4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene

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

Procedure: 66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum

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

Procedure: 66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwise at -75° C. to a mixture of 12 g of 4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of 4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture is stirred for a further 20 minutes at -75° C. and then, at from -75° C. to -60° C., a suspension of magnesium bromide in tetrahydrofuran (freshly prepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethane in 150 ml of tetrahydrofuran) is added. The reaction mixture is stirred for a further 30 minutes and then, at -75° C., a solution of 8.84 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 75 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 15 minutes at -75° C. and subsequently 70 ml of saturated ammonium chloride solution are added. The reaction mixture is then poured into 180 ml of saturated sodium chloride solution:water (1:1) and extracted with ethyl acetate (2×360 ml). The organic phases are dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained by purifying the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2): Rf (ethyl acetate/hexane =1:2)=0.16; HPLC Rt =18.53 and 19.49 minutes (diastereoisomeric mixture). is added The reaction mixture is stirred for a further 30 minutes The reaction mixture is then stirred for 15 minutes at -75° C. water (1:1) and extracted with ethyl acetate (2×360 ml) The organic phases are dried over magnesium sulfate concentrated by evaporation

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwise at -75° C. to a mixture of 12 g of 4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of 4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture is stirred for a further 20 minutes at -75° C. and then, at from -75° C. to -60° C., a suspension of magnesium bromide in tetrahydrofuran (freshly prepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethane in 150 ml of tetrahydrofuran) is added. The reaction mixture is stirred for a further 30 minutes and then, at -75° C., a solution of 8.84 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 75 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 15 minutes at -75° C. and subsequently 70 ml of saturated ammonium chloride solution are added. The reaction mixture is then poured into 180 ml of saturated sodium chloride solution:water (1:1) and extracted with ethyl acetate (2×360 ml). The organic phases are dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained by purifying the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2): Rf (ethyl acetate/hexane =1:2)=0.16; HPLC Rt =18.53 and 19.49 minutes (diastereoisomeric mixture). is added The reaction mixture is stirred for a further 30 minutes The reaction mixture is then stirred for 15 minutes at -75° C. water (1:1) and extracted with ethyl acetate (2×360 ml) The organic phases are dried over magnesium sulfate concentrated by evaporation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7.9 g of 4-bromo-1-methoxy-2-(3-methoxypropoxy)-benzene in 125 mL of tetrahydrofuran is cooled to −78° C. A solution of n-butyllithium (14.219 g of a 1.6 M solution in hexane) is added within 50 minutes. The reaction mixture is stirred for 90 minutes at −78° C. and treated slowly with 75 mL of a tetrahydrofuran solution of 8.93 g of (3S, 5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester. The resulting reaction mixture is stirred for 3 hours at −78° C. Finally the temperature is raised to −40° C. and the mixture stirred for 45 minutes. Acetic acid (4 mL) was added and the solvent removed by evaporation. The residue is dissolved in 100 mL of ethyl acetate and washed with two 75 mL portions of saturated sodium bicarbonate solution followed by one portion of 150 mL of water. The organic phase was dried and the solvent removed to give an oil. Chromatography on silica-gel, eluting with hexane/ethyl acetate gives, after combination of the product containing fractions and removal of the solvent, affords the title compound as an oil. The resulting reaction mixture is stirred for 3 hours at −78° C Finally the temperature is raised to −40° C. the mixture stirred for 45 minutes the solvent removed by evaporation The residue is dissolved in 100 mL of ethyl acetate washed with two 75 mL portions of saturated sodium bicarbonate solution The organic phase was dried the solvent removed to give an oil Chromatography on silica-gel, eluting with hexane/ethyl acetate gives after combination of the product containing fractions and removal of the solvent

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

Procedure: 66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Re (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum

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

Procedure: 66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Re (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum

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

Procedure: 6.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Rf (hexanedethyl acetate=4: 1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwise at -75° C. to a mixture of 12.1 g of 4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of 4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture is stirred for a further 20 minutes at -75° C. and then, at from -75° C. to -60° C., a suspension of magnesium bromide in tetrahydrofuran (freshly prepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethane in 150 ml of tetrahydrofuran) is added. The reaction mixture is stirred for a further 30 minutes and then, at -75° C. (2, a solution of 8.84 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 75 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 15 minutes at -75° C. and subsequently 70 ml of saturated ammonium chloride solution are added. The reaction mixture is then poured into 180 ml of saturated sodium chloride solution:water (1:1) and extracted with ethyl acetate (2×360 ml). The organic phases are dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained by purifying the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2)=Rf (ethyl acetate/hexane=1:2)=0.16; HPLC Rt =18.53 and 19.49 minutes (diastereoisomeric mixture). is added The reaction mixture is stirred for a further 30 minutes The reaction mixture is then stirred for 15 minutes at -75° C. water (1:1) and extracted with ethyl acetate (2×360 ml) The organic phases are dried over magnesium sulfate concentrated by evaporation

