RU2434005C1 - Method of producing 7,8-difluoro-2,3-dihydro-3-methyl-4h-1,4-benzoxazine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine. The method is realised via hydrogenation of 2-acetonyloxy-3,4-difluoronitrobenzene with hydrogen in the presence of palladium on a Sibunit carbon support as a catalyst. The process takes place in isopropyl alcohol at pressure 3.0-3.5 bars and temperature 30-50°C. Extraction and drying of the desired product is carried out by successively turning it into 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine hydrochloride by treating with 1.5-1.7-fold excess hydrochloric acid in a water-toluene solution and then into free 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by treating 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine hydrochloride with an aqueous alkaline solution and vacuum distillation.

EFFECT: improved method of obtaining a composition with high content of basic substance.

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Description

1. The technical field to which the invention relates.

The invention relates to the field of biologically active compounds and relates to a method for producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine, a key intermediate in the synthesis of the antibiotic levofloxacin, intended for the treatment of a wide range of human infectious diseases . The invention can be used in the pharmaceutical industry, hospitals, as well as in research laboratories.

It should be noted that in Russia levofloxacin is not produced and all drugs used on its basis are of imported origin.

2. The prior art.

Several methods have been described for the synthesis of racemic 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine starting from 2-acetyloxy-3,4-difluoronitrobenzene, including the stage of nitro group reduction accompanied by intramolecular cyclocondensation.

One method is to reduce 2-acetonyloxy-3,4-difluoronitrobenzene to 7.8-difluoro-3-methyl-2H-1,4-benzoxazine in the presence of a palladium catalyst and triethylamine in anhydrous tetrahydrofuran [A new convenient method for the synthesis of 2H-1,4-benzoxazine derivatives from nitroketones via intermolecular reductive cyclization / J. Het. Chem., 39, 1065-1069, 2002]. Moreover, 7,8-difluoro-3-methyl-2H-1,4-benzoxazine is isolated by column chromatography using a mixture consisting of ethyl acetate, hexane and triethylamine as an eluent, which is very difficult under production conditions.

Further restoration of the multiple bond of the heterocycle can be carried out in several ways. A method for such reduction using metal hydrides or catalytic hydrogenation is described. As a result of such reduction, racemic 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is obtained [Optical resolution of benzoxazines. U.S. Pat., 4880926, 1989]. Another method involves stereoselective reduction with complex chiral metal hydrides, resulting in S-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine [Asymmetric reduction of 7,8-difluoro-3 -methyl-2H-1,4-benzoxazine. Synthesis of a key intermediate of (S) - (-) - ofloxacin. / J. Het. Chem., 28, 329-331, 1991]. A common disadvantage of the above methods is the need for the synthesis and isolation of 7,8-difluoro-3-methyl-2H-1,4-benzoxazine, an additional stage of recovery. In addition, in the case of stereoselective reduction, preliminary synthesis of complex hydrides is necessary, carried out using absolute solvents, an inert gas, and at low temperatures (-40 ° C).

Another method is the exhaustive reduction of 2-acetonyloxy-3,4-difluoronitrobenzene to the desired 7.8-difluoro-3-methyl-4H-1,4-benzoxazine. A method is described for preparing analogues of 2,3-dihydro-3-methyl-4H-1,4-benzoxazine by exhaustively hydrogenating the corresponding derivatives of 2-acetonyloxynitrobenzene, in the presence of a Raney nickel catalyst, in dioxane [Benzofurano-oxazines. By J. Hill and G.R. Ramage / J. Chem. Soc., 1967, 783-784].

The closest in technical essence to the claimed method is a method for producing the target 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by catalytic hydrogenation of 2-acetyloxy-3,4-difluoronitrobenzene in the presence of nickel Raney as a catalyst [Benzoxazine derivatives US Patent, 4382892, 1983] - prototype.

