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With potassium carbonate; triethylamine; In dichloromethane;
EXAMPLE 1 [This Example describes a procedure for the preparation of the Compound] Triethylamine (3.4 mL, 25 mM) is added dropwise to a stirred solution of 2-nitro-4-trifluromethylbenzoyl chloride (19 mM; itself obtained by reaction of <strong>[320-94-5]2-nitro-4-trifluoromethylbenzoic acid</strong> with an excess of oxalyl chloride) and cyclohexane-1,3-dione (19 mM) in dichloromethane (100 mL). The mixture is stirred for one hour at ambient temperature and then further triethylamine (57 mM) and acetone cyanohydrin (0.4 mL) is added. Stirring is continued for a further 2.5 hours and then the mixture is washed thoroughly with 2M hydrochloric acid to remove triethylamine. The organic phase is then extracted thoroughly with potassium carbonate (5% w/v). The combined basic extracts are then acidified with 2M hydrochloric acid and extracted with ether. The ether extracts are washed with saturated sodium chloride solution, dried (magnesium sulphate) and the volatile material removed by rotary evaporation in vacuo. There may thus be obtained 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione as a solid, m.p. 88-84 C. (recrystallized from ethyl acetate) having a satisfactory microanalysis and infra-red and proton magnetic resonance spectra.
With hydrogenchloride; sodium hydroxide; triethylamine
C.1 COMPARATIVE EXAMPLE 1
COMPARATIVE EXAMPLE 1 This example demonstrates the use of trimethylsilylcyanide in the preparation of 2-(2'-nitro-4'-trifluoromethylbenzoyl)-1,3-cyclohexanedione. It is presented for comparative purposes and illustrates the process described in European Published Patent Application No. 186,118. A 250-ml flask was fitted with a condenser, addition funnel, thermometer, and magnetic stirrer. The reaction set-up was flushed with dry nitrogen, and the following reaction was carried out under a nitrogen atmosphere. The reaction flask was charged with 1,3-cyclohexanedione (8.9 gm, 0.079 mole) dissolved in alcohol-free chloroform (100 ml). This solution was cooled to below 10° C. with an ice bath. Triethylamine (24 gm, 0.24 mole) was added with stirring through the addition funnel so that the reaction temperature remained in the range of about 5° to about 10° C. The addition funnel was rinsed with a small amount of chloroform and was charged with 2-nitro-4-trifluoromethylbenzoyl chloride (20 gm, 0.079 mole). This acid chloride was added dropwise, again keeping the reaction temperature in the range of about 5° to 10° C. The reaction was allowed to stir at room temperature for 1.5 hours after the addition was completed. Trimethylsilylcyanide (0.4 gm, 0.004 mole) was added in one portion, and the reaction was allowed to stir at room temperature for 22 hours. The color of the reaction mixture darkened during this time. The reaction mixture was cooled to below 15° C. with an ice bath and was kept at this temperature while 10% hydrochloric acid (60 ml) was added dropwise. The resulting mixture was transferred to a separatory funnel, and the lower organic phase separated and washed with water (40 ml). The organic phase was placed back in the reaction flask and cooled to below 15° C. with an ice bath. Aqueous 4% sodium hydroxide (120 ml) was added with stirring while the reaction temperature remained below 15° C.. The lower chloroform layer was separated, and the upper aqueous base layer was acidified by adding 10% hydrochloric acid (60 ml). Again, the reaction temperature was kept below 15° C. during the acidification. The resulting precipitate was collected by filtration through a sintered glass funnel. This solid product was dried in a vacuum oven at 40° C., giving 23.6 gm of the desired product. The yield was 91%.
