HU194147B - Process for production of 2-hydroxi-6-nitro-tulud - Google Patents

Abstract

The present invention relates to 2-hydroxy-6-nitro-toluene of formula IV for the production of toluene nitration, dinitro toluenes isomeric mixture, the 2,6-dinitro- Toluene reduction followed by 2-amino-6-nitro-toluene by diazotizing and brewing, such that a dinitro toluene is obtained by nitration of toluene. ■ a mixture with sodium hydroxide in the presence of methanol reacted for a prolonged period of time, the excellent formula (H) Separates 2,6-dinitro toluene and then with sodium sulfide reduced in the presence of ammonium chloride and a 2-Amino-nitro-toluene of formula III is 34-56% sulfuric acid diazotals and then diazonium salt At 70-90 ° C and given in the case of a solution of the diazonium salt to an additional amount sulfuric acid.

Description

The present invention relates to a novel and improved process for the preparation of 2-hydroxy-6-nitrotoluene.

The 2-hydroxy-6-nitrotoluene of formula (IV) is an important pharmaceutical intermediate, e.g. can be used in the preparation of the 1- (1H-indoJ) oxy-3-yl-1-methylethylamino-2-propanol of formula (Visken, a known antiarrhythmic).

According to the literature, 2-hydroxy-6-nitrotoluene of formula IV can be prepared by nitrating toluene, separating the mixture of isomers formed by nitration, and then diazotizing the resulting 2-amino-6-nitrotoluene of formula III. and cook it.

Numerous publications and patents have been published in the literature for each step. However, the commercial realization of the synthesis and the preparation of a product which is free of by-products but is of sufficient purity for further pharmaceutical transformation present serious difficulties.

Nitrogenation of toluene results in a mixture of different mono- and polynitrotoluenes, which generally contain 2,4- and 2,6-dinitrotoluene as the main components. Several methods for separating the isomeric mixture are known. No. 2,765,348. According to U.S. Pat. No. 5, isomers are separated by adding aromatic amines (e.g., N-methylaniline or N, N-dimethylaniline). The disadvantage of the process is the medium yield, which in the examples of the patent is 15-53% of the 2,6-dinitrotoluene in the isomer mixture.

No. 3,931,347. According to U.S. Pat. No. 4,600, a mixture of 2,4- and 2,6-dinitrotoluene is separated from the isomeric dinitrotoluene impurities by treatment with an aqueous alkali metal disulfide solution. However, according to the examples of the patent, 2,4-dinitrotoluene is not separated by

2,6-dinitro-toluoltól.

No. 3,949,008. The United States patent also separates 2,4- and 2,6-dinitrotoluene from other nitrotoluene derivatives, but does not disclose the separation of the two dinitro compounds. The impurities are removed by treatment with 5 to 8 carbon atoms in the alkane.

No. 173,735. According to the US patent, 2,6-dinitrotoluene is obtained from a mixture of 2,4- and 2,6-dinitrotoluene isomers by adding a solution of potassium hydroxide in isopropanol to the crude isomeric mixture, and the resulting dark brown mass is immediately is filtered into sulfuric acid and the opropanol is removed from the harvest by vacuum distillation. The yield of crude 2,6-dinitrotoluene was 63% based on the content of the starting mixture in 2,6-dinitrotoluene.

According to the patent, the crude product is purified by recrystallization, which obviously entails further losses.

Reduction of 2,6-dinitrotoluene to 2-amino-6-nitrotoluene has been reported in various ways in the literature. In one method, the reduction is carried out with ammonium alcohol using hydrogen sulfide gas (Cunerth, Ann. 172, 223 (1874), Bemthsen: Bér. 15, 3016 (1882), Noelting: Bér. 37, 1018 (1904 ^ Wheeler: Am. Chem. J. 44.136 (19)) J.

The disadvantages of the processes are that the reaction is less selective, a mixture of different reduced products is formed and the end point is very difficult to detect. In another procedure, JF Kuffner, G. Lenney, H.Bauer Monatsh. Chem. 91, 1156 (1960) 3 Dissolve 2,6-dinitrotoluene in a mixture of alcohol and ammonium hydroxide and introduce sulfuric hydrogen gas into the solution for several days, filter the excellent sulfur, acidify the filtrate with hydrochloric acid, -nitro-6-amino-toluene is precipitated by the addition of sodium hydroxide. In addition to the above-mentioned drawbacks of the hydrogen sulfide method, the process is unsuitable for industrial scale production because of the multi-day reaction time.