The reaction is carried out as follows. 2.3 g of 2-acetonyloxy-3,4-difluoronitrobenzene are dissolved in 30 ml of ethanol and catalytically reduced in the presence of 2 g of Raney nickel. After completion of the reduction, the catalyst was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography using chloroform as eluent. The product yield is 75.5%.

The disadvantage of this method is the use of Raney nickel as a catalyst for hydrogenation, which requires preliminary synthesis of the catalyst. In addition, the catalyst is inconvenient to use due to its pyrophoricity and instability during storage.

The use of Raney nickel as a catalyst in the synthesis of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine leads to the formation of by-products of reductive defluorination (monofluoro-2,3-dihydro-3-methyl -4H-1,4-benzoxazines and 2,3-dihydro-3-methyl-4H-1,4-benzoxazines), the purification of which the target product is very difficult.

In addition, the disadvantages of the known methods for producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine include the inconvenience of isolating the target product, including chromatography, which excludes the possibility of scaling the process and the use of this method in industry.

The objective of the invention is to develop a method for producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine in high yield and purity, suitable for producing the product on an industrial scale and, further, to obtain from it the antibiotic levofloxacin.

The problem is solved in that in the method for producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by catalytic hydrogenation of 2-acetonyloxy-3,4-difluoronitrobenzene in an alcohol medium, followed by filtration , evaporation and isolation of the target product as a catalyst use palladium on a carbon carrier "Sibunit", the process is carried out in isopropyl alcohol at a pressure of 3.0-3.5 bar and a temperature of 30-50 ° C, and the selection and purification of the target product is carried out by sequential converting it first to 7.8-dif hydrochloride p-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by treatment with a 1.5-1.7-fold excess of hydrochloric acid in an aqueous toluene solution, and then in free 7.8-difluoro-2, 3-dihydro-3-methyl-4H-1,4-benzoxazine by treating 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine hydrochloride with an aqueous solution of alkali and vacuum distillation.

It was established that the use of Raney nickel as a catalyst for hydrogenation leads to side processes, namely, reductive defluorination of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine formed during the reduction, moreover, the formation of products of both monodefluorination and exhaustive defluorination is observed, the purification of which of the desired 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is very difficult due to the close physicochemical properties of the resulting compounds . It should be noted that there are no data on the formation of these by-products in the literature. In addition, it was found that an increase in pressure above 3.5 bar and temperature above 50 ° C contributes to the occurrence of side processes of defluorination; a decrease in pressure and temperature leads to a decrease in the hydrogenation rate. The use of Sibunit as a catalyst for hydrogenation of palladium on a carbon support at a hydrogen pressure of 3.0-3.5 bar and in the temperature range of 30-50 ° C reduces the formation of by-products to 0.1-0.15% in the reaction mass (according to GLC). Also in the reaction mass there is always 7,8-difluoro-2,3-dihydro-3-methyl-2H-1,4-benzoxazine in an amount of from 1.5% to 3.0%, which can be purified from the target product by sequential transfer to the hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by the action of a 1.5-1.7-fold excess of a solution of hydrochloric acid in an aqueous toluene solution, then into free 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by treatment of the hydrochloride with an aqueous alkali solution. The product is purified from other impurities by vacuum distillation, which was used for the first time for this target product.

In a steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 2-acetyloxy-3,4-difluoronitrobenzene, 10% (mass) catalyst (Pd / sibunit, 5%) and isopropyl alcohol are placed. The reactor is closed, the required hydrogen pressure is created and stirring is turned on. The process is conducted for 5-7 hours, maintaining the temperature of the reaction mass in the range of 30-50 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil is dissolved in toluene and, with stirring, added to a 1.5-1.7-fold excess of hydrochloric acid. The resulting mass is stirred for 1.5-2.5 hours. The precipitated 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine hydrochloride was separated by filtration, washed with toluene and dried in air.

To an aqueous solution of potassium hydroxide heated to 50-60 ° C, with stirring, in portions, for 30-40 minutes, the obtained dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4- benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring for another 30-40 minutes, the mixture is gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine was separated by filtration, washed with water and dried.

