2-(2,6-dichlorophenoxy)propanamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH). The resulting solution was warmed to room temperature evaporated to dryness The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL) The organic layer was dried (Na2SO4) evaporated under reduced pressure Recrystallization of the residue

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a variation of the present process, the (-)-2-(2,6-dichlorophenoxy)-propionic acid ethylester obtained as above described, is reacted with an ethanolic solution of ammonia at room temperature and is converted into (+)-2-(2,6-dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofurane complex and 4-methyl-morpholine in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride. This compound is dissolved in ethanol and is cyclized by adding 1,2-diaminoethane to produce (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (-)-base thus obtained.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH). The resulting solution was warmed to room temperature evaporated to dryness The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL) The organic layer was dried (Na2SO4) evaporated under reduced pressure Recrystallization of the residue

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH). The resulting solution was warmed to room temperature evaporated to dryness The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL) The organic layer was dried (Na2SO4) evaporated under reduced pressure Recrystallization of the residue

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a variation of the present process, the (-)-2-(2,6-dichlorophenoxy)-propionic acid ethylester obtained as above described, is reacted with an ethanolic solution of ammonia at room temperature and is converted into (+)-2-(2,6-dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofurane complex and 4-methyl-morpholine in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride. This compound is dissolved in ethanol and is cyclized by adding 1,2-diaminoethane to produce (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (-)-base thus obtained.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH). The resulting solution was warmed to room temperature evaporated to dryness The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL) The organic layer was dried (Na2SO4) evaporated under reduced pressure Recrystallization of the residue

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Another process is also based on (+)-2-(2,6-dichlorophenoxy)-propionic acid ethylester which is reacted with an ethanolic solution of ammonia at room temperature and is converted in to (-)-2-(2,6dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofuran complex and 4-methyl-morpholine in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (+)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride, this compound is dissolved in ethanol and is cyclised by adding 1,2-diaminoethane to produce (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (+)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (+) base thus obtained.