DE3446871A1 - Process for the preparation of 3,4,5-trimethoxybenzonitrile - Google Patents

Abstract

The invention relates to a process for the preparation of 3,4,5-trimethoxybenzonitrile from 3,4,5-trimethoxybenzoic acid with isolation of the former, in which 3,4,5-trimethoxybenzoic acid is reacted with urea and sulfamic acid. <??>The 3,4,5-trimethoxybenzonitrile is a useful intermediate in the chemical industry, in particular the pharmaceutical industry. <??>The main advantages of this process lie in the fact that it can also be carried out conveniently on the industrial scale and with low expenditure, and yields the desired product in a good yield.

Description

DR. STEPHAN G. BESZiDES "" "

VNR: 101265

APPROVED REPRESENTATIVE ALSO AT THE EUROPEAN PATENT OFFICE

PROFESSIONAL REPRESENTATIVE ALSO BEFORE THE EUROPEAN PATENT OFFICE 30 * 60 -DACHAU NEAR MÖNCHEN

PO Box 11 68

MDNCHENER STRASSE 8OA Federal Republic of Germany

TELEPHONE: D ACH AU 081 31/4371 TELEX: 527537 bepat d

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Account No. 1 368 71-801 Bank account No. 906 370 at the Sparkasse Dachau

(Sort code 700 515 40)

(VIA Bayerische Landesbank

Girozentrale, Munich)

P 2 086

Claims and Description

for patent application

SGYT GYOGYSZERVEGYESZETI

Budapest, Hungary

concerning

Process for the preparation of 3,4-, 5-tri- (methox.y) -be nzonitrile

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H ν * * U

Description;

The invention relates to a better new process for the preparation of 3,4,5-tri (methoxy) benzonitrile.

The 3, ^ 5-tri- (methoxy) -benzonitrile is a known intermediate which is used in the chemical industry, especially in the pharmaceutical industry. This intermediate product can be used in the manufacture of 2,4-di- [amino] -5- [3 ', 4', 5'-tri- (methoxy) -benzyl] - -pyriraidines f Trimethoprimes \ , a valuable antibacterial agent and sulfonamide potentxators, can be used. Furthermore, the 3,4,5-tri- (methoxy) -benzonitrile can be used for the production of the 3,4,5-tri- (methoxy) -benzaldehyde; this latter compound is a difficult to access derivative, which is mostly produced from 3,4,5-tri- (methoxy) - -benzonitrile.

There are several methods of making 3,4,5-tri- - (methoxy) benzonitrile known.

According to one group of these processes, 3,4,5-tri (methoxy) benzoic acid is used as the starting material. So will 3,4,5-tri- (methoxy) -benzoic acid with Thionyl chloride reacted, the 3,4,5-tri- (methoxy) - formed -benzoyl chloride converted into the 3,4,5-tri- (methoxy) -benzoic acid amide by reaction with ammonium hydroxide and the the latter compound by dehydrating with phosphorus oxychloride into the desired 3 »4,5-tri (methoxy) benzonitrile transferred (J. Org. Chem. 24 [1959], 1 387). This There are several disadvantages associated with this method. So this synthesis consists of 3 process steps and the Intermediate products have to be isolated. The acid-chloride formation carried out with thionyl chloride is also a very corrosive acting process, which occurs during operation

technical difficulties encountered. Furthermore, the overall yield of the 3 stages, based on 3,4,5-tri (methoxy) benzoic acid, is rather mediocre. According to another method, 5,4-, 5-T ^ i- (niethoxy) -benzoic acid is heated with the same amount of lead rhodanide. The disadvantage of this process is that the lead compound used is very toxic and hydrogen sulfide is formed in the course of the reaction. This process is therefore (jtö reports, 3635) because of the environmental and health problems to carry out the operation unsuitable · In another process (Journal of the American Pharmaceutical Society 277, [1934], 221-233) is 3,4,5 Tri- (methoxy) benzoic acid heated to 200 ° C with lead thiocyanate. The disadvantages of this method are identical to those of the method discussed above. The toxic properties of the lead compounds preclude the applicability of this process on an industrial scale. No yields are given in the references cited.