Another group of reduction methods are electrolytic processes. Brand, Zoli Dinner; Wage. 40,330 (1907) states that the reduction is carried out electrochemically in hydrochloric acid in the presence of copper (II) chloride. Hoffer et al. [Hoffer, Jacob Bér. 41.3196 (1908)], Reduction of 2,6-dinitrotoluene in sulfuric alcohol in the presence of vanadium compounds However, the realization of electrochemical reduction under industrial conditions is difficult.

A further group of reduction processes are those employing catalytic hydrogenation. Brand and Steiner [Bér. 55, 884 (1905)], hydrogenation of 2,6-dinitrotoluene in aqueous alcohol in the presence of palladium on charcoal. Alternatively (Vesely, Rein Collect. Chim. Tchehosl. 365), hydrogenation of 2,6-dinitrotoluene in anhydrous alcohol is carried out in the presence of a platinum catalyst. The disadvantage of catalytic hydrogenation methods is that they are not sufficiently selective and only allow the production of contaminated products.

Alternatively, aqueous ammonium sulfide is added to an alcoholic solution of 2,6-dinitrotoluene and the reaction mixture is refluxed (Brady, Taylor. J. Chem. Soc. Iendon 117, 887 (1920)). the process was also carried out at room temperature (Gibson, Johnson J. Chem. Soc. London 1929, 1244), but this resulted in a significant reduction in the yield, the disadvantage of the ammonium sulfide method being that it cannot be carried out selectively and results in a mixture of different products.

Most of the known reduction methods are not selective, so at the end of the process, extraction purification with hydrochloric acid is usually used

2-Amino-6-nitrotoluene can be converted to 2-hydroxy-6-nitrotoluene by diazotization and boiling [Ullmann Bér. 17, 1961 (1884), Noelting Bér. 37, 1020 (19O4)] 7a 2-Amino-6-nitrotoluene is diazotized in 20% sulfuric acid with sodium nitrite and the diazonium salt solution is poured into 10% sulfuric acid. The disadvantage of the method is to provide impure product, according to the quoted publications are hereby 143 ° C, and ^this melting point 145 ° C for 2-hydroxy-6-nitrotoluene. Reproducing the methods known in the literature and analyzing the product obtained, it was found that a significant amount (5-10%) of the formula (IV) was obtained. 4-Nitroindazole is present.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the known methods discussed above and to provide a process for the production of 2-hydroxy-6-nitrotoluene that is economically feasible, in good yield, and provides a pure product.

The present invention relates to a process for the preparation of 2-hydroxy-6-nitrotoluene of formula (IV) by the nitration of toluene, the separation of an isomeric mixture of dinitrotoluenes, the reduction of 2,6-dinitrotoluene, and the subsequent reduction of diazotizing and boiling toluene such that

194.147 dinitrotoluene isomer mixture obtained in the toluene nitration is reacted with sodium hydroxide in the presence of methanol for an extended period of time to produce an excellent compound of formula (II).

2.6-Dinitro-toluene was isolated and then reduced with sodium sulfide in the presence of ammonium chloride and the sulfuric 2-anino-6-nitrotoluene (III) was azotized with 34-56% sulfuric acid and the diazonium salt was boiled at 70-90 ° C. It is carried out at a temperature of C and optionally additional sulfuric acid is added to the solution of the diazonium salt.

One of the foundations of our invention is the recognition that

The separation of 2,6- and 2,4-dinitrotoluene can be advantageously achieved by enhancing the solubility difference of these two nitro compounds by chemical modification of the molecule. In the case of 2,4-dinitrotoluene of formula (I), carbon number 3 is very strongly activated by adjacent nitro groups and this condition is not the case for 2,6-dinitrotoluene of formula (II). Thus, 2,4-dinitrotoluene is more susceptible to orders of magnitude greater than 2,6-dinitrotoluene for aromatic nucleophilic substitution reactions on carbon 3 due to the strong electron withdrawing effect of the two adjacent nitro groups. Thus, under appropriate conditions, 2,4-dinitrotoluene forms a complex which is highly soluble in the reaction mixture, while unconverted 2,6-dinitrotoluene precipitates and can be isolated by conventional means (e.g., filtration or centrifugation).

