1-(4-bromo-2-hydroxyphenyl)ethanone

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

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

Procedure: To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone (28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63 ml) was added methyl iodide (25 g, 176 mmol), and the mixture was stirred for 20 hours. The mixture was poured into water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31.5 g, 99% yield). The whole was extracted with diethylether The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was used for next reaction without purification

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

Procedure: 4.42 ml of methanesulphonyl chloride are added dropwise to a solution of 10.0 g 1-(4-bromo-2-hydroxy-phenyl)-ethanone [30186-18-6] and 13.0 ml of triethylamine in 200 ml dichloromethane at 0° C. The reaction mixture is worked up after 1 hour by pouring into 250 ml cold 1N HCl and extracting with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as light yellow crystals from the residue by re-crystallization from diisopropyl ether. Rf=0.51 (1:1 EtOAc-heptane). Rt=3.94 (gradient I). m.p. 62.0-62.1° C. extracting with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine dried over sodium sulphate concentrated by evaporation

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

Procedure: 4.42 ml of methanesulphonyl chloride are added dropwise to a solution of 10.0 g 1-(4-bromo-2-hydroxy-phenyl)-ethanone [30186-18-6] and 13.0 ml of triethylamine in 200 ml dichloromethane at 0° C. The reaction mixture is worked up after 1 hour by pouring into 250 ml cold 1N HCl and extracting with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as light yellow crystals from the residue by re-crystallization from diisopropyl ether. Rf=0.51 (1:1 EtOAc-heptane). Rt=3.94 (gradient I). m.p. 62.0-62.1° C. extracting with tert-butyl methyl ether (2×)—the combined organic layers are washed successively with water and brine dried over sodium sulphate concentrated by evaporation

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

Procedure: Methyl iodide (3 mL, 47.3 mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate (6.54 g, 47.3 mmol) in acetone (20 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to low volume and diluted with water. The aqueous mixture was extracted with dichloromethane (3×50 mL) and the combined organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10 mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140 mmol) were added and the reaction mixture was heated at 150° C. for 60 hours. The reaction mixture was then quenched with 1M hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by Kugel Rohr fractional distillation (150° C./0.05 mbar) to provide the title compound as a yellow oil (128 mg). The reaction mixture was concentrated in vacuo to low volume diluted with water The aqueous mixture was extracted with dichloromethane (3×50 mL) the combined organic solution was washed with water dried over sodium sulfate concentrated in vacuo The residue was dissolved in 1,2-ethanediol (10 mL) the reaction mixture was heated at 150° C. for 60 hours The reaction mixture was then quenched with 1M hydrochloric acid extracted with ethyl acetate (3×20 mL) The combined organic solution was dried over sodium sulfate concentrated in vacuo the residue was purified by Kugel Rohr fractional distillation (150° C./0.05 mbar)

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

Procedure: 1-(4-Bromo-2-hydroxy-phenyl)ethanone (10.1 g, 47.0 mmol) was coupled with N—BOC-4-piperidone according to the procedure for preparation of Intermediate 1, Step A, giving 7-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (18 g) as an orange solid.

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

Procedure: 1-(4-Bromo-2-hydroxy-phenyl)ethanone (10.1 g, 47.0 mmol) was coupled with N—BOC-4-piperidone according to the procedure for preparation of Intermediate 1, Step A, giving 7-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (18 g) as an orange solid.

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

Procedure: 3-Bromo-phenol (10.0 g, 57.8 mmol) was dissolved in 10 ml of pyridine and 10 ml of acetic anhydride and stirred overnight at RT. The mixture was then poured into water, and 1 M HCl was added until reaching a neutral pH value. Extraction with AcOEt furnished a crude product, which was treated with AlCl3 (13.25 g, 100 mmol) at 140° C. After 2 h, the mixture was poured into water and extracted with diethyl ether. The crude residue was purified by column chromatography (eluent: hexane/AcOEt 70:30) to give 1-(4-bromo-2-hydroxy-phenyl)-ethanone (10.1 g) as a red solid. was added Extraction with AcOEt furnished a crude product, which extracted with diethyl ether The crude residue was purified by column chromatography (eluent: hexane/AcOEt 70:30)

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

Procedure: A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.35 g, 6.28 mmol) in anhydrous DMF (16 mL) was treated in several portions with sodium hydride (377 mg of 60% in oil, 226 mg, 9.42 mmol) followed by stirring at room temperature for 30 min. The mixture was then treated with methyl bromo-acetate (871 μL, 1.45 g, 9.48 mmol) dropwise (solution became warm after addition was complete) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (4×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel, eluting with 20-100% ethyl acetate in hexanes. These procedures afforded the title compound as a colorless solid (1.47 g, 82%). by stirring at room temperature for 18 h extracted with water (4×) and saturated sodium chloride solution Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel eluting with 20-100% ethyl acetate in hexanes

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

Procedure: A solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.35 g, 6.28 mmol) in anhydrous DMF (16 mL) was treated in several portions with sodium hydride (377 mg of 60% in oil, 226 mg, 9.42 mmol) followed by stirring at room temperature for 30 min. The mixture was then treated with methyl bromo-acetate (871 μL, 1.45 g, 9.48 mmol) dropwise (solution became warm after addition was complete) followed by stirring at room temperature for 18 h. The mixture was diluted with ethyl acetate and extracted with water (4×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel, eluting with 20-100% ethyl acetate in hexanes. These procedures afforded the title compound as a colorless solid (1.47 g, 82%). by stirring at room temperature for 18 h extracted with water (4×) and saturated sodium chloride solution Drying (Na2SO4) and concentration in vacuo afforded a nearly colorless solid, which was purified by column chromatography on silica gel eluting with 20-100% ethyl acetate in hexanes

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

Procedure: To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone (28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63 ml) was added methyl iodide (25 g, 0.176 mmol), and the mixture was stirred for 20 hours. The mixture was poured into water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31.5 g, 99% yield). The whole was extracted with diethylether The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was used for next reaction without purification

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

Procedure: To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone (28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63 ml) was added methyl iodide (25 g, 0.176 mmol), and the mixture was stirred for 20 hours. The mixture was poured into water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31.5 g, 99% yield). The whole was extracted with diethylether The organic layer was washed with brine dried over MgSO4 concentrated in vacuo The residue was used for next reaction without purification