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.1 ml of a 1N n-butyllithium solution (in hexane) are added dropwise at -75° C. to a mixture of 12.1 g of 4-methoxy-3-(3-methoxypropyloxy)-bromobenzene and 9.7 ml of 4-methylmorpholine in 75 ml of tetrahydrofuran. The reaction mixture is stirred for a further 20 minutes at -75° C. and then, at from -75° C. to -60° C., a suspension of magnesium bromide in tetrahydrofuran (freshly prepared from 1.6 g of magnesium powder and 5.7 ml of 1,2-dibromoethane in 150 ml of tetrahydrofuran) is added. The reaction mixture is stirred for a further 30 minutes and then, at -75° C. (2, a solution of 8.84 g of 3(S)-isopropyl-5(S)-[1(S)-azido-3(S)-isopropyl-4-oxobutyl]-tetrahydrofuran-2-one in 75 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 15 minutes at -75° C. and subsequently 70 ml of saturated ammonium chloride solution are added. The reaction mixture is then poured into 180 ml of saturated sodium chloride solution:water (1:1) and extracted with ethyl acetate (2×360 ml). The organic phases are dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained by purifying the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2)=Rf (ethyl acetate/hexane=1:2)=0.16; HPLC Rt =18.53 and 19.49 minutes (diastereoisomeric mixture). is added The reaction mixture is stirred for a further 30 minutes The reaction mixture is then stirred for 15 minutes at -75° C. water (1:1) and extracted with ethyl acetate (2×360 ml) The organic phases are dried over magnesium sulfate concentrated by evaporation

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7.9 g of 4-bromo-1-methoxy-2-(3-methoxypropoxy)-benzene in 125 mL of tetrahydrofuran is cooled to −78° C. A solution of n-butyllithium (14.219 g of a 1.6 M solution in hexane) is added within 50 minutes. The reaction mixture is stirred for 90 minutes at −78° C. and treated slowly with 75 mL of a tetrahydrofuran solution of 8.93 g of (3S,5S)-5-tert-butoxycarbonyloxymethyl-3-isopropyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester. The resulting reaction mixture is stirred for 3 hours at −78° C. Finally the temperature is raised to −40° C. and the mixture stirred for 45 minutes. Acetic acid (4 mL) was added and the solvent removed by evaporation. The residue is dissolved in 100 mL of ethyl acetate and washed with two 75 mL portions of saturated sodium bicarbonate solution followed by one portion of 150 mL of water. The organic phase was dried and the solvent removed to give an oil. Chromatography on silica-gel, eluting with hexane/ethyl acetate gives, after combination of the product containing fractions and removal of the solvent, affords the title compound as an oil. The resulting reaction mixture is stirred for 3 hours at −78° C Finally the temperature is raised to −40° C. the mixture stirred for 45 minutes the solvent removed by evaporation The residue is dissolved in 100 mL of ethyl acetate washed with two 75 mL portions of saturated sodium bicarbonate solution The organic phase was dried the solvent removed to give an oil Chromatography on silica-gel, eluting with hexane/ethyl acetate gives after combination of the product containing fractions and removal of the solvent

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

Procedure: 66.0 g of potassium carbonate and 3-methoxy-1-bromopropane are added at room temperature to a solution of 64.6 g of 5-bromo-2-methoxyphenol in 350 ml of acetonitrile. The reaction mixture is stirred under reflux for 14 hours. After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction is carried out with ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Distillation under a high vacuum yields the title compound: Rf (hexane/ethyl acetate=4:1)=0.33; b.p.=126°-129° C./1.4 mbar; HPLC Rt =16.38 minutes; MS (M+)=274, 276. under reflux for 14 hours After removal of the solvent by evaporation, 1200 ml of ice/water are added to the residue and extraction The organic extracts are washed with saturated sodium chloride solution dried over magnesium sulfate concentrated by evaporation Distillation under a high vacuum