| 51.3% |
With boron tribromide; In dichloromethane; at 0℃; |
To an ice-cooled solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (0.71 g, 4.79 mmol) in dichloromethane (8.0 mL) was added 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol). The mixture was stirred at 0 C for 1.0 h. HPLC indicated ca 30-40%starting material still remaining. Then another portion of 1.0 M boron tribromide in dichloromethane (4.79 mL, 4.79 mmol) was added and the mixture was stirred from 0 C to room temperature over an hour. HPLC indicated a complete conversion of starting material. The mixture was poured into ice water, stirred for 15 mm, extracted with dichloromethane. The organic layer was dried over sodium sulfate. After evaporation ofsolvent, Intermediate 44A (0.33 g, 2.460 mmol, 51.3 % yield) was obtained as slightlybrown oil. It was used for the next step without further purification. ?H NMR (500MHz,chloroform-d) 7.60 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H),6.82 (dd, J=8.8, 2.8 Hz, 1H), 6.69-6.67 (m, 1H), 4.78 (s, 1H); LC-MS: Method A, 50 to100% B. RT = 2.32 mm, MS (ESI) m/z: no (M+H) |
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With lithium iodide; In 2,3,5-trimethyl-pyridine; |
Reference Example 202 To a solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (3.6 g) in collidine (20 ml) was added lithium iodide (6.5 g), and the mixture was refluxed, under argon atmosphere, overnight, cooled, made acidic (pH=4) with hydrochloric acid and extracted with ethyl acetate (three times). The organic layer was washed with 1N hydrochloric acid (twice) and then washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give yellow oil of 5-hydroxybenzofuran (1.6 g). 1H-NMR (200 MHz, CDCl3) delta 6.61 (dd, 1H, J=2.2, 0.6 Hz), 6.82 (dd, 1H, J=8.8, 2.6 Hz), 7.01 (d, 1H, J=2.6 Hz), 7.34 (d, 1H, J=8.8 Hz), 7.58 (d, 1H, J=2.2 Hz). |
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With boron tribromide; In dichloromethane; at 0 - 20℃; |
To a stirred solution of <strong>[13391-28-1]5-methoxybenzofuran</strong> (1) (0.50 g, 3.38 mmol) in dichloromethane (15 mL), boron tribromide (16.87 mL, 16.87 mmol, IM solution in dichloromethane) was added slowly at O0C. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then cooled to O0C, quenched with aqueous saturated NaHCO3 solution and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound (2) as an off white solid (300 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-J) delta: 7.59 (d, J=I.95 Hz, 1 H), 7.35 (d, J=8.59 Hz, IH), 7.00 (d, J=2.73 Hz, IH), 6.80 (dd, 8.59, 2.74 Hz, IH), 6.67 (m, IH), 4.66 (s, IH) |
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With boron trichloride; tetra-(n-butyl)ammonium iodide; In dichloromethane; at -78 - 20℃; for 16h; |
Preparation 15 Benzofuran-5-ol To a mixture of <strong>[13391-28-1]5-methoxybenzofuran</strong> (10.0 g, 67.5 mmol) and tetrabutylammonium iodide (31.2 g, 84.4 mmol) in CH2Cl2 (100 mL) at -78 C. was added BCl3 (169 mL of a 1 M solution in CH2Cl2, 169 mmol) dropwise over 1 h. The reaction mixture was stirred for 1 h, warmed to rt, stirred for 14 h, poured slowly into sat. NaHCO3 and ice, and extracted with CH2Cl2 (2*). The combined extracts were dried (MgSO4), filtered, concentrated, and chromatographed (20% EtOAc in hexanes) to provide 9.16 g of benzofuran-5-ol as an orange solid. 1H NMR (400 MHz, CDCl3): delta 7.57 (d, 1, J=2.1), 7.34 (d, 1, J=8.7), 7.03 (d, 1, J=2.7), 6.84 (dd, 1, J=8.8, 2.6), 6.64 (dd, 1, J=2.2, 0.9), 6.20 (s, 1). Previously synthesised but data are not provided. Rene, L.; Royer, R. Bull. Soc. Chim. France, 1973, 7-8 (Pt. 2), 2355-6. The TBAl/BCl3 procedural reference is Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719-9721. |
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prepared from <strong>[13391-28-1]5-methoxybenzo[b]furan</strong> according to a similar demethylation method as described in WO 04/043904). |
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To a solution of BBr3-SMe2 (9.45 g; 30.22 mmol) in dichloroethane (50 mL) was added 5-Methoxy-benzofuran (1.28 g; 8.64 mmol), and the mixture was refluxed for 4 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. To the resultant mixture was added water carefully, and the reaction mixture was stirred for 20 minutes. The resultant mixture was diluted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford the title compound. 1H NMR (400 MHz, CDCl3) delta: 7.60 (d, J=2.3 Hz, 1H), 7.37 (d, 1H), 7.02 (d, 1H), 6.82 (dd, 1H), 6.68 (dd, 1H), 4.59 (s, 1H). |
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To a solution of the product of Step B (50 g, 0.34 mol) in CH2C12 (1200 mL) was addedBBr3 (32.5 mL, 0.34 mol) in drops at -20C under N2. After the addition, the mixture waswarmed to 20C and stirred for 2 hrs. The reaction mixture was cooled to 0 C and added into a solution of NH3/MeOH (3 mol/L, 500 mL) using a canula at -20 C over a period of 15 mm carefully. The mixture was concentrated and the residue was added EA (500 mL). The solid was filtered off through a silica pad and the filtrate was concentrated under reduced pressure to give the crude product (crude, 48 g) as a oil which was used for the next step directly. ?H NIVIR (400MHz, DMSO-d6) 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J 8.8 Hz, 1H), 6.94 (d, J2.4 Hz, 1H), 6.79 (dd, J= 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS: IVJIe 135 (M+1). |
