, 1 mole of 3,4,5-trimethoxy-benzoic acid is reacted with 1.5-2.5 moles of urea and 1.5-3.0 moles of sulfamic acid. The use of 2 moles of urea and 2.0-2.50 moles of sulfamic acid to 1 mole of 3.4.5-25-trimethoxy-benzoic acid is preferred. The reaction can be carried out at 190-21Q®C, in particular at a temperature of about 200 ° C. The reaction proceeds within a few hours, the reaction time usually being 3-5 hours.

The reaction can be carried out by adding a solvent boiling above 200 ° C to the reaction mixture. Preferably, a dialkylene glycol mono- or dialkyl ether (eg diethylene glycol dimethyl ether or diethylene glycol diethyl ether), a glycol (eg propylene glycol) or an aromatic hydrocarbon (eg decalin) is used for this purpose. Diethylene glycol monoethyl ether has been shown to have special advantages.

In another embodiment of the present process, sulfamic acid is prepared in situ by reacting urea with chlorosulfonic acid. The reaction of urea 40 and chlorosulfonic acid can be carried out with heating 8403885 .. - 4 - at a temperature of about 100 ° C, after which 3,4,5-trimethoxy-benzoic acid is added after cessation of the gas evolution. Keling. The reaction can be carried out at 190-210 ° C / preferably at a temperature of about 200 ° C. In this case, 2.5-3.5 moles of urea and 1.5-3.0 moles of chlorosulfonic acid are used on 1 mole of 3,4,5-trimethoxybenzoic acid. It is advantageous to use 3 mol urea and 1.5-2.5 mol chlorosulfonic acid on 1 mol 3,4,5-trimethoxybenzoic acid.

The reaction mixture can be worked up by various methods. According to one method, the reaction mixture can be poured into water, after which the solution is made alkaline (for example with an aqueous alkali metal hydroxide solution). The inorganic salts and the unreacted 3,4,5-trimethoxy-benzoic acid enter the aqueous solution, whereby the precipitated 3,4,5-trimethoxy-benzonitrile can be separated by filtration or centrifugation. In another method, the 3,4,5-trimethoxy-benzonitrile is extracted with a suitable solvent (e.g. toluene) and the extract is evaporated.

The 3,4,5-trimethoxy-benzonitrile obtained by the present process can generally be used for further reactions without any purification, but can also be purified by recrystallization (eg from methanol) if necessary.

In a preferred embodiment of the method of the invention, the 3,4,5-trimethoxy-benzoic acid is recovered by acidifying the aqueous solution obtained after isolating 3,4,5-trimethoxy-benzonitrile. The acidification can preferably take place with the aid of a mineral acid (eg hydrochloric acid). The 3,4,5-trimethoxy-benzoic acid thus obtained can be reused for the preparation of 3,4,5-trimethoxy-benzonitrile.

The advantage of the method according to the invention is that it can be realized economically on an industrial scale, yielding high yields.

Further details of the present invention can be found in the following examples without limiting the invention to any extent thereto.

8403885 "- 5 - *

EXAMPLE I

125 kg (0.59 kmol) of 3,4,5-trimethoxy-benzoic acid, 71 kg (1.18 kmol) of urea and 144 kg (1.48 kmol) of sulfamic acid are melted at 140 ° C, with the temperature being 5 passed to 190 ° C. The reaction mixture is stirred at this temperature for 2 hours, after which 90 liters of diethylene glycol monoethyl ether are added. The temperature of the reaction mixture rose again to 190 ° C, the mixture being stirred at that temperature for an additional 2 hours.

The reaction mixture was poured into 1000 l of water, after which the aqueous suspension was cooled to 20 ° C, followed by addition of 670 kg of a 25% aqueous sodium hydroxide solution. The inorganic salts and the unreacted 3,4,5-trimethoxybenzoic acid transition to the aqueous phase. The suspension is centrifuged. 95 kg of 3,4,5-tri-methoxy-benzonitrile were obtained, which corresponds to a yield of 83.5%. Melting point; 90 ° C. After recrystallization from methanol, 76.5 kg of 3,4,5-trimethoxy-benzonitrile was obtained, which corresponds to a yield of 67.22% with a melting point of 94 ° C.

The mother liquor thus obtained after centrifugation was heated to boiling and then cooled to 40-50 ° C, after which the pH was adjusted to a value of 1 by adding concentrated hydrochloric acid. The suspension thus obtained was cooled to 0-5 ° C, the precipitated 3,4,5-trimethoxy-benzoic acid being separated by centrifugation and washed with acid-free water. This produced 50 kg of moist 3,4,5-trimethoxy-benzoic acid. This product was suspended in 200 l of water. 25 L of an aqueous ammonium hydroxide solution was added to the suspension until the product dissolved. The solution was filtered or centrifuged and the filtrate was adjusted to pH by adding concentrated hydrochloric acid. The precipitated 3,4,5-trimethoxy-benzoic acid was separated by centrifugation, washed without acid and dried.

This yielded 25 kg of 3,4,5-trimethoxy-benzoic acid; this acid was used again for the preparation of 3,4,5-trimethoxybenzonitrile. The conversion of 3,4,5-trimethoxy-benzonitrile in relation to the converted 3,4,5-trimethoxy-benzoic acid is 84.0% (recrystallized 3,4,5-trimethoxy-40-benzonitrile).