Next, 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round-bottom flask equipped with a Wurz nozzle and a thermometer. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 76-81%.

The resulting product is analyzed by GLC. The purity of the product is 99.6-99.9%.

The method of obtaining 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is illustrated by the following examples.

Example 1. In a 1.5 liter steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 90 g of 2-acetonyloxy-3,4-difluoronitrobenzene, 9 g of catalyst (Pd / C, 5%) and 900 ml of isopropyl alcohol were placed. The reactor is shut down. Create a hydrogen pressure of 3.0 bar and include stirring. The process is carried out for 6 hours, maintaining the temperature of the reaction mass 30 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil was dissolved in 80 ml of toluene and 70 ml of concentrated hydrochloric acid in 210 ml of water was added to a solution with stirring. The resulting mass was stirred for 2 hours. The precipitated benzoxazine hydrochloride was separated by filtration, washed with 20 ml of toluene and dried.

To a solution of 32 g of potassium hydroxide in 278 ml of water heated to 50 ° C, with stirring, in portions, for 30 min, the resulting dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4 is added -benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring for another 30 minutes, the mixture was gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine was separated by filtration, washed twice with water, in 100 ml portions and dried in air.

Next, the resulting 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round bottom flask equipped with a Wurz nozzle and a thermometer. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 78%, purity 99.6%.

Example 2. In a 1.5 liter steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 90 grams of 2-acetyloxy-3,4-difluoronitrobenzene, 9 grams of catalyst (Pd / C, 5%) and 900 ml of isopropyl alcohol are placed. The reactor is shut down. Create a hydrogen pressure of 3.0 bar and include stirring. The process is carried out for 6 hours, maintaining the temperature of the reaction mass 40 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil was dissolved in 80 ml of toluene and 70 ml of concentrated hydrochloric acid in 210 ml of water was added to a solution with stirring. The resulting mass is stirred for 2 hours. The precipitated benzoxazine hydrochloride is separated by filtration, washed with 10-20 ml of toluene and dried.

To a solution of 32 g of potassium hydroxide in 278 ml of water heated to 50 ° C, with stirring, in portions, for 30 min, the resulting dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4 is added -benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring, for another 30 minutes, the mixture was gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is separated by filtration, washed twice with water, in 100-200 ml portions and dried in air.

Next, the obtained 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round-bottom flask equipped with a Wurz nozzle and a thermometer at 150 ° C. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 80%, purity 99.8%.

Example 3. In a 1.5 liter steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 90 grams of 2-acetyloxy-3,4-difluoronitrobenzene, 9 grams of catalyst (Pd / C, 5%) and 900 ml of isopropyl alcohol are placed. The reactor is shut down. Create a hydrogen pressure of 3.0 bar and include stirring. The process is conducted for 6 hours, maintaining the temperature of the reaction mass 50 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil was dissolved in 80 ml of toluene and 70 ml of concentrated hydrochloric acid in 210 ml of water was added to a solution with stirring. The resulting mass is stirred for 2 hours. The precipitated benzoxazine hydrochloride is separated by filtration, washed with 10-20 ml of toluene and dried.

To a solution of 32 g of potassium hydroxide in 278 ml of water heated to 50 ° C, with stirring, in portions, for 30 min, the resulting dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4 is added -benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring, for another 30 minutes, the mixture was gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is separated by filtration, washed twice with water, in 100-200 ml portions and dried in air.

Next, the obtained 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round-bottom flask equipped with a Wurz nozzle and a thermometer at 150 ° C. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 76%, purity 99.6%.

Example 4. In a 1.5 liter steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 90 grams of 2-acetyloxy-3,4-difluoronitrobenzene, 9 grams of catalyst (Pd / C, 5%) and 900 ml of isopropyl alcohol are placed. The reactor is shut down. Create a hydrogen pressure of 3.5 bar and turn on stirring. The process is carried out for 6 hours, maintaining the temperature of the reaction mass 35 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil was dissolved in 80 ml of toluene and 70 ml of concentrated hydrochloric acid in 210 ml of water was added to a solution with stirring. The resulting mass is stirred for 2 hours. The precipitated benzoxazine hydrochloride is separated by filtration, washed with 10-20 ml of toluene and dried.

