2-(3-bromo-4-methoxyphenyl)ethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By working as described for preparation 1c), but using compound 2b) from the previous step instead of compound 1b), the title compound is obtained.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By working as described for preparation 1b), but using compound 2a) from the previous step instead of compound 1a), the title compound is obtained.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution 45.0 g of the compound obtained in Step 216-2 in DMF (50 ml) was added 29.0 g of imidazole and 32.0 g of TBSCl, and stirred at room temperature for 16 hours. Water was added to the solution, and the resulting mixture was extracted with Et2O. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=10/1; v/v) to obtain 62.0 g of the title compound (colorless oil). the resulting mixture was extracted with Et2O The extract was dried over Na2SO4 the drying agent was separated by filtration the solvent was evaporated under reduced pressure The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=10/1; v/v)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 10.7 g of LAH in THF (600 ml) was added dropwise a solution of 70.0 g of ethyl(3-bromo-4-methoxyphenyl)acetate in THF (200 ml) at an internal temperature of −12 to −3° C. After stirring at an internal of 0° C. or lower for one hour, Na2SO4/10 hydrate was added slowly. After foaming ended, filtration was carried out. The filtrate was concentrated under reduced pressure to obtain 45.0 g of the title compound (light yellow oil). filtration The filtrate was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrogen chloride gas that is dried for 5 hours is introduced into a suspension of 7.50 g (32.4 mmol) of 2-(3-bromo-4-methoxy-phenyl)-ethanol, 4.90 g (32.4 mmol) of 4-nitro-benzaldehyde and 4.39 g (32.4 mmol) of freshly melted zinc chloride in anhydrous benzene (96 ml). The reaction mixture is then diluted with ethyl acetate and washed neutral with water. After drying and concentration by evaporation, the solid residue is recrystallized from ethyl acetate (25 ml). 7.91 g (67%) of 6-bromo-7-methoxy-l-(4-nitrophenyl)-isochroman, melting point 144-147° C., is obtained. Hydrogen chloride gas that is dried for 5 hours washed neutral with water After drying concentration by evaporation the solid residue is recrystallized from ethyl acetate (25 ml)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled mixture of 2-[3-bromo-4-(methyloxy)phenyl]ethanol (9.5 g, 41 mmol) and ethyl bis(ethyloxy)acetate (8.7 g, 48 mmol) in 60 mL of CH3NO2 was added TiCl4 (31.2 g, 169 mmol) over a period of 20 min. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatography to give methyl 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate. the ice bath was removed to stir at room temperature over night The mixture was poured onto ice/aqueous 1N HCl Extracted by DCM dried over anhydrous sodium sulfate concentrated The residue was purified via column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [3-bromo-4-(methyloxy)phenyl]acetic acid (10.0 g, 40.8 mmol) in anhydrous THF (50 mL) was added BH3.(CH3)2S (5.3 mL, 53 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The mixture was then treated with MeOH until gas evolution subsided, and then concentrated under reduced pressure. The residue was then partitioned between water and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 2-[3-bromo-4-(methyloxy)phenyl]ethanol, which was used without further purification for the next step. dropwise at 0° C concentrated under reduced pressure The residue was then partitioned between water and EtOAc The organic layers were washed with brine dried over Na2SO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cooled mixture of 2-[3-bromo-4-(methyloxy)phenyl]ethanol (9.5 g, 41 mmol) and ethyl bis(ethyloxy)acetate (8.7 g, 48 mmol) in 60 mL of CH3NO2 was added TiCl4 (31.2 g, 169 mmol) over a period of 20 min. After stirring for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatography to give methyl 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate. the ice bath was removed to stir at room temperature over night The mixture was poured onto ice/aqueous 1N HCl Extracted by DCM dried over anhydrous sodium sulfate concentrated The residue was purified via column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [3-bromo-4-(methyloxy)phenyl]acetic acid (10.0 g, 40.8 mmol) in anhydrous THF (50 mL) was added BH3.(CH3)2S (5.3 mL, 53 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 3 h. The mixture was then treated with MeOH until gas evolution subsided, and then concentrated under reduced pressure. The residue was then partitioned between water and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give crude 2-[3-bromo-4-(methyloxy)phenyl]ethanol, which was used without further purification for the next step. dropwise at 0° C concentrated under reduced pressure The residue was then partitioned between water and EtOAc The organic layers were washed with brine dried over Na2SO4 concentrated