8402885 - 6 -

EXAMPLE II

A mixture of 396 g (6.6 mole) urea, 639 g (6.59 mole) sulfamic acid and 700 g (3.30 mole) 3,4,5-trimethoxy benzoic acid was heated at 190 ° C for 4 hours. The reaction mixture was cooled to room temperature, after which 1.5 l of water, 5 l of toluene and 100 g of calcium carbonate were added. 1 The 3,4,5-trimethoxy-benzonitrile formed changes to the toluene phase. The reaction mixture was heated at 100 ° C for 20 min, followed by cooling to room temperature, where 10 ml of concentrated aqueous ammonium hydroxide solution and 25 g of active charcoal were added to 200 ml. The solution was filtered and the filtrate was separated into an organic and aqueous layer. The toluene phase was evaporated under vacuum. The residue was suspended in 1.5 L of acetone, followed by addition of 25 g of active charcoal, then the mixture was heated and filtered. The filtrate was poured into water with stirring, the precipitated product was filtered off and dried. There were obtained 510 g of 3,4,5-tri-methoxy-benzonitrile in 80% yield, melting point; 93 ° C.

The pH of the aqueous filtrate was adjusted to a value of 2 by adding concentrated hydrochloric acid with stirring. The mixture was left to stand, the precipitated product was filtered off, washed with water neutral and dried. This gave 35 g of 3,4,5-trimethoxybenzoic acid; this acid was used again for the preparation of 3,4,5-trimethoxybenzonitrile. The conversion of 3,4 ', 5-trimethoxy-benzonitrile to the converted 3,4,5-trimethoxy-benzoic acid was 84.3%.

EXAMPLE III

To 18.0 g (0.3 mole) of urea was added dropwise at a temperature below 50 ° C with stirring and water cooling 20.4 g (0.18 mole) of chlorosulfonic acid. The mixture was heated to 100 ° C and stirred at that temperature until gas evolution ceased. 21.2 g (0.10 mol) of 3,4,5-trimethoxy-benzoic acid were added, the reaction mixture was stirred at 190-200 ° C for 4 hours and then cooled to room temperature, after which 100 ml of a 10% sodium hydroxide solution was added. The suspension thus obtained was filtered off, after which the product was dissolved at 8403885-7.

The filter was washed with acid-free water. 15 g of 3,4,5-trimethoxy-benzonitrile were obtained in 77.7% yield, melting point: 92 ° C. After recrystallization from methanol, 12.5 g of 3,4,5-trimethoxy-benzonitrile obtained with a melting point of 94 ° C in a yield of 64.7%.

The 3,4,5-trimethoxy-benzonitrile was obtained from the filtrate by the method described in Example I (4.5 g). The conversion of 3,4,5-trimethoxy-benzonitrile in relation to the converted 3,4,5-trimethoxy-benzoic acid is 82.2% (recrystallized 3,4,5-trimethoxy-benzonitrile).

8403885

Claims (10)

Process for the preparation of 3,4,5-trimethoxy-benzonitrile from 3,4,5-trimethoxy-benzoic acid, characterized in that 3,4,5-trimethoxy-benzoic acid is reacted with urea and sulfamic acid, after which the 3,4,5-trimethoxy-benzonitrile thus obtained is isolated. 1 2. Process according to claim 1, characterized in that sulfamic acid is used, which is prepared in situ by reacting chlorosulfonic acid with urea. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature between 190 ° C and 210 ° C for 3-5 hours. Process according to claim 1, characterized in that 1.5-2.5 mol, preferably 2 mol urea and 1.5-3.0 mol, preferably 2.0-2.50 mol sulfamic acid are used 15 to 1 mole of 3,4,5-trimethoxy-benzoic acid. Process according to claim 2, characterized in that 2.5-3.5 mol, preferably 3 mol urea and 1.5-3.0 mol, preferably 1.5-2.5 mol chlorosulfonic acid are used 1 mol 3,4,5-trimethoxy-benzoic acid. Process according to claim 1, characterized in that a solvent with a boiling point above 200 ° C is added to the reaction mixture, preferably a dialkylene glycol mono or dialkyl ether, a glycol, a glycol ether or an aromatic hydrocarbon . Process according to claim 6, characterized in that the solvent used is diethylene glycol monomethyl ether with a boiling point above 200 ° C. 8. Process according to claim 1, characterized in that 3,4,5-trimethoxy-benzonitrile is isolated by dissolving the inorganic salts and unreacted 3,4,5-trimethoxy-benzoic acid in an aqueous alkali metal hydroxide solution, . followed by separation of the 3,4,5-trimethoxy-benzonitrile by filtration or centrifugation. 9. Process according to claim 1, characterized in that the 3,4,5-trimethoxy-benzonitrile is isolated by extraction with a suitable solvent, preferably toluene, followed by evaporation of the extract. 10. Process according to any one of the preceding claims 1-9, characterized in that the aqueous filtrate obtained after isolation of 3,4,5-8403885 * -9- .. trimethoxy-benzonitrile is acidified and precipitated 3,4,5-trimethoxybenzoic acid is isolated and used again in the process. 8403885