JPH04983B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-chloro-6-alkoxy-3-
This invention relates to a method for producing pure nitropyridine. This compound is an important intermediate for producing painkillers.

Due to the pharmaceutical use of the final products, increased demands are placed on the purity even of the intermediate products.

2-Chlor-6-alkoxy-3-nitropyridine is made by nitration of 2-chloro-6-alkoxypyridine with nitric acid. A crude product is obtained, which must be purified before further processing. Usually this purification is carried out by recrystallization from a solvent mixture. However, this makes separation of undesirable impurities extremely difficult and requires several recrystallizations. Apart from the huge labor and energy costs of this process, the yield is compromised, so that pure products are obtained only at about 50-55% of the theoretical yield. The product which remains in the mother liquor in each case can no longer be separated. This purification process cannot be improved by the selection of different solvent systems.

Therefore, the product obtained by nitration of 2-chloro-6-alkoxypyridine is a 2-chloro-6-alkoxy pyridine which can be obtained in the purest possible form in a simple process and with as little loss of yield as possible. The problem arose of finding a pure method for producing -3-nitropyridine.

The solution to the problem lies in claims 1 to 6.
It is carried out by the method according to the section. To solve this problem, the nitration method of 2-chloro-6-alkoxypyridines has already been found to be decisive for the yield, purity and purification possibilities of the nitrated products. Ta. The nitration is carried out in the manner that is customary in the nitration of organic substances, i.e. with a mixture of sulfuric acid and nitric acid.
-chloro-6-alkoxypyridine, thus producing 2 as the main by-product.
-Chloro-6-alkoxy-5-nitropyridine is produced. These isomers can only be separated from the respective main product with extreme effort.

Surprisingly, after the nitration carried out according to the invention, in which 2-chloro-6-alkoxypyridine is added in portions to the initially charged mixture of sulfuric acid and nitric acid, 2-chloro-6-alkoxy-5-
Nitropyridine is rarely observed.

Furthermore, all impurities in the crude product obtained during the nitration of 2-chloro-6-alkoxypyridine can be removed by cooling the crude product with a solution of an alkaline-acting compound in a polar solvent at room temperature or at a slightly elevated temperature. It has been found that it can be separated in a simple manner when treated for several hours with stirring. This treatment is carried out either by leaching the isolated crude nitrated product for several hours in an alkaline solution, followed by filtering off, washing with distilled water and drying, or else by leaching the isolated crude nitrated product for several hours. It can be carried out by dissolving in a water-insoluble inert organic solvent such as toluene or xylol, contacting the solution with an aqueous alkaline solution for several hours with vigorous mixing, and then separating. Purified 2-chloro-6-
The alkoxy-3-nitropyridine is isolated by distillation of the solvent. This isolation can also be carried out by precipitating the purified product, optionally from an already concentrated solution, with other solvents, such as hexane.

This step involves 2-chloro-6-alkoxy-3
- Allows nitropyridine to be produced easily, with high purity and good yields. Another advantage of this method is that it can be carried out continuously.

This process includes all 2-chloro-6-alkoxypyridines with straight-chain or branched alkyl chains, especially those with alkyl chains of 1 to 4 carbon atoms, such as 2-chloro-6-alkoxypyridines. Methoxypyridine 2-chloro-6-ethoxypyridine 2-chloro-6-propoxypyridine 2-chloro-6-i, propoxypyridine 2-chloro-6-butoxypyridine 2-chloro-6-i, butoxypyridine can be used. . These are nitrated at temperatures in the range from 0 DEG to 40 DEG C. in a metered manner to the initial nitration mixture. The raw pyridine is then separated from the preferably acidic reaction mixture and treated with an alkaline acting compound.

It is clear that the treatment time is inversely proportional to the alkalinity of the solution and the treatment temperature. So,
When using strong alkaline alcoholate, 0℃
Short-term treatment using solutions cooled to In fact, leaching with a cooled aqueous alkaline solution is also possible, but this is economically unimportant due to the long processing times. On the other hand, at temperatures above 50 °C, a decomposition reaction of 2-chloro-6-alkoxy-3-nitropyridine in alkaline solvents is expected, and the more alkaline the solvent, the more this reaction It happens easily.

A polar solvent is a solvent capable of releasing protons, such as water or alcohol. Alkaline solutions in polar solvents are obtained by dissolving alkaline-acting compounds in such polar solvents. Such compounds are alkali metal oxides and alkaline earth metal oxides, alkali metal hydroxides and alkaline earth metal hydroxides, and ammonium hydroxide, but also salts which exhibit an alkaline reaction upon hydrolysis, e.g. Salts such as alkali carbonates or trialkali phosphates, but also water-soluble organic amino compounds such as, for example, methyl, dimethyl, trimethyl, ethylamine, ethanolamine or piperidine.

