A PROCESS FOR THE PREPARATION OF HIGHLY PURE 6,7-DICHLORO-5- NITRO-2,3-DIHYDROQUINOXALINE-2,3-DIONE

Abstract: The present invention provides a process for the production of highly pure 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione, wherein the crude 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione is recrystallized from solution of highly polar solvents and water.

Description: A PROCESS FOR THE PREPARATION OF HIGHLY PURE 6,7-DICHLORO-5- NI- TRO-2,3-DIHYDROQUINOXALINE-2,3-DIONE 5 Technical Field of the Invention This invention relates to a process for the purification of 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione. 10 Background of the Invention 6,7-Dichloro-5-nitro-2,3-dihydroquinoxaline-2,3-dione (CAS 153504-81 -5; ACEA- 1021 ) has the following structure: 1 15 ACEA 1021 is being developed as a glycine site antagonist of the N-methyl-D-aspartate receptor for the treatment of head trauma and stroke. In the course of developing a large scale synthesis of 1 a suitable procedure for purification and isolation of the product was required. Previous efforts, see, e.g., Leeson, et al, J. Med. 0 Chem., 1994, 37, 4053; WO 94/00124; Chem. Abstr. 1994, 121, 73906; Keana, J. F. W., et al. J. Med. Chem., 1995, 38, 4367, in this area had taken advantage of the acidity of the nitrogen protons on the electron-deficient nitroquinoxalinedione to bring the highly insoluble product into solution in aqueous sodium hydroxide as 25 the disodium salt, thereby allowing insoluble impurities to be filtered off. Addition of acid led to precipitation of the monosodium salt, which was separated from soluble impurities by filtration, and the free product was then recovered by addition of acid. While this procedure served well on a laboratory scale, 30 difficulty was encountered on a larger scale due to incomplete reprotonation of the insoluble monosodium salt of 1. Furthermore, low solubility of the disodium salt required the use of very large volumes of solution and resulted in a tedious neutralization procedure requiring very precise pH control. Brief Summary of the Invention Provided is a method for producing 6,7-dichloro-5-nitro- 2,3-dihydroquinoxaline-2,3-dione. Also provided is 6,7-dichloro- 5-nitro-2,3-dihydroquinoxaline-2,3-dione free of sodium salt wherein the crude 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline- 2,3-dione is recrystallized from a solution of highly polar solvents and water. Preferably, the solution is comprised of dimethylsulfoxide or dimethylformamide in water. More preferably, the solution is one part DMSO to three parts water. Most preferably, the solution is at an elevated temperature in the range of 80 to 95 °C . Also provided is a composition of 6,7-dichloro-5-nitro-2,3- dihydroquinoxaline-2,3 -dione produced by the process of the invention. Brief Description of the Figures Figure 1 shows the increase in ACEA 1021 purity and decrease in impurity levels at each stage of purification. Figure 2 shows the dependence of per cent residual DMSO on stir time and precipitation temperature at two ratios of water.DMSO. Figure 3 shows the dependence of per cent residual DMSO on temperature and ratio of water.DMSO. Detailed Description The synthesis of 1 was essentially unchanged from that reported previously. While previous synthesis of 1 involved nitration of quinoxalinedione with solid potassium nitrate in concentrated sulfuric acid at temperatures of 0 to 22 °C for extended periods of time, see, e.g., WO 94/00124, I have discovered that the reaction proceeds more cleanly at 0-10°, and that reaction times longer than 1 hr after addition of the potassium nitrate result in no further consumption of the starting material, but did result in degradation of the product to impurities. In order to achieve this temperature control, gradual addition of the potassium nitrate was required. This was achieved by dissolving the potassium nitrate in sulfuric acid and adding the resulting solution to the solution of the substrate in sulfuric acid. Isolation of crude 1 was achieved by precipitation of the product upon addition of the reaction mixture to water. This resulted in an exceptionally fine precipitate which was very difficult to filter. It was found that addition of a diatomaceous earth filter aid facilitated the filtration or centrifugation and the washing of this precipitate without introducing any impurities which would contaminate the final product. The filter aid was easily removed by filtering the solution of the crude product just prior to recrystallization Given the extreme insolubility of 1 , alternative solvents were investigated with the discovery that highly