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With sulfuryl dichloride; azobisisobutyronitrile In fluorobenzene
4 EXAMPLE 4
EXAMPLE 4 This Example illustrates the preparation of 3-isochromanone from recrystallized 2-chloromethylphenylacetic acid using different work-up procedures. o-Tolylacetic acid (100 g) was slurried in fluorobenzene (153.4 g) under a nitrogen blanket, and heated to reflux. An additional amount of fluorobenzene (100 ml) was then added to the reaction mixture and the solution dried by azeotropic distillation under atmospheric pressure at 85-90° C. The reaction mixture was then cooled to 80° C. and AIBN (2.14 g) was charged to the vessel in one portion. Sulphuryl chloride (105.55 g) was then added to the refluxing reaction mixture (temperature maintained at 80-85° C.) over a period of 3 hours, closely monitoring the progress of the reaction by means of 1 H NMR. Analysis showed ~80% conversion to 2-chloromethylphenylacetic acid at this point. After the addition was complete, the reaction mixture was allowed to cool slowly to ambient temperature, cooling finally to 0-5° C. The precipitate was filtered by suction, washed with n-hexane (70 g) and pulled dry on the filter, to give a fine off-white powder (75.73 g); 1 H NMR (CDCl3)δ 3.8(s,2H); 4.6(s,2H); 7.2-7.5(m,4H) ppm; mp 114.5-117.1° C.; quantitative yield 62.15%; % strength 95.7% by 1 H NMR. A sample of the 2-chloromethylphenylacetic acid was recrystallized from toluene which, following a hot filtration, gave a white solid of strength 97.75%.
With sulfuryl dichloride at 120℃;
1-5 Example 5:
50 grams of o-methylphenylacetic acid and50 grams of sulfonyl chloride are configured separately250 ml of tetrachloroethylene solution,Set the microchannel reactor temperature to 120 ° C to 5 mL / minThe flow rate of the two raw materials of tetrachloroethylene into the microchannel reactor for reaction;After collecting the reaction solution, wash it once in cold water.Adjust the pH to 7.2 with a saturated aqueous solution of potassium hydrogencarbonate, and keep the reaction at 50 ° C.The reaction system was detected by HPLC without change, washed with 100 ml of water and dried with an organic phase.The solvent was removed by concentration, and the residue was recrystallized from methanol.Drying gave 39 g of 3-isochromanone in a yield of 79% and a purity of 99.5%.
870 g
With 2,2'-azobis(isobutyronitrile); chlorine In dichloromethane at 75℃;
1.5; 2.5; 3.5
The specific process of step (5) is to add 800 g of o-toluene acetic acid and 440 g of dichloroethane in a 2000 liter reaction flask, increase the temperature to 75°C, then add 88 g of azobisisobutyronitrile, and then start the introduction of chlorine gas 488.89 g. When the content of the raw material is between 1% and 5%, the reaction is stopped, and 870 g of 2-chloromethylphenylacetic acid solid is obtained by cooling and centrifuging.
With hydrogenchloride; potassium hydrogencarbonate; In fluorobenzene; cyclohexane;
2-Chloromethylphenylacetic acid (97.75% strength; 10 g) was dissolved in fluorobenzene (20.6 g) at 70 C. over ~20 minutes. The pH of the reaction mixture was found to be 7-8 during the course of the addition. The mixture was then separated at 60 C., the lower aqueous layer being back-extracted with fluorobenzene (10 ml). The combined fluorobenzene phases were then dried by azeotropic distillation at 85-90 C. Slow addition of cyclohexane (20 g) at 80 C. gave a colourless solution which was then slowly cooled to ambient temperature. Further cooling to 0-5 C. gave a white precipitate which was filtered, washed with n-hexane (11.5 g), pulled dry on the filter and dried in air to constant weight (6.60 g); 1 H NMR (CDCl3)delta 3.7 (s,2H); 5.3(s,2H); 7.2-7.6 (m,4H) ppm; quantitative yield 83.9%; chemical yield 94.8%; % strength 99.7% by quantitative HPLC. Acid Drown-out Work-up 2-Chloromethylphenylacetic acid (97.75% strength; 10 g) was dissolved in fluorobenzene (12.6 g) at 70 C., and aqueous hydrochloric acid (18% strength; 6.45 g) added in one portion. The reaction mixture was stirred at 70-80 C. for 30 minutes. Potassium bicarbonate solution (20% strength; 10.15 g) was then added slowly followed by portionwise addition of solid potassium bicarbonate (6.7 g). The mixture was then separated at 60 C., the lower aqueous layer being back-extracted with fluorobenzene (10 ml). The combined fluorobenzene phases were then dried by azeotropic distillation at 85-90 C. Slow addition of cyclohexane (20 g) at 80 C. gave a colourless solution which was then slowly cooled to ambient temperature. Further cooling to 0-5 C. gave a white precipitate which was filtered, washed with n-hexane (11.5 g), pulled dry on the filter and dried in air to constant weight (6.45 g); 1 H NMR (CDCl3)delta3.7 (s,2H); 5.3 (s,2H); 7.2-7.6 (m,4H)ppm; quantitative yield 81.9%; chemical yield 99.1%; % strength 99.61% by quantitative HPLC.
39 g
With potassium hydrogencarbonate; In water; at 50℃;pH 7.2;
50 grams of o-methylphenylacetic acid and50 grams of sulfonyl chloride are configured separately250 ml of tetrachloroethylene solution,Set the microchannel reactor temperature to 120 C to 5 mL / minThe flow rate of the two raw materials of tetrachloroethylene into the microchannel reactor for reaction;After collecting the reaction solution, wash it once in cold water.Adjust the pH to 7.2 with a saturated aqueous solution of potassium hydrogencarbonate, and keep the reaction at 50 C.The reaction system was detected by HPLC without change, washed with 100 ml of water and dried with an organic phase.The solvent was removed by concentration, and the residue was recrystallized from methanol.Drying gave 39 g of 3-isochromanone in a yield of 79% and a purity of 99.5%.
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