The amount of alkaline solution should be such that a well-processable suspension or sufficient accessibility of the reactants is achieved. The amount of alkali used should be at least equal to the expected amount of impurities. On the other hand, it is preferable to work with an excess of alkali in order to be able to carry out the purification quantitatively in the shortest possible time.
The method according to the invention is illustrated in detail by the following examples.

Example 1 143.6g of 2-chloro-6-methoxypyridine (1
mol) is cooled to 0° C. in 1 hour and added dropwise to a stirred mixture consisting of 1600 ml of concentrated sulfuric acid and 800 ml of fuming nitric acid. Subsequently, the temperature was raised to 20°C for 3 hours, and the mixture was stirred at the same temperature for another 3 hours. The mixture is then poured onto 5 kg of crushed ice, the precipitated product is filtered off with suction and washed with plenty of water until free of acid. After drying, 151-156 g (80-83% of theory) of yellow crystals are obtained with a melting point of 67-69 °C and a purity of 84-85%.

Example 2 Finely ground impure 2 obtained according to Example 1
-chloro-6-methoxy-3-nitropyridine
A mixture of 3,300 g, 6,600 ml of water, and 910 g of potassium carbonate is stirred at 40°C for 2 hours. continuation,
The product was absorbed and filtered, washed with 4000ml of water, 40-45
Dry at °C. 2- with a melting point of 79℃ and a purity of 99-100%.
Chlor-6-methoxy-3-nitropyridine 2772
Gain ~2805g.

Example 3 2-chloro-6-ethoxypyridine 157.6g (1
190 mol) of concentrated sulfuric acid while stirring for 45 minutes.
ml, 24% oleum 190ml and 97% nitric acid 100ml
Dispense into a mixture consisting of. The reaction mixture is kept at a temperature of 20-40°C by cooling. Thereafter, the reaction is continued for a further 5 hours with stirring, the temperature being adjusted to room temperature. Subsequently, the reaction mixture was cooled to 0° C., filtered with suction through a glass frit, and the solid crude product obtained was dissolved in 100 g of potassium carbonate.
Suspend the mixture in 250 ml of water and stir at 30℃ for 3 hours. The product is then filtered with suction, washed with water and dried at 40°C.

Yield: 2-chloro-6-ethoxy- with 98% purity
192 g of 3-nitropyridine (93% of theory) Example 4 84 obtained according to Example 1 in 1500 ml of toluene
A solution of 500 g of ~85% 2-chloro-6-methoxy-3-nitropyridine was added to 500 g of 24% aqueous ammonia.
Stir vigorously for 12 hours at 40°C with ml. Subsequently, the precipitate is filtered off with suction, the phases are separated, the solvent is distilled off from the toluene layer under vacuum at an internal temperature of up to 90 DEG C., and heptane (~1000 ml) is stirred into the liquid distillation residue. After cooling, the resulting crystals are filtered with suction and dried at 40-45°C. Purity with melting point 79℃
345 g of 99-100% 2-chloro-6-methoxy-3-nitropyridine are obtained. By concentrating the organic mother liquor to almost dryness and thoroughly stirring it with heptane, 47g of a substance with a melting point of 78-79℃ can be obtained.
isolate. The overall yield is therefore 92% of theory.

Example 5 84~ obtained according to Example 1 in 1500 ml of toluene
A solution of 500 g of 85% 2-chloro-6-methoxy-3-nitropyridine was mixed with a solution of 124 g of monomethylamine in 600 ml of 50% methanol at 0-5°C for 10 min.
Stir for a while. Subsequently, the precipitate was separated by filtration,
Separate the phases. Isolation of pure 2-chloro-6-methoxy-3-nitropyridine is carried out as described in Example 4. Yield is 90-93% of theory.

Claims (1)

[Claims] 1. A method for the pure production of 2-chloro-6-alkoxy-3-nitropyridine by nitrating 2-chloro-6-alkoxypyridine with nitric acid and isolating the nitrated product, comprising: 2
-Chloro-6-alkoxy-pyridine from 0 to 40℃
The still impure 2-chloro-6-alkoxy-3-nitropyridine obtained is dissolved in a polar solvent in small amounts at a temperature of A process for the pure preparation of 2-chloro-6-alkoxy-3-nitropyridine, characterized in that it is treated with a solution of an alkaline-acting compound and then isolated in pure form. 2. Immerse the impure product in an alkaline aqueous solution,
2. The method according to claim 1, further comprising filtering, washing and drying. 3. A patent for dissolving an impure product in an inert solvent insoluble in water, contacting this solution with an aqueous alkaline solution with vigorous mixing, then separating and then isolating the purified product in a manner known per se. The method according to claim 1. 4. Process according to any one of claims 1 to 3, wherein the treatment of the impure product is carried out at a temperature of 0 to 50°C. 5. The method according to any one of claims 1 to 3, wherein an aqueous solution of alkali carbonate is used as the aqueous alkali solution. 6. Any one of claims 1 to 3, in which ammonia water is used as the aqueous alkaline solution.
The method described in section.