CS211801B1 - Process for preparing ω-bromo-p-nitroacetophenone - Google Patents

Abstract

The invention relates to a method for preparing ω-bromp-nitroacetophenone by bromination of p-nitroacetophenone in an environment of inert solvents of the aromatic hydrocarbon type, the essence of which consists in that after the bromination is completed, the reaction mixture is diluted with an equal volume of water, heated to 50 to 60 °C, cooled to 10 to 20 °C and the precipitated product is isolated. The mother liquor is used as a medium for further bromination after dewatering and replenishing with pure solvent to the original volume.

Description

The invention relates to a process for the preparation of ω-bromop-nitroacetophenone, an important intermediate of the synthesis of the antibiotic chloramphenicol. This bromoketone is usually prepared by brominating p-nitroacetophenone with one equivalent of bromine in an inert organic solvent (benzene, toluene, trichlorethylene, etc.) at room temperature.

However, the bromination is not unambiguous. At the end of the reaction, an equilibrium state is formed in which, in addition to the main product, i.e., ω-bromo-p-nitroacetophenone, unreacted p-nitroacetophenone is present in a small amount, and the above-accumulated product, i.e. ω, ω-dibroma -pnitroacetophenone, i traces of ω, ω, ω-tribromo-pnitroacetophenone.

There are two ways of working up the reaction mixture:

1. The desired ω-bromo-p-nitroacetophenone is crystallized from the reaction mixture and filtered off with suction. There are no mother liquors containing by-products, which is unused waste;

2. After bromination is completed, the reaction mixture is diluted with the same solvent (benzene, toluene), washed neutral with water and dried, and then the ω-bromop-nitroacetophenone present in the solution is reacted with hexamethylenetetramine to form the so-called urotropin salt (p-nitroacetophenone and ω). , ω-dibromo-p-acetophenone do not react with hexamethylenetetraminen). The salt is again decomposed in the reaction solution by a mixture of methanol and hydrochloric acid, whereby the ω-aminop-nitroacetophenone hydrochloride formed by the decomposition of the urotropin salt is transferred to the lower aqueous layer. In the upper layer, unreacted starting p-nitroacetophenone and ω, ω-dibromo-pnitroacetophenone remain unreacted. By treating the benzene or toluene solution, a small portion of p-nitroacetophenone is recovered, and the dibromketone is decomposed by shaking with a 10% aqueous sodium hydroxide solution.

Under these conditions, losses occur which are not negligible on a production scale. Therefore, options were either studied to prevent losses or to assess the by-products of the economy. One possibility is that the solution of p-nitroacetophenone and ω, ω-dibromo-p-nitroacetophenone in an organic solvent is saturated with hydrogen bromide to a concentration of at least 3%, and then reacts at 20 to 25 ° C within 4 to 6 hours in which about 70 to 80% of ω-bromo-p-nitroacetophenone is formed. The remainder consists of approximately equal proportions of unreacted starting materials. However, this method cannot be practically used.

However, if a solution of the two is used for further bromination of p-nitroacetophenone, where a very high concentration of hydrogen bromide is formed in the reaction medium, their content in the reaction mixture remains constant after the bromination is complete. Based on this finding, the process for the preparation of ω-bromo-p-nitroacetophenone by bromination of p-nitroacetophenone with one equivalent of bromine in an inert inert solvent environment, in particular benzene and its homologs, at room temperature according to the invention.

The process consists in diluting the reaction mixture with an equal volume of water after the bromination, heating to 50 to 60 ° C, cooling to 10 to 20 ° C, isolating the precipitated product, and then separating the organic layer containing unreacted -nitroacetophenone and ω, ω-dibromo-p-nitroacetophenone, dewatered and after addition of pure solvent to the required volume used as a medium for further bromination.

The process described above yields very pure ω-bromo-p-nitroacetophenone, m.p. 95-98 ° C. Dilution of the reaction mixture with water also reduces the amount of hydrogen bromide present, so that when the temperature rises, no more build up occurs and the reaction is finally completed. After aspiration of the crystalline product, all the side-substances remain in the organic layer, ie unreacted p-nitroacetophenone, ω, ω-dibromo-p-nitroacetophenone and partially dissolved monobromketone. This layer, after dewatering and making up to the required volume with pure solvent, serves as a medium for brominating further p-nitroacetophenone. As confirmed by analytical control, the amount of by-products remains constant and does not increase even with repeated use of the mother liquor. Should an in-product by-product imbalance (usually due to faulty feedstocks) be found during in-process inspection (thin layer chromatography), this can be avoided by adjusting the bromine loadings (within + 3% for each turnover).

