| 82 - 91% |
With sulfuric acid; water; at 70 - 110℃; for 3 - 6.45h;Product distribution / selectivity; |
EXAMPLE 3 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid (according, to step (b)) Into a 250 ml reaction vessel 41.6 g of 96% H2SO4 are loaded and 8.4 g of water added dropwise (to adjust the acid concentration to 80%). The temperature of the acid is adjusted to 70C and the portionwise addition of 10 g of purified 2-chloro-4-fluoro-5-nitrobenzotrichloride (titre by GC = 99.5%) commenced. The temperature is then set to 100-110C, observing the progressive formation of a white solid product dispersed in the mixture. The temperature is kept for 3 hours, then the reaction mixture cooled to 50C and diluted with 100 g of water, and the product then extracted with 40 g of ethyl acetate at room temperature. The phases are separated and the organic solution washed with 46 g of water. Finally, the solvent is evaporated to give 7 g of the title product, as a white solid. Titre by HPLC = 94.5%, molar yield 88%. Melting point (C): 148-151.EXAMPLE 4 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid (according to step (b)) Into a 250 ml reaction vessel inside a 1 I glass equipped with mechanical means of stirring, thermometer, bubble condenser, thermostatically controlled oil heater, acid vapour water traps, 750 g of 96% sulfuric acid are loaded and 75 g of deionised water added dropwise to dilute the acid to 85%. The operation is completed over 1.5 hours, reaching a maximum temperature of 45C. The acid is then heated to 80-90C, and the portionwise addition of 302.6 g of crude 2-chloro-4-fluoro-5-nitrobenzotrichloride commenced. The production of HCl may be observed immediately, both in the reaction mixture (seen by foaming), and in the water absorption traps. The reaction is moderately exothermic, however, the portionwise addition continues in safety, avoiding the accumulation of gas with vigorous stirring. The temperature is kept between 80-100C for the entire duration of the reaction, and for ¾ of the duration, the reaction has the appearance of a solution, then the acid product begins to form a suspension despite the high temperature. Addition of the organic component is completed in 3 hours 45 minutes, divided into 15 minute periods with the addition of 20-30 g each. The reaction mixture is kept stirring at 100C for a further 3 hours, until the reaction is complete. The gas absorbed in the traps (97.5 g) is an indication of the state of completion of the reaction. The reaction mixture is then cooled to 20C, and then the product filtered to give 233 g of a creamy white, damp solid. It is then further purified by washing with water, filtration and drying to obtain 171.0 g of product. Hydrolysis molar yield: 82%. Melting point (C): 148-152.EXAMPLE 5 Preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid (according to step (b)) Into a 250 ml reaction vessel 50 g of 96% sulfuric acid are loaded then diluted to 80% by the addition of 10 g of water. The mixture is then heated to 70C and then the portionwise addition of 12 g of crude nitration product 2-chloro-4-fluoro-5-nitrobenzotrichloride (titre by GC = 98%) commenced. The reaction mixture is heated to 100-110C and kept at said temperature for 3 hours to promote the formation of the hydrolysis product. While cooling, it is diluted with the addition of 50 g of water and 50 g of ice, and the product extracted with 60 g of ethyl acetate. Following separation of the phases, the organic phase is washed with 60 g of water, and the ethyl acetate concentrated under reduced pressure. 10 g of heptane are then added and 8 g of title product isolated as a white solid. Titre by HPLC = 96.5%, molar yield 91%. Melting point (C): 150-153. |
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