2-(8-bromooctoxy)oxane

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

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

Procedure: (Method G) A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml) dried (Na2SO4) evaporated to dryness under reduced pressure The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) the mixture was heated under reflux for 2.5 h After being cooled the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient)

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

Procedure: A solution of 1-bromo-8-tetrahydropyranyloxyoctane (9.8 g) and triphenyl phosphine (8.8 g) in acetonitrile (50 ml) was heated under reflux for 8 hours. The solution was evaporated and the residue washed with ether to give the title compound as a hygroscopic white solid which was dried by addition of benzene and re-evaporation. under reflux for 8 hours The solution was evaporated the residue washed with ether

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

Procedure: A solution of 1-bromo-8-tetrahydropyranyloxyoctane (9.8 g) and triphenyl phosphine (8.8 g) in acetonitrile (50 ml) was heated under reflux for 8 hours. The solution was evaporated and the residue washed with ether to give the title compound as a hygroscopic white solid which was dried by addition of benzene and re-evaporation. under reflux for 8 hours The solution was evaporated the residue washed with ether

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

Procedure: A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml) dried (Na2SO4) evaporated to dryness under reduced pressure The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) the mixture was heated under reflux for 2.5 h After being cooled the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient)

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

Procedure: (Method G) A solution of commercially available 2-[(8-bromooctyl)oxy]tetrahydro-2H-pyran (1.0 g, 3.4 mmol, 1 equiv.) in DMSO (5 ml), was added, slowly, dropwise, at r.t., under N2, to a stirred suspension of lithium acetylide ethylenediamine complex (350 mg, 3.8 mmol, 1.1 equiv.) in DMSO (5 ml). The reaction mixture was stirred at r.t. for 18 h and diluted with n-pentane (50 ml). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) and the mixture was heated under reflux for 2.5 h. After being cooled, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient), to give the desired compound as a colourless oil (240 mg, overall yield 48%). The organic phase was washed with 1N HCl solution (2×20 ml) and water (2×20 ml) dried (Na2SO4) evaporated to dryness under reduced pressure The residue (colourless liquid, 570 mg, yield 70%) was dissolved in 95% EtOH (20 ml) together with p-toluenesulfonic acid (150 mg) the mixture was heated under reflux for 2.5 h After being cooled the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%-30% gradient)

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

Procedure: To 30 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 30 minutes a solution of 10.0 g of 2-(3-pyridyl)indole in 60 ml of tetrahydrofuran. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of tetrahydrofuran. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 3-(8-hydroxyoctyl)-2-(3-pyridyl)-indole. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour extracted with ether The ether extract is washed with water dried over MgSO4 evaporated to dryness The residue is dissolved in 100 ml of 3N hydrochloric acid the resulting mixture is kept at room temperature for 0.5 hour washed with ether extracted with methylene chloride The methylene chloride solution is evaporated to dryness

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

Procedure: To a stirred, room temperature suspension of Amberlyst 15 resin (2.37 g) in a solution of 8-bromo-1-octanol (9.50 g, 0.0454 mol) in heptane (95 mL) was added dropwise neat 3,4-dihydro-2H-pyran (5.0 mL, 0.055 mol) under a nitrogen atmosphere, and the mixture was stirred for 22 hours. The resin was filtered off, and the filtrate was rotoevaporated to an oil. The oil was chromatographed on silica gel (400 g, 230-400 mesh) using PET ether-diethyl ether (10:1, 10×500 mL) as eluent. Fractions containing title compound were rotoevaporated and dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%). 1H NMR (CDCl3): δ 4.6 (dd, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (m, 3H), 1.8 (m, 3H), 1.7 (m, 1H), 1.6 (m, 6H), 1.4 (m, 1H), 1.3 (m, 7H). The resin was filtered off The oil was chromatographed on silica gel (400 g, 230-400 mesh) Fractions containing title compound dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%)

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

Procedure: To a stirred, room temperature suspension of Amberlyst 15 resin (2.37 g) in a solution of 8-bromo-1-octanol (9.50 g, 0.0454 mol) in heptane (95 mL) was added dropwise neat 3,4-dihydro-2H-pyran (5.0 mL, 0.055 mol) under a nitrogen atmosphere, and the mixture was stirred for 22 hours. The resin was filtered off, and the filtrate was rotoevaporated to an oil. The oil was chromatographed on silica gel (400 g, 230-400 mesh) using PET ether-diethyl ether (10:1, 10×500 mL) as eluent. Fractions containing title compound were rotoevaporated and dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%). 1H NMR (CDCl3): δ 4.6 (dd, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (m, 3H), 1.8 (m, 3H), 1.7 (m, 1H), 1.6 (m, 6H), 1.4 (m, 1H), 1.3 (m, 7H). The resin was filtered off The oil was chromatographed on silica gel (400 g, 230-400 mesh) Fractions containing title compound dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%)

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

Procedure: To a stirred, room temperature suspension of Amberlyst 15 resin (2.37 g) in a solution of 8-bromo-1-octanol (9.50 g, 0.0454 mol) in heptane (95 mL) was added dropwise neat 3,4-dihydro-2H-pyran (5.0 mL, 0.055 mol) under a nitrogen atmosphere, and the mixture was stirred for 22 hours. The resin was filtered off, and the filtrate was rotoevaporated to an oil. The oil was chromatographed on silica gel (400 g, 230-400 mesh) using PET ether-diethyl ether (10:1, 10×500 mL) as eluent. Fractions containing title compound were rotoevaporated and dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%). 1H NMR (CDCl3): δ 4.6 (dd, 1H), 3.9 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.4 (m, 3H), 1.8 (m, 3H), 1.7 (m, 1H), 1.6 (m, 6H), 1.4 (m, 1H), 1.3 (m, 7H). The resin was filtered off The oil was chromatographed on silica gel (400 g, 230-400 mesh) Fractions containing title compound dried in vacuo to give a clear, colorless oil, yield 10.92 g (82%)

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

Procedure: The title compound, m/e=407.6 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran, which was reacted in step 2 with 2-phenoxyethanol, affording 2-(8-(2-phenoxy-ethoxy)-octyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 8-(2-phenoxy-ethoxy)-octan-1-ol. This was oxidized in step 4 to 8-(2-phenoxy-ethoxy)-octanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-4-dimethylamino-3-[8-(2-phenoxy-ethoxy)-octanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 6.

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

Procedure: The title compound, m/e=405.7 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 8-bromo-1-octanol was protected in step 1, leading to 2-(8-bromo-octyloxy)-tetrahydro-pyran, which was reacted in step 2 with 3-phenoxypropanol, affording 2-(8-(3-phenyl-propoxy)-octyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 8-(3-phenyl-propoxy)-octan-1-ol. This was oxidized in step 4 to 8-(3-phenyl-propoxy)-octanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-4-dimethylamino-3-[8-(3-phenyl-propoxy)-octanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 6.