2-[2-(2-chloroethoxy)ethoxy]oxane

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

Procedure: In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.4 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof. stirring for 2.5 hours at room temperature stirred for 8 hours at 170° C The above reaction was subjected to the reaction subjected to extraction with ethyl acetate by washing with water drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel)

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

Procedure: In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.9 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof. stirring for 2.5 hours at room temperature stirred for 8 hours at 170° C The above reaction was subjected to the reaction subjected to extraction with ethyl acetate by washing with water drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methyl-5-(3,3-dimethylbutanoyl)catechol (12 g, 0.054 mole), 2-(2-[2-chloroethoxy]ethoxy)tetrahydropyran (24.8 g, 0.119 mole) and potassium carbonate (16.6 g, 0.12 mole) in 100 ml dimethylformamide was stirred under a nitrogen atmosphere at 140° C. for 16 hours. The reaction mixture was cooled to 25° C. and 500 ml diethyl ether and 300 ml water were added. The layers were separated and the organic layer was washed with four 250 ml portions of water and 100 ml brine, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform. The title compound was isolated as a yellow oil (13.5 g, 44% yield). The layers were separated the organic layer was washed with four 250 ml portions of water and 100 ml brine dried over anhydrous magnesium sulfate the solvent evaporated in vacuo The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methyl-5-(3,3-dimethylbutanoyl)catechol (12 g, 0.054 mole), 2-(2-[2-chloroethoxy]ethoxy)tetrahydropyran (24.8 g, 0.119 mole) and potassium carbonate (16.6 g, 0.12 mole) in 100 ml dimethylformamide was stirred under a nitrogen atmosphere at 140° C. for 16 hours. The reaction mixture was cooled to 25° C. and 500 ml diethyl ether and 300 ml water were added. The layers were separated and the organic layer was washed with four 250 ml portions of water and 100 ml brine, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform. The title compound was isolated as a yellow oil (13.5 g, 44% yield). The layers were separated the organic layer was washed with four 250 ml portions of water and 100 ml brine dried over anhydrous magnesium sulfate the solvent evaporated in vacuo The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform

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

Procedure: In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.4 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof. stirring for 2.5 hours at room temperature stirred for 8 hours at 170° C The above reaction was subjected to the reaction subjected to extraction with ethyl acetate by washing with water drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel)

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

Procedure: In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.9 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof. stirring for 2.5 hours at room temperature stirred for 8 hours at 170° C The above reaction was subjected to the reaction subjected to extraction with ethyl acetate by washing with water drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methyl-5-(3,3-dimethylbutanoyl)catechol (12 g, 0.054 mole), 2-(2-[2-chloroethoxy]ethoxy)tetrahydropyran (24.8 g, 0.119 mole) and potassium carbonate (16.6 g, 0.12 mole) in 100 ml dimethyformamide was stirred under a nitrogen atmosphere at 140° C. for 16 hours. The reaction mixture was cooled to 25° C. and 500 ml diethyl ether and 300 ml water were added. The layers were separated and the organic layer was washed with four 250 ml portions of water and 100 ml brine, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform. The title compound was isolated as a yellow oil (13.5 g, 44% yield). The layers were separated the organic layer was washed with four 250 ml portions of water and 100 ml brine dried over anhydrous magnesium sulfate the solvent evaporated in vacuo The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methyl-5-(3,3-dimethylbutanoyl)catechol (12 g, 0.054 mole), 2-(2-[2-chloroethoxy]ethoxy)tetrahydropyran (24.8 g, 0.119 mole) and potassium carbonate (16.6 g, 0.12 mole) in 100 ml dimethyformamide was stirred under a nitrogen atmosphere at 140° C. for 16 hours. The reaction mixture was cooled to 25° C. and 500 ml diethyl ether and 300 ml water were added. The layers were separated and the organic layer was washed with four 250 ml portions of water and 100 ml brine, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform. The title compound was isolated as a yellow oil (13.5 g, 44% yield). The layers were separated the organic layer was washed with four 250 ml portions of water and 100 ml brine dried over anhydrous magnesium sulfate the solvent evaporated in vacuo The resulting brown oil was purified by column chromatography over silica gel with 10% ethyl acetate--90% chloroform