It has been found that when the isomeric mixture of 2,4- and 2,6-dinitrotoluene is reacted with sodium hydroxide in a methanolic medium at a suitable temperature for a prolonged period, the 2,4-dinitrotoluene complexes and remains in solution, the

2.6-Dinitro-toluene does not react, precipitates and can be isolated.

The isomeric mixture is treated preferably at ^that temperature 20-30 C, for 2-6 h in methanolic NaOH. It is particularly preferred to carry out the reaction at 28 ° C for 3-5 hours.

After completion of the reaction, the precipitated 2,6-dinitrotoluene can be isolated by filtration or centrifugation. The product is of very high purity, at least 99% isomeric purity by gas chromatography, and can be used directly for further transformation without purification.

The pure 2,6-dinitrotoluene isolated in this manner is reduced with sodium sulfide in the presence of ammonium chloride. Another basis of the present invention is the discovery that, when the reduction of 2,6-dinitrotoluene is carried out under the above conditions, selectively and in good yields yield high purity 2-amino-6-nitrotoluene to such an extent that most of the previous processes do not require mandatory extraction with hydrochloric acid to purify the product. The reduction may preferably comprise from 1.0 to 5 mol, preferably from 1.7 to 3.75 mol, of sodium sulphide per mole of 2,6-dinitrotoluene. The reduction was carried out, as already mentioned, in the presence of ammonium chloride. Ammonium chloride may be used in an amount of 1 to 8 moles, preferably 1.2 to 6 moles, particularly preferably 1.4 to 4 moles, per mole of 2,6-dinitrotoluene.

In a preferred embodiment of the process, the sodium sulfide and ammonium chloride are dissolved in water and the solution is mixed with a solution of 2,6-dinitrotoluene in a suitable organic solvent. The 2,6-dinitrotoluene is preferably dissolved in a lower alkanol (e.g., methanol or ethanol). The reaction is carried out at 50-60 ° C. The reaction is complete within a few hours and the desired product is obtained in almost theoretical yield. After cooling the reaction mixture, the 2-amino-nitrotoluene precipitates and can be isolated by filtration or centrifugation. The resultant 2-amino-6-nitrotoluene is of such purity that it can be used for further conversion without purification (e.g., hydrogen chloride extraction).

The 2-amino-6-nitro-0-toluene thus obtained is converted to the desired 2-hydroxy-6-nitrotoluene by diazotization and cooking. The present invention is further based on the discovery that 2-hydroxy-6-nitrotoluene is highly purified and has no or only minimal contamination of 4-nitroindazole by diazotizing 2-amino-6-nitrotoluene. After 34-56% sulfuric acid, the diazonium salt is boiled at 70-90 ° C and optionally additional sulfuric acid is added to the diazonium salt solution.

In the preferred embodiment above until complete dissolution of 2-amino-6-nitro-toluene and mixtures of 40-55% sulfuric acid at a temperature of - preferably 90 to 100 ^o C - is heated and then cooled, and sodium nitrite after addition of an aqueous solution, diazotization is carried out at 0-5 ° C. The excess sodium nitrite was quenched by the addition of urea. Preferably, an additional amount of 40-55% sulfuric acid is added to the reaction mixture and the mixture is boiled at 75-80 ° C. It is also possible to obtain 2-hydroxy-6-nitrotoluene by adding no more sulfuric acid to the mixture during the cooking process; in a preferred embodiment, an additional amount of 40-55% by weight sulfuric acid is added to the system.

Hydrolysis can also be carried out in a continuous reactor.

The reaction mixture is easily processed. After cooling the reaction mixture, the precipitated crystalline 2-hydroxy-6-naphthol is washed and dried. The 2-hydroxy-6-nitrotoluene obtained in this way is of high purity and can be used for further pharmaceutical conversion without any purification. A particular advantage of the process is that the resulting 2-hydroxy-6-nitrotoluene indazole content is less than 0.5%. 4-Nitroindazole is a very difficult, difficult to remove contaminant.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

A mixture of dinitrotoluene (20 g, 50% by weight of 2,6-dinitrotoluene) obtained by filtration of toluene was dissolved in 40 ml of methanol. In another flask, 2.2 g of sodium hydroxide was dissolved in 13.5 ml of water and the aqueous alkaline solution was added to a solution of dinitrotoluenes at 20 ° C for 2 hours. The reaction mixture was stirred at 20 ° C for 3 hours, then filtered and washed with aqueous methanol. 8.9 g of 2,6-dinitrotoluene are obtained.