polar solvents, for example dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidine (NMP), diethyl sulfoxide, and sulfolane are effective for recrystallization of 1. Impurity removal was more efficient with DMSO, and recovery was improved by using a mixture of water and DMSO. When utilizing a mixture of solvent in water the ratio 1 : 1 to 10:1. The preferred ratios are from 1 :4 to 1 :6 water:DMSO. Crude 1 was taken up in DMSO, filtered to remove filter aid and insoluble impurities, and diluted with water until crystallization ensued. Cooling and filtration gave purified 1 as a 1 : 1 solvate with DMSO. In preferred embodiments the mixture is cooled to 0° to 25° C, preferably 0° to 5°C. The mixture should not be cooled to less than 0°C in order to avoid freezing the solvent. The cooling can be carried out over a period of not less than about 0.1 hour and not more than about 24 hr. The recrystallization can be repeated as often as necessary until the desired degree of purity is attained, typically twice, and this results in product purity comparable to that attained previously using acid-base partition. Attempts to remove the DMSO by heating under vacuum led to decomposition, and other methods were investigated for the final isolation of 1. The following illustrates an embodiment of the invention and is not limiting of the specification and claims in any way. All materials are reagent grade or better and are available from commercial vendors (e.g., Sigma Chemical Company St. Louis, MO; Aldrich Chemical Company, Milwaukee, WI). Example 1 : Synthesis and Isolation of Crude 6,7-Dichloro-l ,4- dihydro-5-nitro-quinoxaline-2,3-dione ( 1 ). A solution of 231 g (1.0 mole) dried 6,7-dichloro-l ,4- dihydro-2,3-quinoxalinedione (2)l b,c in 2160 g concentrated sulfuric acid was cooled to <5°. A solution of 126.4 g (1.25 mole) potassium nitrate in 490 g concentrated sulfuric acid was prepared and cooled to ambient temperature. The potassium nitrate was added dropwise to the vigorously stirred solution of 2 with ice-salt bath cooling at a rate such that the internal temperature of the reaction did not exceed 10°; the addition required 18 min. Part way through the addition a precipitate formed with a slight exotherm and the mixture became very thick. The mixture was stirred at 0-5° for 1 hr and quenched by pouring into 3000 ml water with external ice-salt bath cooling at a rate such that the internal temperature of the mixture did not exceed 30°. To the slurry of yellow product was added 64 g diatomaceous earth filter aid and the product isolated by centrifugation or filtration using a filter medium coated with filter aid. The product cake was washed with water until the filtrate or centrate was colorless. Example 2: Recrystallization of Crude 1. The crude product was taken up in 2000 g dimethylsulfoxide at 90° and filtered to remove filter aid, and the cake was washed with 500 g additional dimethylsulfoxide. The filtrate was heated to 90° and 500 ml water was added with stirring. The product began to precipitate and the mixture was cooled in an ice bath to <5°. The solid product was isolated by filtration and washed with water. If the desired degree of purity was not attained a second recrystallization was carried out from 1000 g dimethylsulfoxide and 200 ml water under the same conditions. The purified product wet cake was taken up in 750 g dimethylsulfoxide at 90° and treated with 55 g Darco G60 charcoal _ for 15 min. The solution was filtered through a pad of filter aid and the cake was washed with 250 g dimethylsulfoxide. The filtrate was reheated to 90° and added to 3000 ml water at 90° with stirring. The resulting yellow slurry was stirred 30 min. at 90°, then cooled to <5°, and the solid product was isolated by filtration and washed with water. The solid was dried overnight under vacuum at 90-95° with a slow nitrogen purge. The dried solid was a pure yellow color and contained <0.1 % dimethylsulfoxide and <0.1 % water. HPLC purity was >99.5%. Example 3: Precipitation Conditions Further investigations into precipitation conditions were carried out as follows. Solutions of 4.0 g (1) in 32.0 g dimethylsulfoxide were prepared. Solutions which were to be run at 25° were heated to dissolve the solid and cooled. The required quantities of water were measured out, and the solutions of 1 and the water were heated to the precipitation temperature. The solution of 1 was added to the water with heating or cooling as necessary to maintain the temperature within ± 5°. (Some heat was evolved due to mixing of the dimethylsulfoxide and water.) The precipitation was either immediately filtered or held for the required period