According to another group of known processes for the preparation of the 3,4,5-tri- (methoxy) -benzonitrile, 3> 4,5-tri- (niethoxy) -benzaldehyde is used as the starting substance. Thus, according to a method (Reports 4I _- , 1921) 3,4,5- ⁱ 2i ^> i- (methoxy) -benzaldehyde is converted into the corresponding oxime 3,4,5-tri- (methoxy) -benzaldoxime and this with the "0 times the amount of acetic anhydride heated to the boil. The heating carried out in acetic anhydride is a water-sensitive and extremely corrosive process and the selection of the material, which is associated with high expenditure, encounters difficulties on an industrial scale. No yield is given at this point in the literature. J. Am. Ghem. Ooc. 8_3 [1961], 2 203 and Österr. Chemiker Zeitung 6 ^ £ ö * ("1962J, 177 to 182) the 3,4,5Ttri- (methoxy) -benzaldeh./d in Ki '-. "Fisif; nls Mod ium with Nitropropnn and Diammonium-

et * V β * *

b implemented, the yield on. 3,4-, 5-tri- (mothoxy) -ben2ioni (; riL '/ ¹ V ¹ Zo , in this process the reaction mixture is refluxed for a long time (16 hours). However, this process has its disadvantages that the reaction medium glacial acetic acid has a very corrosive effect and the nitropropane is an extremely explosive, difficult to handle dangerous substance.

In addition to the above disadvantages, the processes starting from 3,4-, 5-tri- (methoxy) -benzaldehyde for the production of 3, ^ -, 5-tri- (methoxy) -benzonitrile on an industrial scale are therefore unsuitable or costly connected because the 3,4,5-tri- (methoxy) -benzaldehyde is a very difficult to access starting material. The 3, ^z i-, 5-tri- (methoxy) -benzonitrile could be produced satisfactorily on an industrial scale from 3,4.5-tri (methoxy) -benzoic acid, but the relevant known processes can because of the disadvantages described above can not be carried out on an operational scale cheaply and without great effort.

The invention is based on the object, while eliminating the disadvantages of the known method, also in the Operational scale good, simple and with good yields and a process for the production that can be carried out without great effort of 3,4-, 5-tri- (methoxy) -benzoritrile from 3,4,5-tri- - (methoxy) benzoic acid.

The above has surprisingly been made by the invention achieved.

The invention is based on the surprising finding that when 3,4,5-tri (methoxy) benzoic acid _m j_t; Urea and sulfamic acid is reacted, the 3,4-, 5-tri- (methoxy) -benzonitrile in good yield in a single

Process stage is obtained.

The invention relates to a method for production of 3> 4,5-tri- (methoxy) -benzonitrile from 3 * 4,5- -Tri- (methoxy) -benzoic acid with isolating the former, which is characterized in that 3i4) 5-tri- (methoxy) - -benzoic acid reacted with urea and sulfamic acid will.

According to the process according to the invention, the sulfamic acid can either be used per se as a finished compound or are used in the reaction mixture formed in situ. According to an advantageous embodiment of the process according to the invention is therefore the sulfamic acid which is derived from chlorosulfonic acid with urea formed in situ is used.

The reaction is advantageously carried out at temperatures of 190-210 ⁰ C. It is particularly advantageous to work at 200.degree. It is also advantageous, first, the mixture of the starting substances, preferably to melt at temperatures of 140 to 150 ° C, such as 140 ⁰ C, and only then to bring the reaction mixture to temperatures of 190-210 ⁰ C.

The implementation takes a few hours. Preferably it is carried out for 3 to 5 hours.

According to one embodiment of the method according to the invention are ever ΓΊοΙ 3,4,5-tri- (methoxy) -benzoic acid 1.5 to 2.5 moles, especially 2 moles, of urea and 1.5 to 3.0 moles, especially 2.0 to 2.5 moles, of sulfamic acid are used.

