2-piperidin-4-yloxyethanol

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: 40 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 350 ml of methyl ethyl ketone and 17.6 g of sodium iodide, 11.8 g of triethylamine, then 17 g of 2-(4-piperidyloxy)-ethanol were successively added to this solution. It was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil which was added to a mixture of ether and dilute hydrochloric acid. The formed precipitate was recovered by vacuum filtration and was crystallized from 95% ethanol to obtain 40.5 g of 2-trifluoromethyl-10-[-3(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride as white crystals. Then a current of ammonia was led into an ether suspension of this product and the formed precipitate was removed by filtration. The filtrate was evaporated to dryness to obtain 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine as an oil. It was refluxed for 20 hours after cooling the precipitate was removed by vacuum filtration The filtrate was evaporated to dryness

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

Procedure: 7 g (0.0469 mole) of sodium iodide were added to a solution of 15.1 g (0.0469 mole) of 2-methylthio-10-(3-chloropropyl)-phenothiazine in 250 ml of methyl ethyl ketone followed by the addition of 4.74 g (0.0469 mole) of triethylamine and then 6.8 g (0.0469 mole) of 2-(4-piperidyloxy)-ethanol. The mixture was refluxed for 20 hours and after cooling, the precipitate formed was removed by filtration. The filtrate was evaporated to dryness and the oil residue was dissolved in methylene chloride. The organic phase was washed with aqueous sodium bicarbonate, then with water, dried and concentrated. The resulting oil was dissolved in ethanol and an ether solution of hydrogen chloride was added thereto. The precipitate formed was recovered by vacuum filtration and twice crystallized from an ether-absolute ethanol mixture to obtain 9 g (41% yield) of 2-methylthio-10-[3-(4-β-hydroxyethoxypiperidino)propyl]-phenothiazine hydrochloride in the form of white crystals melting at 158°-160° C. The mixture was refluxed for 20 hours after cooling the precipitate formed was removed by filtration The filtrate was evaporated to dryness the oil residue was dissolved in methylene chloride The organic phase was washed with aqueous sodium bicarbonate with water, dried concentrated The resulting oil was dissolved in ethanol an ether solution of hydrogen chloride was added The precipitate formed was recovered by vacuum filtration twice crystallized from an ether-absolute ethanol mixture

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

Procedure: 17.6 g (0.117 mole) of sodium iodide were added to a solution of 40 g (0.17 mole) of 10-(3-chloropropyl)-2-trifluoromethyl-phenothiazine in 350 ml of methyl ethyl ketone followed by the addition of first 11.8 g (0.117 mole) of triethylamine and then 17 g (0.117 mole) of 2-(4-piperidyloxy)-ethanol. The resulting solution was refluxed for 20 hours and after cooling, the precipitate was removed by vacuum filtration. The filtrate was evaporated to dryness. The oil residue was stirred with a mixture of ether and dilute hydrochloric acid and the precipitate formed was recovered by vacuum filtration and crystallized from a 95% ethanol-ether mixture to obtain 40.5 g (71% yield) of 10-[3-(4-β-hydroxyethoxypiperidino) propyl]-2-trifluoromethyl-phenothiazine hydrochloride in the form of white crystals melting at 218°-219° C on a heated microscopic stage. The resulting solution was refluxed for 20 hours after cooling the precipitate was removed by vacuum filtration The filtrate was evaporated to dryness the precipitate formed was recovered by vacuum filtration crystallized from a 95% ethanol-ether mixture

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

Procedure: 22.5 g (0.15 mole) of sodium iodide was added to a solution of 41.5 g (0.15 mole) of 10-(3-chloropropyl)-phenothiazine in 400 ml of methyl ethyl ketone and then 15.2 g (0.15 mole) of triethylamine followed by 21.7 g (0.15 mole) of 2-(4-piperidyloxy)-ethanol were added to the reaction mixture. The solution was refluxed with stirring for 20 hours and after cooling, the precipitate formed was removed by vacuum filtration. The filtrate was evaporated to dryness and the oily residue was extracted with aqueous hydrochloric acid. The acidic extract was washed with ether, made alkaline and was extracted with benzene. The benzene phase was repeatedly washed with water, dried and concentrated to obtain an oil. The oil was dissolved in ether and hydrogen chloride in ether was added thereto. The precipitate was recoved by vacuum filtration and was crystallized from a 95% ethanol-ether mixture to obtain 35 g (55% yield) of 10-[3-(4-β-hydroxyethoxypiperidino)-propyl]-phenothiazine hydrochloride in the form of white crystals melting at 183° C on a heated microscopic stage. The product was identical to that of Example XI. were added to the reaction mixture The solution was refluxed after cooling the precipitate formed was removed by vacuum filtration The filtrate was evaporated to dryness the oily residue was extracted with aqueous hydrochloric acid The acidic extract was washed with ether was extracted with benzene The benzene phase was repeatedly washed with water dried concentrated to obtain an oil The precipitate was recoved by vacuum filtration was crystallized from a 95% ethanol-ether mixture

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

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

Procedure: 4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium toluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H). the mixture was stirred for 30 min The chloroform layer was separated the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL) The combined extracts were dried (Na2SO4) filtered concentrated

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

Procedure: 4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium toluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H). the mixture was stirred for 30 min The chloroform layer was separated the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL) The combined extracts were dried (Na2SO4) filtered concentrated

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

Procedure: 4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium toluene-4-sulfonate. To a solution of 1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in toluene (20 mL) at 0° C. was added 1.0 M diisobutylaluminum hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was warmed to 80° C. and stirred for 12 h. Methanol (20 mL), satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol in chloroform (100 mL) were added and the mixture was stirred for 30 min. The chloroform layer was separated and the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a white solid. The solid was dissolved in dichloroethane (20 mL) and 37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was added and the mixture was stirred for 1.5 h. The reaction mixture was diluted with satd. aq. NaHCO3 (20 mL) and extracted six times with 10% 2-propanol in chloroform (80 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was dissolved in dichloromethane, cooled to 0° C., and pyridine (463 μL, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7 mmol) were added. The solution was warmed to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partially purified by Method 2. The resulting material, toluene-4-sulfonic acid 2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and K2CO3 (699 mg, 5.1 mmol) in DMF. The mixture was heated to 100° C. and stirred for 16 h. After cooling to rt, the mixture was poured into water and extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude product was purified by Method 2 to afford 409 mg of the title compound. 1H NMR (400 MHz, CD3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H), 3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H). the mixture was stirred for 30 min The chloroform layer was separated the aqueous mixture was extracted five times with 10% 2-propanol in chloroform (25 mL) The combined extracts were dried (Na2SO4) filtered concentrated