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With potassium <i>tert</i>-butylate In tetrahydrofuran; water
EXAMPLE 1 300 ml of THF are initially introduced at room temperature, and 84.7 g of potassium tert-butoxide are added with stirring 76.0 g of 2,2,2-trifluoroethanol are added dropwise to this reaction mixture, with the temperature being kept below 35° C. When the addition is complete, stirring is continued, and 29.6 g of 5-bromo-2-chlorobenzoic acid are subsequently introduced. After the subsequent addition of 27.3 g of copper(I) bromide, the reaction mixture is heated to reflux. After 43 hours, the reaction mixture is cooled to 5° C. and allowed to run into dilute hydrochloric acid at 5° C. The organic phase is separated from the aqueous phase,. and the solvent is distilled off, during which the product precipitates. 100 ml of water are added to the residue and then filtered. For purification, the crude product is taken up in MTB ether (methyl tert-butyl ether). Undissolved components are separated off by filtration through neutral aluminium oxide, and the solvent is subsequently removed. Recrystallisation from an ethanol/water mixture gives 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in a yield of 45percent. Melting point: 120-122° C., purity>98percent (HPLC).
METHOD CEXAMPLE 3: (l-r4-Chloro-3-(3H-imidazo[4,5-clpyridin-2-vn- phenyll-piperidin-4-vU-piperidin-l-yl-niethanone5-Bromo-2-chloro-N-(4-nitro-pyridin-3-yO-benzamide; Method C - Step a To a mixture of 5-Bromo-2-chlorobenzoic acid (5.00 g, 21.23 mmol) in DMF (40 mL), HATU (8.48 g, 22.29 mmol) and triethylamine (2.97 mL, 21.44 mmol) were added. After 30 min stirring at room temperature <strong>[13505-02-7]4-nitro-pyridin-3ylamine</strong> (2.36 g, 16.99 mmol) was added, the reaction mixture stirred at 400C overnight and solvent removed. The crude was then diluted with EtOAc (40 mL) and washed first with saturated Na2CO3 solution (6 x 30 mL) then IN HCl (3 x 30 mL). The organic layer was dried over Na2SO4, filtered and left standing. The precipitate obtained was filtered to get 4.75 g of the title compound (63%).1H-NMR (400 MHz, DMSO): delta 7.56 (IH, d), 7.77-7.92 (3H, m), 8.82 (IH, d), 9.14 (IH, s), 11.35 (IH, s); m/z 355 (M+H)+, retention time (method a)= 2.32 (5 min run)
Add all the above-obtained <strong>[57381-44-9]5-bromo-2-chlorobenzonitrile</strong> products to a mixed solution containing 1000ml of water and 72g (1.8mol, 1.8eq) of sodium hydroxide, slowly raise the temperature to 90C in a hot water bath, and keep stirring for 4 hours (HPLC detection of 3-bromo-2-chlorobenzonitrile <1.0%), the second product system is obtained; then the hot water bath is removed, the temperature of the system is slowly cooled to 5±5C through an ice-water bath, and 281.6g concentrated Hydrochloric acid (HCl about 2.7mol, 2.7eq), a large amount of white solids are generated in the system. After the dripping is completed, heat and stir for 3 hours to obtain the third product system; the third product system is suction filtered, and the obtained The filter cake was rinsed, then sucked dry, and then dried in a circulating oven at 40C for 12 hours to obtain 5-bromo-2-chlorobenzoic acid product (white solid, about 200g) with a yield of 85.9% and HPLC purity Is 99.90%.The product of 5-bromo-2-chlorobenzoic acid was detected by 1HNMR, 13CNMR, and LC-MS, and the results were consistent with Example 1, which proved that the obtained white solid was 5-bromo-2-chlorobenzoic acid.
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