According to another embodiment of the invention, when the sulfamic acid used is one which has been formed from chlorosulfonic acid with urea in situ, per mole of 3,4-, 5-tri (methoxy) benzoic acid 2 , 5 to 3.5 mol, in particular 3 mol, urea and 1.5 to 3.0 mol, in particular 1.5 to 2.5 mol, chlorosulfonic acid are used. The conversion of urea is preferably carried out with chlorosulfonic acid to form the sulfamic acid in situ under heating at a temperature of about 100 ⁰ C. The 3,4-> 5-tri- (niethoxy) -benzoic acid is expediently only added after the evolution of gas has ceased. Thereafter, the reaction of the urea and the BuIfaminsäure carried with it, and that, as already mentioned, at temperatures from 190 to 210 ⁰ C, in particular 200 ⁰ C.

Advantageously, or [a] will be in the reaction mixture even over 200 ⁰ C boiling [s] solvent, in particular 1 or more Di al kyl englyko Iraono alky lather and / or -dialkyläther, for example Diäthylenglykoldi- methyl ether and / or Diäthylenglykoldiäthyläther, Gl. ykoXe), for example propylene glycol and / or ethyl englyko 1, G-glycol- "ether, for example propylene glycol and / or ethylene glycol- raoxDalkylether and / or -dialkylätiKr, like -dLmeöiyläther and / or -diethy 1 -ether, uid / or aromatic Kohlenwasserstof f (e), for example decahydronaphthalene used. particularly preferred as more than 200 ⁰ C boiling solvent diethylene glycol monomethyl ether used because this to be particularly proved advantageous. the addition of more than 200 ⁰ C boiling solvent is advantageously carried out during the reaction.

The reaction mixture can be worked up by various procedures.

Thus, according to an expedient procedure, the isolation of the 3 ₅ 4-, 5-tri- (methoxy) -benzonitrile by dissolving the inorganic salts and unreacted 3i4-, 5-tri- (methoxy) -benzoic acid in an alkaline medium is preferred in an aqueous alkali metal hydroxide solution, and from filtering or centrifuging off the 3, 4 ·, 5-tri- (methoxy) -benzonitriles carried out. The procedure can be that the reaction mixture is poured into water and made alkaline. However, the aqueous alkali metal hydroxide solution can also be added directly. An aqueous sodium hydroxide solution is advantageously used as the aqueous alkali metal hydroxide solution. The inorganic salts and the unreacted 3,4-, 5-tri- (methoxy) -benzoic acid pass into the aqueous phase and from this the precipitated 3 » ^z H5-tri- (methoxy) -benzonitrile is filtered through the Ab or separated by centrifugation.

According to another expedient procedure, the 3,4-, 5-tri (methoxy) benzonitrile is isolated by extracting with an organic solvent, in particular toluene, and evaporating the extract. The addition is expediently carried out after the reaction mixture has cooled, preferably to room temperature, and heating to a temperature lower than the reaction temperature given above, preferably 100 to 120 ^° C., in particular 100 ^° C., is carried out.

The 3,4-, 5-tri (methoxy) benzonitrile obtained by the process according to the invention can be used in the further reactions generally used without purification. It can, however, if necessary, by recrystallization, for example from methanol.

According to an advantageous embodiment of the invented in Vorfnhr'on.-i becomes, (inr, rmch dfiin ΓμοΙ invn dn: t

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- 10 -

The aqueous filtrate obtained from 3,4,5-tri- (methoxy) -benzonitriles is acidified and the precipitated 3i4,5-tri- (methoxy) -benzoic acid is isolated and used in the process for the preparation of the 3,4,5-tri- (methoxy ) -benzonitriles recycled. The acidification of the aqueous solution can advantageously be carried out with a mineral acid, for example hydrochloric acid. The acidification can be advantageously carried out at temperatures of 30 to 50 ⁰ C, especially 40 to 45 ° C, followed by lowering the temperature to even lower values, preferably 0 to 10 ⁰ C, to 5 ° C, made in particular 0, this case is preferably acidified to a pH of 0.5 to 1.5> in particular 1.0.

The main advantages of the process according to the invention are that it is cheap and with an operational scale can be carried out with little effort and delivers the desired product in good yield.

