2-(4-Methoxybenzyl)-4-bromo-1-chlorobenzene

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

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

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

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

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

Procedure: A solution of 14.8 g 1-bromo-4-chloro-3-(4-methoxy-benzyl)-benzene in 150 mL dichloromethane is cooled in an ice bath. 50 mL of a 1 M solution of boron tribromide in dichloromethane are added and the resulting solution is stirred for 2 h at ambient temperature. The solution is then cooled in an ice bath again and saturated aqueous potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted with aqueous 1 M hydrochloric acid to pH 1, the organic phase is separated off and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed completely. The solution is then cooled in an ice bath again At ambient temperature the organic phase is separated off the aqueous phase is extracted three times with ethyl acetate The combined organic phases are dried over sodium sulfate the solvent is removed completely

Conditions: temp:47.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 86.2 g (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mL triethylsilane in 75 mL dichloromethane and 150 mL acetonitrile is cooled to 10° C. Then with stirring 50.8 mL of boron trifluoride etherate are added so that the temperature does not exceed 20° C. The solution is stirred for 14 h at ambient temperature, before another 9 mL triethylsilane and 4.4 mL boron trifluoride etherate are added. The solution is stirred for a further 3 h period at 45-50° C. and then cooled to ambient temperature. A solution of 28 g potassium hydroxide in 70 mL water is added and the resultant mixture is stirred for 2 h. The organic phase is separated and the aqueous phase is extracted another three times with diisopropylether. The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After the solvent is evaporated, the residue is washed with ethanol and dried at 60° C. are added so that the temperature does not exceed 20° C are added cooled to ambient temperature The organic phase is separated the aqueous phase is extracted another three times with diisopropylether The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with brine dried over sodium sulfate After the solvent is evaporated the residue is washed with ethanol dried at 60° C.

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

Procedure: Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and anisole. Synthesis

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

Procedure: A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in 150 ml dichloromethane is cooled in the ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added and the solution is stirred for 2 h at ambient temperature. The solution is then cooled again in the ice bath, and saturated potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted to a pH of 1 with aqueous 1 M hydrochloric acid, the organic phase is separated off and the aqueous phase is extracted another three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is totally eliminated. is added dropwise At ambient temperature the organic phase is separated off the aqueous phase is extracted another three times with ethyl acetate The combined organic phases are dried over sodium sulphate

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

Procedure: A solution of 14.8 g 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene in 150 ml dichloromethane is cooled in the ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added and the solution is stirred for 2 h at ambient temperature. The solution is then cooled again in the ice bath, and saturated potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted to a pH of 1 with aqueous 1 M hydrochloric acid, the organic phase is separated off and the aqueous phase is extracted another three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, and the solvent is totally eliminated. is added dropwise At ambient temperature the organic phase is separated off the aqueous phase is extracted another three times with ethyl acetate The combined organic phases are dried over sodium sulphate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyl lithium (0.97 mL, 2.5 M/hexanes, 3.15 equivalents) was added dropwise (1 drop every 5 seconds) to an oxygen degassed solution (placed in a pre dried Biotage™ microwave vial 10-20 mL sealed with its cap and placed under a positive stream of nitrogen gas) of 4-bromo-1-chloro-2-(4-methoxy-benzyl)-benzene (725 mg, 2.95 equivalents) in anhydrous tetrahydrofuran (2.7 mL) at −78° C. and the resulting solution was stirred at this temperature for an additional hour. A solution of (2R,3S,4S)-2,3,4-tris-benzyloxy-5-hydroxy-6-(4-methoxy-benzyloxy)-5-(4-methoxy-benzyloxymethyl)-hexanoic acid methoxy-methyl-amide (I-1g) (616 mg) in anhydrous tetrahydrofuran (1.35 mL) was then added dropwise over 1.5 hours using a syringe pump and the resulting mixture was stirred at −78° C. for 1 hour before being allowed to warm to −20° C. over 14 hours (put in a deep Dewar covered with aluminum foil to maintain cold temperature; size of Dewar: external diameter 10 cm, internal diameter 8 cm, height 9 cm). Diethyl ether was added and the reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution. The resulting biphasic mixture was stirred at room temperature for 15 minutes. The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatography over silica gel using a gradient of 10 to 40% ethyl acetate in heptane gave the product as a mixture of isomers (530 mg, 71% yield). dried Biotage™ microwave vial 10-20 mL sealed with its cap at −78° C. the resulting mixture was stirred at −78° C. for 1 hour to maintain cold temperature the reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution The resulting biphasic mixture was stirred at room temperature for 15 minutes The organic phase was separated washed with brine dried over magnesium sulfate filtered concentrated Chromatography over silica gel using a gradient of 10 to 40% ethyl acetate in heptane gave the product as a mixture of isomers (530 mg, 71% yield)

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

Procedure: 4-bromo-1-chloro-2-(4-methoxybenzyl)-benzene (10 g, 32 mmol) was dissolved in dichloromethane (32 mL) and cooled to 0° C. under nitrogen. A 1.0 M boron tribromide solution in dichloromethane (35.3 mL, 34.3 mmol) was added dropwise over 10 minutes. Following the addition, the ice bath was removed and the solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and quenched by addition of 1N aqueous hydrochloric acid solution (45 mL). The mixture was stirred for 30 minutes, transferred to a separatory funnel, the organic layer was collected, and the aqueous layer was extracted with dichloromethane (45 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-(5-bromo-2-chlorobenzyl)phenol (9.5 g, 99% yield) as a white solid. the addition the ice bath was removed The reaction mixture was cooled to 0° C. quenched by addition of 1N aqueous hydrochloric acid solution (45 mL) The mixture was stirred for 30 minutes transferred to a separatory funnel the organic layer was collected the aqueous layer was extracted with dichloromethane (45 mL) The combined organic extracts were dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under a nitrogen protection and in a protection from light. To the resulting mixture was slowly added dropwise a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at −78° C. After the completion of dropwise addition, the reaction mixture was warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture was slowly added dropwise water in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted with methylene chloride (1 L) for two times. The organic phases were combined, washed with water for two times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce 210 g of a product in a yield of 97%. After the completion of dropwise addition reacted for 2 hr the completion of reaction The methylene chloride phase was collected The residual aqueous phase was extracted with methylene chloride (1 L) for two times washed with water for two times and with a saturated sodium chloride solution for one time dried over anhydrous sodium sulphate evaporated by rotation