Yield: 89% (based on 2,6-dinitrotoluene feed). The product was found to be 99-100% pure by gas chromatography.

Example 2

A mixture of dinitrotoluene (80 g, 50% by weight of 2,6-dinitrotoluene) obtained by nitration of toluene was dissolved in 115 ml of methanol, followed by a solution of 4.84 g of sodium hydroxide in 48 ml of methanol.

194.147 was added dropwise at 25 ° C. The reaction mixture was stirred for an additional 2 hours at 24-28 ° C, then cooled to 0 ° C, filtered and washed with aqueous methanol. 34 g of 2.6 dinitrotoluene are obtained.

Yield: 85% (based on 2,6-dinitrotoluene feed). The product was found to be 99-100% pure by gas chromatography.

Example 3

A mixture of 210 g of 2,6-dinitrotoluene (1.15 mol) and 600 ml of methanol was heated to 50 ° C. In another flask was dissolved 315 g of sodium sulphide melt (sodium sulphide content 60%, 2.44 moles) and 148 g of ammonium chloride (2.82 moles) in 800 ml of water. 6-dinitrotoluene solution with cooling for approx. In 5 hours. The reaction was carried out at 55 ° C. At the end of the addition, the reaction mixture was cooled to 0 ° C. The crystal suspension was filtered and the yellow crystals washed with water. 157 g (89.6%) of 2-amino-6-nitrotoluene were obtained.

90.0-91.0 'C.

Example 4

18.2 g (0.1 mol) of 2,6-dinitrotoluene are dissolved in 50 ml of ethanol. Thereafter, at a temperature of 55 [deg.] C. A solution of 28.6 g (0.37 mol) of sodium sulfide and 29 g (0.54 mol) of ammonium chloride in 100 ml of water was added over 2 hours. The mixture 'was stirred at C and 0 ° 55 to 60 a further 2 h _o is cooled. The precipitated crystals are filtered off and washed with water. 14.6 g (96.1%) of 2-amino-6-nitrotoluene are obtained.

90.5-91.0'C.

Example 5

18.2 g (0.1 mol) of 2,6-dinitrotoluene are dissolved in 50 ml of methanol. A solution of sodium sulfide (21.0 g, 0.27 mol) and ammonium chloride (32.9 g, 0.61 mol) in water (90 ml) was added over 2 hours. After stirring for an additional 2 hours at 55-60 ° C, the precipitated crystals were filtered off and washed with water. 13.7 g (90.1%) of 2-amino-6-nitrotoluene are obtained.

90-91.0 ° C.

Example 6

18.2 g (0.1 mol) of 2,6-dinitrotoluene are dissolved in 50 ml of methanol. Thereafter, at a temperature of 50 ° C, it was cooled to ca. A solution of sodium sulfide (13.1 g, 0.168 mol) and ammonium chloride (7.3 g, 0.136 mol) in water (80 ml) was added over 2 hours. The reaction mixture was stirred at 50-55 ° C for half an hour and then ^this was cooled to 0. The precipitated crystals are filtered off and washed with water. 13.8 g (90.8%) of 2-amino-6-nitrotoluene were obtained. Op .: 89.5-90.5 'C.

Example 7

A solution of 160 g of 2-amino-6-nitrotoluene and 1700 g of 40% sulfuric acid was heated to 95-100 ° C and stirred until the 2-amino-6-nitrotoluene was completely dissolved. After cooling to 0 ° C, a solution of sodium nitrite (80 g) in water (175 ml) was added at such a rate that the internal temperature did not rise above 5 ° C. Addition of the nitrite solution is approx. It takes 4 hours. The reaction mixture was reacted at 0-5 ° C for a further 2 hours, then ca. 18 g of urea are added in portions over 1 hour to decompose the excess sodium nitrite. 800 g of 44% sulfuric acid were added to the reaction mixture, which was heated to 75-80 v and allowed to stand at this temperature for 5 hours. The reaction mixture is then cooled to 10 ° C, the precipitated crystals are filtered off and washed with water. 140g

2-hydroxy-6-nitrotoluene was obtained in 87% yield. Mp 150-151'C.