The method of the invention is illustrated by the following Examples explained in more detail.

example 1

A mixture of 125 ^ g (0.59 kmol) 3,4,5-tri- (methoxy) -benzoic acid, 1 kg (1.18 kmol) urea and 144 kg (1.48 kmol) sulfamic acid was added 140 ⁰ C melted, whereupon the temperature was increased to 190 ⁰ C. The reaction mixture was stirred or shaken at this temperature for 2 hours. After addition of 90 1 Diäth.ylengiykolmonomethyläther the temperature was again raised to 190 ⁰ C and the reaction mixture stirred for a further 2 hours at this temperature or shaken.

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The reaction mixture was poured into Λ000 l of water, whereupon the suspension, which warms up slightly, was cooled to 20.degree. After 670 kg of a 25% strength by weight aqueous sodium hydroxide solution had been added, the inorganic salts and the unreacted 3,4,5-tri- (methoxy) -benzoic acid passed into the aqueous phase. The suspension was centrifuged. 95 kg (83.3% of theory) of 3,4,5-tri (methoxy) benzonitrile with a melting point of 90 ^° C. were thus obtained. After recrystallization from methanol, 76.5 kg (67.22% of theory) of 3,4,5-tri- (methoxy) -benzonitrile with a melting point of 94 ° C. were obtained.

The aqueous mother liquor obtained after centrifugation was cooled to 40 to 45 ° C and the pH was adjusted adjusted to 1 by adding concentrated hydrochloric acid. The suspension formed was cooled to 0 to 5 ° C and the precipitated 5 \ 4 »5-tri- (mebhoxy) -benzoic acid was washed acid-free with water. There were 50 kg of the centrifuge moist 3,4,5-tri (methoxy) benzoic acid obtained. This product was suspended in 200 l of water. The suspension were until dissolved 25 l of an aqueous ammonium hydroxide solution added. The insoluble matter was removed by centrifugation and the filtrate was passed through Adding concentrated hydrochloric acid adjusted to pH 1. The precipitated 3,4,5-tri- (methoxy) - Benzoic acid was centrifuged off, washed free of acid and dried. The obtained 25 kg of 3,4,5-tri- (methoxy) - benzoic acid were returned to the process for the preparation of 3,4-, 5-T-a- (methoxy) -finzonitrilo3. the Conversion to 3,4,5-TrL- (raefchoxy) -benzonitrile was 84.0% of theory [recrystallized 3,4,5-tri- (methoxy) - -benzonitrile], based on the converted 3,4,5-tri-. - (methoxy) benzoic acid.

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Example 2

A mixture of 396 g (6.6 mol) of urea, 639 S (6.59 mol) of sulfamic acid and 700 g (3.3 mol) of 3,4,5- tri (methoxy) benzoic acid was obtained for 4 hours heated to 190 ^{0 C.} The reaction mixture was cooled to room temperature and 1.5 l of water, 5 l of toluene and 100 g of calcium carbonate were added. The 3,4,5-tri- (methoxy) -benzonitrile formed passed into the toluene phase. The reaction mixture was heated to 100 ° C. for 20 minutes and then cooled to room temperature. After adding 200 ml of a saturated aqueous ammonium hydroxide solution and 25 g of bone charcoal, the solution was filtered and the filtrate was divided into an organic and an aqueous phase. The toluene layer was evaporated under reduced pressure. The residue was taken up in 1.5 liters of acetone and 25 g of bone charcoal were added. The mixture was heated and filtered. The filtrate was poured into water with stirring and the precipitated product was filtered and dried. 510 g (80% of theory) of 3,4,5-tri (methoxy) benzonitrile with a melting point of 93 ° C. were obtained.

The pH of the aqueous filtrate was concentrated with Hydrochloric acid adjusted to 1. The mixture was left to stand and the precipitated product was filtered off; washed neutral with water and dried. The 35 g of 3,4,5-tri- (mebhoxy) -benzoic acid thus obtained were recycled to the production of the 3,4,5-tri- (mebhoxy) -benzonitrile. The conversion to 3,4,5-Trl- (methOxy) -benzonitrile was 84.3% of theory [recrystallized 3,4,5-tri - (methoxy) benzonitrile], based on the converted 3,4,5- tri (methoxy) benzoic acid.

