2-[2-(6-bromohexoxy)ethoxymethyl]-1,3-dichlorobenzene

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: Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)—LC RT=6.8 min. to stir at ambient temperature for 20 h extracted with ethyl acetate (300 mL) The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL) before drying over sodium sulfate The solution was concentrated to dryness under vacuum

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

Procedure: 50% aq NaOH (1.89 L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2 g), 1,6-dibromohexane (2.44 kg, 5 eq) and tetrabutylammonium bromide (34.1 g, 5 mol %) in toluene (1.89 L) was heated to 55-60° C. for 8-20 h. On cooling water (558 mL) and toluene (558 mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1 L). The combined toluene extracts were washed twice with water (2.2 L), then evaporated to dryness on a rotary evaporator. The excess 1,6-dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5 kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2 g)—LC RT=7.0 min. were added The aqueous phase was separated diluted with water (1 L) then back extracted with toluene (1.1 L) The combined toluene extracts were washed twice with water (2.2 L) evaporated to dryness on a rotary evaporator The excess 1,6-dibromohexane was removed a wiped film evaporator the resulting crude product chromatographed on silica (5 kg Biotage) eluting with 5% ethyl acetate in petrol 60/80

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

Procedure: 50% aq NaOH (1.89 L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2 g), 1,6-dibromohexane (2.44 kg, 5 eq) and tetrabutylammonium bromide (34.1 g, 5 mol %) in toluene (1.89 L) was heated to 55-60° C. for 8-20 h. On cooling water (558 mL) and toluene (558 mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1 L). The combined toluene extracts were washed twice with water (2.2 L), then evaporated to dryness on a rotary evaporator. The excess 1,6-dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5 kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2 g)—LC RT=7.0 min. were added The aqueous phase was separated diluted with water (1 L) then back extracted with toluene (1.1 L) The combined toluene extracts were washed twice with water (2.2 L) evaporated to dryness on a rotary evaporator The excess 1,6-dibromohexane was removed a wiped film evaporator the resulting crude product chromatographed on silica (5 kg Biotage) eluting with 5% ethyl acetate in petrol 60/80

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

Procedure: Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)—LC RT=6.8 min. to stir at ambient temperature for 20 h extracted with ethyl acetate (300 mL) The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL) before drying over sodium sulfate The solution was concentrated to dryness under vacuum

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

Procedure: 50% aq NaOH (1.89 L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2 g), 1,6-dibromohexane (2.44 kg, 5 eq) and tetrabutylammonium bromide (34.1 g, 5 mol %) in toluene (1.89 L) was heated to 55–60° C. for 8–20 h. On cooling water (558 mL) and toluene (558 mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1 L). The combined toluene extracts were washed twice with water (2.2 L), then evaporated to dryness on a rotary evaporator. The excess 1,6-dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5 kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2 g)—LC RT=7.0 min. were added The aqueous phase was separated diluted with water (1 L) then back extracted with toluene (1.1 L) The combined toluene extracts were washed twice with water (2.2 L) evaporated to dryness on a rotary evaporator The excess 1,6-dibromohexane was removed a wiped film evaporator the resulting crude product chromatographed on silica (5 kg Biotage) eluting with 5% ethyl acetate in petrol 60/80

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

Procedure: Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)−LC RT=6.8 min. to stir at ambient temperature for 20 h extracted with ethyl acetate (300 mL) The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL) before drying over sodium sulfate The solution was concentrated to dryness under vacuum

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

Procedure: Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)−LC RT=6.8 min. to stir at ambient temperature for 20 h extracted with ethyl acetate (300 mL) The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL) before drying over sodium sulfate The solution was concentrated to dryness under vacuum

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

Procedure: 50% aq NaOH (1.89 L), 2-(2,6-dichlorobenzyloxy)ethanol (473.2 g), 1,6-dibromohexane (2.44 kg, 5 eq) and tetrabutylammonium bromide (34.1 g, 5 mol %) in toluene (1.89 L) was heated to 55-60° C. for 8-20 h. On cooling water (558 mL) and toluene (558 mL) were added. The aqueous phase was separated and diluted with water (1 L) then back extracted with toluene (1.1 L). The combined toluene extracts were washed twice with water (2.2 L), then evaporated to dryness on a rotary evaporator. The excess 1,6-dibromohexane was removed using a wiped film evaporator, and the resulting crude product chromatographed on silica (5 kg Biotage), eluting with 5% ethyl acetate in petrol 60/80, to give the title compound (503.2 g)−LC RT=7.0 min. were added The aqueous phase was separated diluted with water (1 L) then back extracted with toluene (1.1 L) The combined toluene extracts were washed twice with water (2.2 L) evaporated to dryness on a rotary evaporator The excess 1,6-dibromohexane was removed a wiped film evaporator the resulting crude product chromatographed on silica (5 kg Biotage) eluting with 5% ethyl acetate in petrol 60/80

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+. The mixture was concentrated under reduced pressure the residue was partitioned between ethyl acetate and water The organic phase was washed with water, brine dried evaporated to dryness The residue was dissolved in ethanol eluting with ethanol The ammoniacal fractions were concentrated under reduced pressure the residue was dissolved in acetic acid (5 ml) water (2 ml) and the mixture was heated to 70° C. for 40 min The solvent was removed under reduced pressure the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3) concentrated the residue dissolved in acetic acid re-evaporated to dryness

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+. The mixture was concentrated under reduced pressure the residue was partitioned between ethyl acetate and water The organic phase was washed with water, brine dried evaporated to dryness The residue was dissolved in ethanol eluting with ethanol The ammoniacal fractions were concentrated under reduced pressure the residue was dissolved in acetic acid (5 ml) water (2 ml) and the mixture was heated to 70° C. for 40 min The solvent was removed under reduced pressure the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3) concentrated the residue dissolved in acetic acid re-evaporated to dryness