Example 8 2-Amino-6-nitrotoluene (g) was dissolved in 290 g of 55% sulfuric acid at 10 ° C. The solution was cooled to 0 ° C and a solution of sodium nitrite (9.1 g) in water (26 ml) was added over half an hour. The reaction mixture was stirred for 1 hour at 0-5 ° C and 0.2 g of urea was added to decompose the excess nitrite. Then 108 g of 43 wt% sulfuric acid is added and the mixture heated to 75 ° and stirred at this temperature until no evolution of nitrogen (approx. 4-5 hours _s). The mixture is cooled to 10 ° C, the precipitated crystals are filtered off and washed with water. 18.7 g (92.9%) of 2-hydroxy-6-nitrotoluene were obtained. M.p. 150.5-151 ° C.

Example 9 was dissolved in a solution of 2-amino-6-nitrotoluene 100 ^o C. 210 g of 39% H ^ 2. To the solution is added dropwise a solution of 9.1 g of sodium nitrite in 26 ml of water at 0 ° C over a period of half an hour. The reaction mixture was heated at 0 ° C for an additional hour and then 0.2 g of urea was added. To the reaction mixture was added 100 g of 43% sulfuric acid and stirred at 75 ° C until the evolution of nitrogen was complete. The reaction mixture was cooled to 10 ° C, the precipitated crystals were filtered and washed with water to neutral. 18.6 g (92.4%) of 2-hydrodi-6-nitrotoluene are obtained. Mp: 151-151,5 ° C.

.0. EXAMPLE 2 g-2-Amino-6-nitrothiol is dissolved in 100 g of 43% sulfuric acid at 100 ° C. The solution was cooled to 0 ° C and a solution of sodium nitrite (9.1 g) in water (26 ml) was added over one hour. The reaction mixture was stirred for 1 hour at 0 ° C and then 0.2 g of urea was added. The diazonium salt solution was hydrolyzed at 75 ° C until nitrogen evolution ceased. The reaction mixture was cooled to 10 ° C, filtered, and the precipitated product was filtered and washed with water until neutral. 18.9 g (93.9%) of 2-hydroxy-6-nitrotoluene were obtained. Mp 150-151 ° C. After aqueous recrystallization, the melting point rises to 151-152.5 ° C.

Claims (9)

A process for the preparation of 2-hydroxy-6-nitrotoluene of formula IV by nitration of toluene, separation of an isomeric mixture of dinitrotoluenes, reduction of 2,6-dinitrotoluene, followed by 2-amino-6-nitrotoluene diazotizing and cooking, wherein the dinitrotoluene isomer mixture obtained by nitration of toluene is reacted with sodium hydroxide in the presence of methanol, preferably at a temperature of 20-30 ° C, for 2 to 6 hours, to give The 6-dinitrotoluene is isolated and then reduced with sodium sulfide in the presence of ammonium chloride, preferably at 50-60 ° C, and the 2-amino-6-nitroctoluene of formula (III) with 34-56% sulfuric acid. diazotize and then boil the diazonium salt at 70-90 ° C and optionally add additional sulfuric acid to the diazonium salt solution. Process according to claim 1, characterized in that the isomeric mixture of dinitrotoluenes is treated with methanolic sodium hydroxide at 78 ° for 3-5 hours. 3. El-41 according to any one of claims 1 to 4 District 194,147, characterized in that 1 mole of sodium sulfide is used in the reduction of 2,6-dinitrololol. A process according to claim 3, characterized in that 1.5 to 4 moles, preferably 1.7 to 3.75 moles, of sodium sulfide are used per mole of 2,6-dinitrotoluene. 5. A process according to any one of claims 1 to 4, wherein 1-8 moles of ammonium chloride are used per mole of 2,6-dinitrotoluene. Process according to claim 5, characterized in that 1.2 to 6 moles, preferably 1.44 moles, of ammonium chloride are used per mole of 2,6-dinitrotoluene. 7. A process according to any one of claims 1 to 3, wherein diazotization of 2-amino-tin-nitrotoluoyl is carried out with 34-56% by weight sulfuric acid. Process according to any one of claims 1 or 7, characterized in that the diazonium salt is cooked at a temperature of 75-80 ° C. 10 4-5 hours. 9. The process according to any one of claims 1 to 4, wherein 40 to 55% by weight of sulfuric acid is added to the diazonium salt solution.