Example 5

There were to a reaction mixture, which by adding dropwise 20.4 g (0.18 mol) of chlorosulfonic acid to 18.0 g (0.5 mol) of urea with stirring or shaking and water cooling at a temperature below 50 ° C, heating the Mixture was obtained at 100 ⁰ C and stirring or shaking until the evolution of gas at this temperature, 21.2 g (0.10 mol) 3,4,5-tri- (methoxy) -benzoic acid was added and the reaction mixture was stirred for 4 hours at 190 to 200 ⁰ C, and shaken, and cooled to room temperature and 100 ml of 1-riner 10 wt% .- - aqueous sodium hydroxide solution was added. The suspension formed was filtered and the product washed on the filter with water and dried. 15 g (77.7% of theory) of 3,4-, 5-tri- (methoxy) -benzonitrile with a melting point of 92 ° C. were obtained. After recrystallization from methanol, 12.5 S (64-, p / o of theory) 3,4-, 5-tri (methoxy) benzonitrile with a melting point of 94 ° C. were obtained.

^{The 3,4,5-Ti>} i- (methoxy) benzoic acid contained in the filtrate was recovered in the manner described in Example 1 (4.5 g). - -benzonitrile was 82.2% of theory [recrystallized 3,4-, 5-tri- (methoxy) -benzonitrile], based on the converted 3,4,5-tri- (methoxy) -benzoic acid.

to

Claims (11)

I - · ιβ β · patent claims 1.) / Process for the preparation of 3,4,5-tri- (methoxy) - benzonitrile from 3,4-, 5-tri (methoxy) benzoic acid with Isolating the former ^ characterized in that 3,4-, 5-tri (methoxy) benzoic acid with urea and sulfarninic acid. 2.) Method according to claim 1, characterized in that that the sulfamic acid is a substance which has been formed in situ from chlorosulfonic acid with urea is used. 3.) Method according to claim 1 or 2, characterized in that that the reaction at temperatures of 190 to. 210 ° C. 4.) Process according to Claim 1 to 3, characterized in that the reaction is carried out for 3 to 5 hours long performs. 5.) Process according to claim 1, 3 or 4-, characterized in that per mole of 3,4-, 5-'l ¹ ri- (methoxy) - benzoic acid 1.5 to 3 P, 5 mol, in particular 2 mol , Urea and 1.5 to 3.0 moles, in particular
2.0 to 2.5 moles, sulfamic acid used. 6.) Process according to claim 1 to 4-, characterized in that per mole of 3,4-, 5-Ti "i- (methoxy)
acid 2.5 to 3.5 mol, in particular 3 mol, urea and 1.5 to 3.0 mol, in particular 1.5 to 2.5 mol, chlorosulfonic acid are used. 7.) The method according to claim 1 to 6, characterized in that in the reaction mixture also [a] over 200 ⁰ C boiling [sj solvent, in particular 1 or more dialkylene glycol monoalkyl ethers and / or dialkyl ethers, glycol (s), glycol ethers and / or aromatic [n] hydrocarbon (s) j used. 8.) Process according to claim 1 to 7, characterized in that the solution boiling above 200 ° C. is used medium diethylene glycol monomethyl ether used. 9.) Process according to claim 1 to 8, characterized in that the isolating of the 3,4-, 5-tri - (methoxy) -benzonitriles by dissolving the inorganic Salts and unreacted 3,4,5-tri- (methoxy) - -benzoic acid in an aqueous alkali metal hydroxide solution and the 3,4,5-tri- (methoxy) -benzonitrile is filtered off or centrifuged off. 10.) Method according to claim 1 to 8, characterized in that that the isolation of the 3,4-, 5-tri - (Methoxy) -benzoritriles by extracting with an organic solvent, especially toluene, and Carries out evaporation of the extract. 11.) The method according to claim 1 to 10, characterized in that after isolating the 5 »4-, 5- -Tri- (methoxy) -benzonitriles obtained aqueous F LItrate acidified and the precipitated ^, 4 ·, 5-tri- - (Methoxy) benzoic acid isolated and returned to the process. description