With the method according to the invention, the initial p-nitroacetophenone can be considerably better evaluated by simple means, and thus the yield of ω-bromo-p-nitroacetophenone can be increased by an average of 5%, which means a considerable effect in large-scale production. The possibility of obtaining pure ω-bromo-pnitroacetophenone has a beneficial effect on the yields and quality of other intermediates, thus improving the conditions for the entire chloramphenicol synthesis.

Example 1

Existing method

100 g of p-nirotacetophenone (0.61 mol) and 0.01 g of amorphous sulfur were suspended in 200 ml of toluene and brominated at room temperature with 97 g of bromine (0.61 mol). The reaction takes about 20 minutes. After an additional 30 minutes of stirring. The reaction mixture is diluted with 1000 ml of toluene and, after homogenization, washed with water to neu3

211 801. The toluene solution of ω-bromo-pnitroacetophenone is washed with water until neutral, dried over anhydrous sodium sulfate and analyzed. Evaporate 5 ml of toluene solution to the dish, weigh and recalculate the total content (evaporation residue A). 78 g of hexamethylenetetramine (0.58 mol) was added to the original solution and the so-called urotrophic salt was prepared. Only ω-bromop-nitroacetophenone reacts in this reaction, while other substances (ie unreacted p-nitroacetophenone and ω, ω-dibromo-p-nitroacetophenone) remain in solution. By decomposing the hexamethylenetetramine salt with a mixture of 400 ml of methanol and 250 ml of concentrated hydrochloric acid, ω-amino-p-nitroaminoacetophenone hydrochloride is prepared which remains in the lower layer. The upper toluene layer contains both unreacted substances. The contents are determined by evaporation again with 5 ml of toluene solution and recalculated to the original volume (residue B). After the decomposition of ω, ω-dibromo-p-nitroacetophenone by shaking the toluene solution twice with 200 ml of 10% aqueous sodium hydroxide solution each time, evaporation of 5 ml of the sample is determined by evaporation C, the amount of unreacted starting p-nitroacetophenone. The evaporation residue is further checked by thin layer chromatography. 2 mass differences of the evaporator determine the content of individual substances:

A - (B + C) = pure ω-bromo-p-nitroacetophenone

B - C = ω, ω-dibromo-p-nitroacetophenone

C = p-nitroacetophenone

The yield of ω-bromo-p-nitroacetophenone 125 g, ie 84.5%, was calculated in this way.

Example 2

The method of the invention

110 g of p-nitroacetophenone (0.67 mol) were suspended in 200 ml of benzene and brominated at room temperature with 104.7 g (0.67 mol) of bromine. About 20 minutes after bromination was completed, 200 ml of water was added to the reaction mixture with stirring, heated to 55 ° C until the solid dissolved, and slowly cooled to 20 ° C over 2 hours. The crystallized ω-bromo-p-nitroacetophenone is filtered off with suction and dried. Yield 140-150 g, i.e. 86-92%, m.p. 95-98 ° C. According to chromatography, this product contains only 1 to 2% by-products.

Example 3

The mother liquors after isolation of the pure product of Example 2 were used as the medium for further bromination after drying and making up to 200 ml with pure benzene. Following the procedure of Example 2, 100 g of p-nitroacetophenone (0.61 mol) was then brominated with 97 g of bromine (0.61 mol). The same treatment of the reaction mixture yielded ω-bromop-nitroacetophenone in a yield of 135-145 g, i.e. 91-98%, melting point 95-98 ° C.

Claims (1)

SUBJECT A process for the preparation of ω-bromo-p-nitroacetophenone by bromination of p-nitroacetophenone with one equivalent of bromine in an inert inert solvent, especially benzene and its homologues, at room temperature, characterized in that after bromination is complete temperature 50 to 60 ° C, cooled to OF THE INVENTION, the precipitated product is isolated, after which the organic layer containing unreacted p-nitroacetophenone and ω, ωdibromo-p-nitroacetophenone is dewatered and, after adding to the desired volume with pure solvent, is used as medium for further bromination.