Stage #1: 1,3-cylohexanedione With triethylamine In dichloromethane at 20℃; for 4h;
Stage #2: 2-nitro-4-trifluoromethyl-benzoyl chloride In dichloromethane at 0 - 20℃; for 1.25h;
Stage #3: With triethylamine; 2-hydroxy-2-methylpropanenitrile In dichloromethane at 40℃; for 1h;
4.1.143. General procedure for the synthesis of NTBC
To a suspension of 2-nitro-4-(trifluoromethyl)benzoic acid 3 g (12.8 mmol), N,N-dimethylformamide (0.1 mL) in toluene (25 mL), thionyl chloride 1.8 g (15.3 mmol) was added with stirringat room temperature for 10 min, and the suspension was then heated at 110 °C for a further 3 h. After removing the reaction solvent under reduced pressure, the intermediate 2-chloro-4-(methylsulfonyl)benzoyl chloride was obtained, it was used directly in the next step without further purification. A reaction mixture of 1,3-cyclohexanedione 1.44 g (12.8 mmol), Et3N 1.9 g (19.2 mmol) in CH2Cl2 (25 mL) was pre-stirred at room temperature for 4 h. Then the intermediate 2-chloro-4-(methylsulfonyl)-benzoyl chloride prepared previously was dissolved in CH2Cl2 (25 mL), and was added dropwise to the reaction mixture at 0 °C in about 15 min. After the mixture was stirred at room temperatefor 1 h, Et3N 1.3 g (12.8 mmol) and acetone cyanohydrin 0.11 g (1.3 mmol) was added, and the obtained mixture was heatedat 40 °C for another hour. After the reaction was completed, asmonitored by TLC, the mixture was extracted twice by 2 mol L-1 HCl (30 mL), and the organic layer was dried by anhydrous Na2SO4. After removal of the solvent by rotary vapor, the residue was recrystallized from methanol to give the final produce NTBC ingood yield. White solid, yield, 73.8%, mp 137.5-138.1 °C.
164 g
With potassium carbonate In acetonitrile at 25℃; for 18h;
1 Example 1
Example 1 (0084) Thionyl chloride (162 g, 1.36 mol) was added dropwise into a suspension of 2-nitro-4-trifluoromethylbenzoic acid (228 g, 0.97 mol) in toluene (630 g) at 80° C. The thus obtained solution was kept under stirring at 80° C. for 20 hours, and then cooled to 50° C. The volatiles were removed under reduced pressure in order to get the expected 2-nitro-4-trifluoromethylbenzoyl chloride as an oil. The latter, cooled to 25° C. was added dropwise to a suspension of 1,3-cyclohexanedione (109 g, 0.97 mol) and potassium carbonate (323 g, 2.33 mol) in CH3CN (607 g). After 18 h the mixture was diluted with water (500 ml) and slowly acidified to about pH=1 with HCl 37%. The mixture was then warmed to about 55° C. and the phases were separated. The organic layer was washed with a 10% aqueous solution of sodium chloride and then, concentrated under reduced pressure at a temperature below 55° C. to reach a volume of 380 ml. The thus obtained mixture was stirred at 55° C. for 1 h and then cooled to 0° C. in 16 to 18 h. The resulting solid was filtered and rinsed several times with pre-cooled (0° C.) toluene. The wet solid was dried at 60° C. under vacuum for 6 h to provide nitisinone (164 g) as a white to yellowish solid with a purity of 98.4% as measured by HPLC and a content of potentially genotoxic impurity no 4 of 6.1 ppm measured by HPLC/MS.
With trimethylsilyl cyanide In dichloromethane for 2h;
1.1 Example 1 - Synthesis of Nitisinone
In the general procedure, 2-Nitro-4-(trifluoromethyl) benzoic acid was converted to the corresponding acid chloride via addition of 1.03 equivalents of oxalyl chloride in dichloromethane. 1 ,3-Cyclohexanedione was converted to the enol via addition of 3.0 equivalents of triethylamine followed by addition of the previously prepared acid chloride. Catalytic trimcthylsilyl cyanide, TMSCN, (0.05 equivalents) was added and the reaction stirred overnight. The reaction was washed with 2M hydrochloric acid, extracted into 1M sodium hydroxide at pi 1- 12, acidified to pH-2, extracted into isopropylacetate and crystallised to give Nitisinone.