[Synthesis]
1. Add methyl 2-methoxy-4-methylbenzoate (10 g, 0.056 mol) and acetic acid (70 mL) to a 250 mL three-necked, round-bottomed flask equipped with a magnetic stirring bar, thermometer, and dropping funnel.
2. Bromine (3 mL, 0.06 mol) was slowly added dropwise to the above solution at a reaction temperature of less than 25 °C. The reaction was carried out at a temperature of less than 25 °C.
3. After the dropwise addition was completed, the reaction mixture was stirred for 2 hours at room temperature and subsequently poured into 600 mL of cold water and the pH was adjusted to 8-9 with sodium carbonate.
4. The crude product was extracted with ether (3 x 300 mL), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 5-bromo-2-methoxy-4-methylbenzoate (14.3 g, 99% yield) as an orange oil, which solidified on standing.
5. 5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (11.64 g, 0.045 mol) was dissolved in a mixed solvent of ethanol and water (1:1, 150 mL), sodium hydroxide (5.8 g, 0.145 mol) was added, and the reaction took place at reflux for 30 min.
6. The ethanol was removed by distillation, the product precipitated as a salt, the residue was diluted with water (75 mL), the pH was adjusted to about 2 with concentrated hydrochloric acid, filtered, washed with water (3 x 50 mL), and dried over air to give 5-bromo-2-methoxy-4-methylbenzoic acid (9 g, 82% yield) as a beige solid.
7. 5-bromo-2-methoxy-4-methylbenzoic acid (9 g, 0.037 mol), thionyl chloride (5 mL, 0.069 mol) and benzene (90 mL) were mixed, refluxed for 4 hours and evaporated to dryness under reduced pressure.
8. The residue was dissolved in anhydrous benzene (40 mL), poured into ice-cooled concentrated ammonia (150 mL), stirred at room temperature for 1 h. The mixture was filtered, washed with water (3 x 25 mL), washed with benzene (2 x 20 mL), and dried over air to give 5-bromo-2-methoxy-4-methylbenzamide (8.5 g, 95% yield) as a beige solid.
9. In a 250 mL three-necked round-bottomed flask (equipped with a magnetic stirring bar, thermometer, dropping funnel and condenser), add 5-bromo-2-methoxy-4-methylbenzamide (6 g, 24.6 mmol), anhydrous methanol (40 mL) and a methanol solution of 25% sodium methanolate (21 mL, 98.4 mmol), cool to 5 ℃, and slowly add bromine (1.4 mL, 27.1 mmol) dropwise. 27.1 mmol).
10. After stirring at room temperature for 30 min, heat and reflux for 1 h. Remove solvent under reduced pressure, the residue is dissolved in ethanol (50 mL), potassium hydroxide (5.5 g, 98.4 mmol) is added, and refluxed for 16 h. The reaction is purified with water (300 mL, 98.4 mmol).
11. The reaction mixture was diluted with water (300 mL), extracted with ether (3 x 100 mL), the organic phases were combined, filtered through a silica gel pad and concentrated under reduced pressure to give 5-bromo-2-methoxy-4-methylaniline (4.8 g, 90% yield) as a light brown solid.
12. The hydrochloride suspension formed by reacting 5-bromo-2-methoxy-4-methylaniline (4.32 g, 20 mmol) with concentrated hydrochloric acid (20 mL) was cooled to 0 °C, and aqueous sodium nitrite (1.224 g, 24 mmol, 5 mL of water) was added slowly, keeping the temperature below 5 °C. The reaction was completed by filtration on a silica pad.
13. after addition of nitrite, stir at 0°C for 30 minutes and pour into a pre-prepared mixture of acetic acid (30 mL) containing 30% sulfur dioxide, copper chloride dihydrate (5.13 g, 30 mmol, 15 mL water) and benzene (20 mL).
14. Slowly heated to 35 °C, nitrogen release was observed, stopped and diluted with water (200 mL), the organic layer was separated, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude sulfuryl chloride (about 3 g) as a brown oil.
15. dissolve the crude product in hexane (20 mL), add concentrated ammonia (20 mL), room temperature vigorous stirring overnight, filtration, 10% potassium hydroxide solution (20 mL) treatment, filtration to remove insoluble matter, acidification of the filtrate, to obtain beige precipitate, filtration, washing, drying, to obtain 5-bromo-2-methoxy-4-methylbenzenesulphonamide (0.586 g, total yield 10.4%).
16. A dry 25 mL three-necked round-bottomed flask (equipped with a magnetic stir bar, thermometer and septum for argon inlet) was charged with 5-bromo-2-methoxy-4-methylbenzenesulfonamide (0.586 g, 2.1 mmol), anhydrous tetrahydrofuran (5 mL), and hexamethylphosphoramidite (0.37 mL, 2.1 mmol), cooled to -75 °C, and 2.0 M lithium diisopropylammonium solution (4.2 mL, 8.4 mmol) was added dropwise via syringe and stirred at -75 °C for 1.5 hours. |