To a solution of 32 g of potassium hydroxide in 278 ml of water heated to 50 ° C, with stirring, in portions, for 30 min, the resulting dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4 is added -benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring, for another 30 minutes, the mixture was gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is separated by filtration, washed twice with water, in 100-200 ml portions and dried in air.

Next, the obtained 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round-bottom flask equipped with a Wurz nozzle and a thermometer at 150 ° C. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 81%, purity 99.7%.

Example 5. In a 1.5 liter steel reactor equipped with a mechanical stirrer, bubbler tube and pressure gauge, 90 grams of 2-acetyloxy-3,4-difluoronitrobenzene, 9 grams of catalyst (Pd / C, 5%) and 900 ml of isopropyl alcohol are placed. The reactor is shut down. Create a hydrogen pressure of 3.5 bar and turn on stirring. The process is carried out for 6 hours, maintaining the temperature of the reaction mass 35 ° C.

After the reaction time, the mixer is turned off, hydrogen is removed, the reaction mass is removed, filtered, the solvent is evaporated. The resulting oil was dissolved in 80 ml of toluene and 70 ml of concentrated hydrochloric acid in 210 ml of water was added to a solution with stirring. The resulting mass is stirred for 2 hours. The precipitated benzoxazine hydrochloride is separated by filtration, washed with 10-20 ml of toluene and dried.

To a solution of 32 g of potassium hydroxide heated to 60 ° C in 278 ml of water, with stirring, in portions, for 30 min, the resulting dry hydrochloride of 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4 is added -benzoxazine. After adding the entire amount of hydrochloride, without stopping stirring, for another 30 minutes, the mixture was gradually cooled to room temperature. The resulting free 7.8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is separated by filtration, washed twice with water, in 100-200 ml portions and dried in air.

Next, the obtained 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine is distilled in an oil bath from a round-bottom flask equipped with a Wurz nozzle and a thermometer at 150 ° C. The receiver is a round-bottom flask with a tap connected to a vacuum pump. The bulk of the substance is distilled at a bath temperature of 120-125 ° C, increasing to the end of the distillation to 135-140 ° C.

Collect the fraction boiling at 106-109 ° C at 2 mbar. The product yield is 80%, purity 99.9%.

Thus, the proposed method for producing 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine allows to obtain the target product with a yield of 76-81% and a purity of 99.6-99.9%.

The advantage of the catalyst - palladium on a carbon carrier "Sibunit" - in comparison with the Raney catalyst is the simplicity of its preparation, storage stability and the absence of side processes during synthesis associated with reductive defluorination. The use of simple operations in the isolation and purification of the product, the simplicity of the hardware design of the technological process, as well as the availability and low cost of the auxiliary reagents used allow large-scale production of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine high purity, which can be used in the synthesis of levofloxacin - a broad-spectrum antibiotic.

Claims (1)

The method of obtaining 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine by catalytic hydrogenation of 2-acetonyloxy-3,4-difluoro-nitrobenzene in an alcohol medium, subsequent filtration, evaporation and isolation of the target product, characterized in that the catalyst used is palladium on a carbon carrier "Sibunit", the process is carried out in isopropyl alcohol at a pressure of 3.0-3.5 bar and a temperature of 30-50 ° C, and the selection and purification of the target product is carried out by sequential converting it first to 7.8-difluoro-2,3-dihydro-3-methi hydrochloride l-4H-1,4-benzoxazine by treatment with a 1.5-1.7-fold excess of hydrochloric acid in an aqueous toluene solution, and then in free 7.8-difluoro-2,3-dihydro-3-methyl-4H- 1,4-benzoxazine by treatment of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine hydrochloride with an aqueous solution of alkali and vacuum distillation.