奈必洛尔杂质N1

反应条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The mixture of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (48 gm), acetic acid (480 gm) and 5% palladium on charcoal (19 gm) was taken into a hydrogenation flask and subjected to hydrogenation under a hydrogen gas pressure of 1.5 kg/cm2 for 3 hours at 25-40° C. Then the reaction mixture was filtered on hi-flo and washed with acetic acid (55 gm). The solvent was distilled off completely under reduced pressure and then co-distilled twice with ethyl acetate (each time 60 ml). To the resulting mass, ethyl acetate (480 ml) was added, refluxed for 1 hour and then cooled to 25-35° C. The reaction mass was stirred for 4 hours, again cooled to 0-10° C. and stirred for 1 hour 30 minutes. Filtered the material and washed with ethyl acetate (60 ml). The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C., cooled to 0-10° C. and then stirred for 1 hour at 0-10° C. Filtered the material and washed with methanol (60 ml) to give 40.5 gm of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (Nebivolol) (HPLC purity: 99.2%). was taken into a hydrogenation flask for 3 hours at 25-40° C Then the reaction mixture was filtered on hi-flo washed with acetic acid (55 gm) The solvent was distilled off completely under reduced pressure To the resulting mass, ethyl acetate (480 ml) was added refluxed for 1 hour again cooled to 0-10° C. stirred for 1 hour 30 minutes Filtered the material washed with ethyl acetate (60 ml) The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C. cooled to 0-10° C. stirred for 1 hour at 0-10° C Filtered the material washed with methanol (60 ml)

反应条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The mixture of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (48 gm), acetic acid (480 gm) and 5% palladium on charcoal (19 gm) was taken into a hydrogenation flask and subjected to hydrogenation under a hydrogen gas pressure of 1.5 kg/cm2 for 3 hours at 25-40° C. Then the reaction mixture was filtered on hi-flo and washed with acetic acid (55 gm). The solvent was distilled off completely under reduced pressure and then co-distilled twice with ethyl acetate (each time 60 ml). To the resulting mass, ethyl acetate (480 ml) was added, refluxed for 1 hour and then cooled to 25-35° C. The reaction mass was stirred for 4 hours, again cooled to 0-10° C. and stirred for 1 hour 30 minutes. Filtered the material and washed with ethyl acetate (60 ml). The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C., cooled to 0-10° C. and then stirred for 1 hour at 0-10° C. Filtered the material and washed with methanol (60 ml) to give 40.5 gm of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (Nebivolol) (HPLC purity: 99.2%). was taken into a hydrogenation flask for 3 hours at 25-40° C Then the reaction mixture was filtered on hi-flo washed with acetic acid (55 gm) The solvent was distilled off completely under reduced pressure To the resulting mass, ethyl acetate (480 ml) was added refluxed for 1 hour again cooled to 0-10° C. stirred for 1 hour 30 minutes Filtered the material washed with ethyl acetate (60 ml) The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C. cooled to 0-10° C. stirred for 1 hour at 0-10° C Filtered the material washed with methanol (60 ml)

反应条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The mixture of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (48 gm), acetic acid (480 gm) and 5% palladium on charcoal (19 gm) was taken into a hydrogenation flask and subjected to hydrogenation under a hydrogen gas pressure of 1.5 kg/cm2 for 3 hours at 25-40° C. Then the reaction mixture was filtered on hi-flo and washed with acetic acid (55 gm). The solvent was distilled off completely under reduced pressure and then co-distilled twice with ethyl acetate (each time 60 ml). To the resulting mass, ethyl acetate (480 ml) was added, refluxed for 1 hour and then cooled to 25-35° C. The reaction mass was stirred for 4 hours, again cooled to 0-10° C. and stirred for 1 hour 30 minutes. Filtered the material and washed with ethyl acetate (60 ml). The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C., cooled to 0-10° C. and then stirred for 1 hour at 0-10° C. Filtered the material and washed with methanol (60 ml) to give 40.5 gm of (±)-[2R*[1S*,5S*(S*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (Nebivolol) (HPLC purity: 99.2%). was taken into a hydrogenation flask for 3 hours at 25-40° C Then the reaction mixture was filtered on hi-flo washed with acetic acid (55 gm) The solvent was distilled off completely under reduced pressure To the resulting mass, ethyl acetate (480 ml) was added refluxed for 1 hour again cooled to 0-10° C. stirred for 1 hour 30 minutes Filtered the material washed with ethyl acetate (60 ml) The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25-35° C. cooled to 0-10° C. stirred for 1 hour at 0-10° C Filtered the material washed with methanol (60 ml)