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With potassium carbonate In N,N-dimethyl-formamide for 2h;
Intermediate INT-26: (4704) 6-Bromo-4-methyl-1-benzofuran-2-carboxylic acid
According to GP3, commercially available 4-bromo-2-hydroxy-6-methylbenzaldehyde (4707) (CAS: 1427438-58-1, 100 mg, 465 µmol), ethyl chloroacetate (50 µL, 470 µmol), potassium carbonate (630 mg, 4.56 mmol) were stirred in DMF (2.2 mL) for 2 h. After reaction completion and workup the desired residue was obtained as a dark brown solid (4708) (80 mg, 57%, 60% pure) which was used directly in the next step. H-NMR (400 MHz, (4709) DMSO-d6) d [ppm]: 10.16 (bs, 1 H), 7.57, 7.46, 7.45 (3 mc, 1 H each), 2.45 (s, 3 H).
With potassium carbonate In acetonitrile at 20℃; for 3h;
22.1 4-Bromo-2-(methoxymethoxy)-6-methylbenzaldehyde 22b
Compound 4-bromo-2-hydroxy-6-methylbenzaldehyde 22a (500 mg, 2.33 mmol, Prepared by the well-known method "Organic Letters, 2017, vol.19, no.23, p.6280-6283") was dissolved in acetonitrile (20 mL),Anhydrous potassium carbonate (1.0 g, 3.11 mmol, Chinese medicine) and bromomethyl methyl ether (350 mg, 2.80 mmol) were added, and the reaction was stirred at room temperature for 3 hours,The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 22b (230 mg, yield: 38.18%).
38.18%
With potassium carbonate In acetonitrile at 20℃; for 3h;
22.1 4-Bromo-2-(methoxymethoxy)-6-methylbenzaldehyde 22b
Compound 4-bromo-2-hydroxy-6-methylbenzaldehyde 22a (500 mg, 2.33 mmol, Prepared by the well-known method "Organic Letters, 2017, vol.19, no.23, p.6280-6283") was dissolved in acetonitrile (20 mL),Anhydrous potassium carbonate (1.0 g, 3.11 mmol, Chinese medicine) and bromomethyl methyl ether (350 mg, 2.80 mmol) were added, and the reaction was stirred at room temperature for 3 hours,The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 22b (230 mg, yield: 38.18%).
2; 3; 4
Into a three-necked flask, inject 60g of 4-bromo-2-hydroxyl-6-methylbenzaldehyde and 480g of DMAC, then slowly add 180g of concentrated sulfuric acid (98%) dropwise, and continue the reaction for 3h after the addition, and separate and purify to obtain 2-bromo -4-Hydroxy-5-formyl-6-methylbenzenesulfonic acid.Inject 40g of 2-bromo-4-hydroxy-5-formyl-6-methylbenzenesulfonic acid and 120g of tetrahydrofuran into a water-free and oxygen-free glass bottle, and slowly add 17g of butyl to the reaction system dropwise at -78°C Lithium (1mol/L), then add 80g triethylamine, rise to room temperature and continue to react for 6h, separate and purify to obtain 2-(diethylamino)-4-hydroxy-5-formyl-6-ethylbenzenesulfonic acid.Dissolve 40g of 2-(diethylamino)-4-hydroxy-5-formyl-6-methylbenzenesulfonic acid, 360g of acetic anhydride and 2g of calcium acetate in DMF, raise the temperature to 160°C for 30min to obtain the extraction modifier 5-methyl-6-sulfono-7-(diethylamino)benzofuran.