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

Procedure: To a solution of 5,6,7,12-tetrahydrodibenz[b,g]azocine (2.5 g, 12 mmol, prepared in a similar way as described in Chem. Pharm. Bull. 1978, 26, 942-950) and 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (3.0 g, 14 mmol) in toluene (50 ml) was added a suspension of sodium amide (1.50 g, 19 mmol, 50% wt suspension in toluene). The reaction mixture was heated at reflux temperature for 10 h. The mixture was allowed to cool to room temperature and water (52.5 ml) was carefully added. The phases were separated and the aqueous phase was extracted with toluene (50 ml). The combined organic phases were washed with water (2×5 ml), brine (15 ml) and dried over magnesium sulphate. The solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (150 g) using a mixture of ethyl acetate and n-heptane (1:4) as eluent. Collecting the proper fractions afforded 3.0 g of crude 12-(2-(2 -((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-5,6,7,12-tetrahydrodibenz[b,g]azocine. TLC: rf=0.11 (SiO2 ; ethyl acetate/n-heptane=1:4). The reaction mixture was heated at reflux temperature for 10 h The phases were separated the aqueous phase was extracted with toluene (50 ml) The combined organic phases were washed with water (2×5 ml), brine (15 ml) dried over magnesium sulphate The solvent was evaporated in vacuo a mixture of ethyl acetate and n-heptane (1:4) as eluent Collecting the proper fractions

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenothiazine (3.8 g, 19 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml) under an atmosphere of nitrogen. The mixture was heated at 135° C. for 1 h and then cooled to approximately 100° C. 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 110° C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml). The combined organic extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo leaving an oil, which was submitted to column chromatography using dichloromethane as eluent. Collecting the proper fractions afforded 3.9 g of crude 10-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-10H-phenothiazine. TLC: rf=0.72 (SiO2 ; dichloromethane/methanol=19:1). cooled to approximately 100° C the mixture was heated overnight at 110° C extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml) The combined organic extracts were washed with brine dried over sodium sulphate The solvent was evaporated in vacuo leaving an oil, which Collecting the proper fractions

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phenothiazine (3.8 g, 19 mmol) was added to a suspension of sodium hydride (0.92 g, 23 mmol, 60% oil dispersion) in dry dibutylether (25 ml) under an atmosphere of nitrogen. The mixture was heated at 135° C. for 1 h and then cooled to approximately 100° C. 2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethylchloride (8 g, 38 mmol) was added in one portion and the mixture was heated overnight at 110° C. The reaction mixture was poured into water (250 ml) and extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml). The combined organic extracts were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo leaving an oil, which was submitted to column chromatography using dichloromethane as eluent. Collecting the proper fractions afforded 3.9 g of crude 10-(2-(2-((tetrahydro-2-pyranyl)oxy)ethoxy)ethyl)-10H-phenothiazine. TLC: rf=0.72 (SiO2 ; dichloromethane/methanol=19:1). cooled to approximately 100° C the mixture was heated overnight at 110° C extracted with dichloromethane (3×50 ml) and diethyl ether (50 ml) The combined organic extracts were washed with brine dried over sodium sulphate The solvent was evaporated in vacuo leaving an oil, which Collecting the proper fractions

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.2 g, 2.54 mmol) in DMF (15 mL) were added 2-(2-(2-chloroethoxy)ethoxy)tetrahydro-2H-pyran (0.79 g, 3.82 mmol, intermediate 1), potassium carbonate (0.7 g, 5.08 mmol), TBAI (2 mg, 0.02 mmol). It was heated at 80° C. overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product (1.6 g, 98.1%) as a yellow oil which was used without purification. LCMS retention time 2.179 min, LCMS MH+-THP 561. The mixture was cooled partitioned between ethyl acetate and water dried over sodium sulfate filtered concentrated