of time at the required temperature. The solid was filtered and the filter cake washed twice with 10 ml water. The solids were dried overnight at 90° C under vacuum with a nitrogen purge, then analyzed for residual dimethylsulfoxide.2 Decolorization and Precipitation. Pure 1 was a bright yellow solid, but low levels of colored impurities in the starting material led to variable color in the final product. Treatment with activated carbon in hot DMSO solution and addition of the filtered DMSO solution to hot water resulted in precipitation of purified 1 largely free of colored impurities and residual DMSO. Conditions for Product Precipitation. Initial investigation of the precipitation showed that the ratio of water to DMSO had little effect on the level of residual DMSO in the range of 8:1 to 3: 1. A two-level experimental design with center replicates was undertaken to investigate the influence of the water:DMSO ratio, the temperature of the precipitation, and the time that the mixture was stirred after precipitation. The run order was randomized, and three center points (Runs 3, 6, and 9) were included. The results shown in Table 1 were obtained. TABLE 1 Table 1. Run Number Water : DMSO Ratio Temperature (°C) Stirring Time (min.) % Residual DMSO 1 0.5 : 1 .0 95 ° 30 0.07 2 3.0 : 1 .0 25 ° 30 0.36 3 1 .75 : 1 .0 60° 15 0.10a 4 3.0 : 1 .0 95 ° 0 0.13 5 0.5 : 1 .0 25 ° 0 0.41 6 1 .75 1 .0 60° 15 0. 16 a 7 3.0 : 1 .0 25 ° 0 0.22 8 0.5 : 1 .0 95 ° 0 0.21 9 1 .75 : 1 .0 60 ° 15 0.26 a 10 0.5 : 1 .0 25 ° 30 0.46 1 1 3 .0 : 1.0 95° 30 0.04 a Average of centerpoints: 0.17; s. d.: 0.07. The results from Table 1 are shown in Figure 2. The residual DMSO levels (vertical lines) were plotted on the Time vs. Temperature plane at two levels of water : DMSO. Using multiple linear regression, equations were derived for % residual DMSO as a function of time and temperature at the two different levels of water : DMSO, and these equations were used to draw in the surfaces in Figure 2. The mismatch between the actual data (vertical bars) and the surfaces was indicative of the fact that no regard was given to the significance of the variables in the regression equations. From the graph it was apparent that temperature was the most significant variable, with water : DMSO being less important and stirring time hardly affecting the results at all. Since the time was not significant, the results for similar runs at different times were averaged (1 and 8; 2 and 7; 4 and 11 ; 5 and 10; 3, 6, and 9). Plotting these points in the same manner gave the graph shown in Figure 3. Equation (2) was used to generate the surface. % DMSO = -0.04 W - 0.00357 T + 0.508952 (2) where W = Parts Water : 1 Part DMSO and T = Temperature in °C. Agreement between the plotted function and the data was better in this graph. Temperature was the most significant determinant of residual DMSO content with the amount of water being barely significant. Residual solvent was determined by gas chromatography.

Claims: We Claim: - 1 . A process for purifying 6,7-dichloro-5-nitro-2,3- dihydroquinoxaline-2,3-dione comprising recrystallization of the crude 6,7-dichloro-5-nitro-2,3-dihydroquinoxaline-2,3 - dione from a solution of highly polar solvents and water. 2. The process of claim 1 wherein the highly polar solvent is selected from dimethylsulfoxide and dimethylformamide. 3. The process of claim 1 wherein the solvent and water is present in a ratio of about 1 : 1 to about 10: 1. 4. The process of claim 2 wherein the solvent is dimethylsulfoxide. 5. The process of claim 3 wherein the ratio of solvent to water is 3 :1. 6. The process of claim 5 wherein the solvent is dimethylsulfoxide. 7. The process of claim 5 wherein the temperature of the solution is between about 0 °C to about 25 °C . 8. The compound 6,7-dichloro-5-nitro-2,3-dihydroquin- oxaline-2,3 -dione produced by the process of claim 1. 9. A process for obtaining purified 6,7-dichloro-5-nitro- 2,3-dihydroquinoxaline-2,3 -dione comprising: _ a. filtering crude 6,7-dichloro-5-nitro-2,3 - dihydroquinoxaline-2,3 -dione in the presence of a dimethylsulfoxide; b. combining the filtered product with water in a ratio of about one part water to about one to up to ten parts dimethylsulfoxide at a temperature of 0° to 5°C for 0.5 to 5 hours to allow the pure 6,7-dichloro-5-nitro-2,3- dihydroquinoxaline-2,3-dione to crystallize; c. repeating steps (a) and (b) until a purity of at least 90 percent is achieved; d. removing residual dimethylsulfoxide and water under vacuum.

Inventors: GAEDE BRUCE, GAEDE, BRUCE
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1998
Main classification: C07D241
IPC codes: C07D241