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To a solution of the product of Step B (50 g, 0.34 mol) in CH2C12 (1200 mL) was added BBr3 (32.5 mL, 0.34 mol) in drops at -20 C under N2. After the addition, the mixture waswarmed to 20C and stirred for 2 hrs. The reaction mixture was cooled to 0 C and added into a solution of NH3/MeOH (3 mol/L, 500 mL) using a canula at -20 C over a period of 15 mm carefully. The mixture was concentrated and the residue was added EA (500 mL). The solid was filtered off through a silica pad and the filtrate was concentrated under reduced pressure to give the crude product (crude, 48 g) as a oil which was used for the next step directly. ?H NMR(400 IVIFIz, DMSO-d6) 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J 8.8 Hz, 1H), 6.94 (d, J 2.4 Hz, 1H), 6.79 (dd, J 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS:IVJIe 135 (M+1). |
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With boron tribromide; In dichloromethane; at -60 - 0℃; for 2h;Inert atmosphere; |
Step 5: BBr3 (2.6 mL, 13.5 mmol) was added dropwise to S22-4 (2.0 g, 13.Smmol) in DCM (20mL) at -60 C under N2. The solution was stirred at 0C for 2h. The mixture was poured into iceand adjusted the pH to 1213. The inorganic phase was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S22-5. |
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With boron tribromide; In dichloromethane; at -60 - 0℃; for 2h;Inert atmosphere; |
Step 5: BBr3 (2.6 mL, 13.5 mmol) was added dropwise to S22-4 (2.0 g, 13.5mmol) in DCM (20 mL) at -60 C under N2. The solution was stirred at 0C for 2h. The mixture was poured into ice and adjusted the pH to 12-13. The inorganic phase was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S22- 5. |
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With sodium ethanolate; ethanethiol; In N,N-dimethyl-formamide; at 110 - 130℃; for 45h;Inert atmosphere; Large scale; |
To a stirred solution of EtONa (154 kg) in DMF (989 kg) was added EtSH (68.6 kg) at an inner temperature ?35 under nitrogen protection. The mixture was stirred for 6090min at the inner temperature ?35. 5-Methoxybenzofuran (58.75 kg) in DMF (55.0 kg) was added. The mixture was heated to 110-130, stirred for 45hrs, and then concentrated under vacuum below 90. After the mixture was cooled to 1020, 2N HCl (1326 kg) was added dropwise, followed by addition of EtOAc (531 kg) and H2O2(129 kg) at the inner temperature ?35. The mixture was stirred for 3060min. After separation of the organic layer, the aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated brine twice, and then the solvent was evaporated to dryness. MeOH and a solution of NaOH (44.5 kg) in water (185 kg) were added dropwise into the residue below 40. The mixture was stirred for 5-7 hrs at 3040. Active carbon (74 kg) wet up with water (77 kg) was added. The mixture was stirred for 4-6 hrs at 3040 and filtered and the filter cake was washed with MeOH and water. DCM was charged into the filtrate and pH was adjusted to 1 with 35aq. HCl below 40. The aqueous phase was extracted with DCM, and the organic phase was washed with 25NaCl and concentrated below 40 . The residue was used in the next step directly.1H NMR (400 MHz, DMSO-d6) delta 9.14 (s, 1H) , 7.86 (d, J 2.0 Hz, 1H) , 7.36 (d, J 8.8 Hz, 1H) , 6.94 (d, J 2.4 Hz, 1H) , 6.79 (dd, J 2.0, 0.9 Hz, 1H) , 6.74 (dd, J 8.8, 2.4 Hz, 1H) ppm. MS: M/e 135 (M+1)+. |
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With sodium ethanolate; ethanethiol; In N,N-dimethyl-formamide; at 110 - 130℃; for 45h;Inert atmosphere; Large scale; |
To a stirred solution of EtONa (154 kg) in DMF (989 kg) was added EtSH(68.6 kg) at an inner temperature ^35C under nitrogen protection. The mixture was stirred for 60~90min at the inner temperature ^35C. 5-Methoxybenzofuran (58.75 kg) in DMF (55.0 kg) was added. The mixture was heated to 110-130C, stirred for 45 hours, and then concentrated under vacuum below 90C. After the mixture was cooled to 10~20C, 2N HCl (1326 kg) was added dropwise, followed by addition of EtOAc (531 kg) and H202 (129 kg) at the inner temperature ^35C. The mixture was stirred for 30~60min. After separation of the organic layer, the aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated brine twice, and then the solvent was evaporated to dryness. MeOH and a solution of NaOH (44.5 kg) in water (185 kg) were added dropwise into the residue below 40C. The mixture was stirred for 5-7 hours at (0191) 30~40C. Active carbon (74 kg) wet up with water (77 kg) was added. The mixture was stirred for 4-6 hours at 30~40C and filtered; and the filter cake was washed with MeOH and water. DCM was charged into the filtrate and pH was adjusted to 1 with 35% aq. HCl below 40C. The aqueous phase was extracted with DCM, and the organic phase was washed with 25% NaCl and (0192) concentrated below 40 C. The residue was used in the next step directly. 1H MR (400 MHz, DMSO-^6) delta 9.14 (s, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.36 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 2.4 Hz, 1H), 6.79 (dd, J= 2.0, 0.9 Hz, 1H), 6.74 (dd, J= 8.8, 2.4 Hz, 1H) ppm. MS: M/e 135 (M+l)+. |
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