1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-[[2-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-2-hydroxyethyl]amino]ethanol

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

Procedure: (±)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (142 g) was converted into the hydrochloric acid salt in ethanol (1000 ml). The crystals were filtered off and crystallized from ethanol. The second fraction of the crystallization was recrystallized from ethanol, yielding 10.3 g (6.6%) of (±)-[2R*[1S*,5S*(S*)]]-α,α'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]hydrochloride; mp. 224.9° C. nebivolol hydrochloride (crystalline compound 1). The crystals were filtered off crystallized from ethanol The second fraction of the crystallization was recrystallized from ethanol

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

Procedure: In a preferred embodiment the said form is obtained by conventional spray drying technique using a LabPlant SPD-005® spray drier. Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution or adjust pH below 2.0 of nebivolol base solution/suspension in alcohol using aqueous HCl/Alcoholic HCl/HCl gas, which is then spray dried for a period of 2 to 5 hours, and further isolating nebivolol hydrochloride Form T1. In a preferred embodiment the said form is obtained by conventional spray drying technique Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution is then spray dried for a period of 2 to 5 hours

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

Procedure: In a preferred embodiment the said form is obtained by conventional spray drying technique using a LabPlant SPD-005® spray drier. Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution or adjust pH below 2.0 of nebivolol base solution/suspension in alcohol using aqueous HCl/Alcoholic HCl/HCl gas, which is then spray dried for a period of 2 to 5 hours, and further isolating nebivolol hydrochloride Form T1. In a preferred embodiment the said form is obtained by conventional spray drying technique Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution is then spray dried for a period of 2 to 5 hours

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

Procedure: Nebivolol free base (3.30 g, 8.70 mmol) is suspended in absolute ethanol (100 mL) and heated to fall until complete dissolution. To this solution, 1.25 M ethanolic HCl (7.5 mL) is added. The obtained solution is concentrated under reduced pressure, until obtaining a 15% concentration of the product. During solvent evaporation, progressive formation of a white precipitate is observed. The solid is filtered by washing with cold absolute ethanol, to obtain 3.10 g of nebivolol hydrochloride salt. The chiral purity of the product and the ratio between the two enantiomers is evaluated by comparison with reference standards, by HPLC with an AKZO NOBEL column, Kromasil 5-AmyCoat, 5 μm, 250 mm×4.6 and a suitable binary gradient. heated to fall until complete dissolution The obtained solution is concentrated under reduced pressure until obtaining a 15% concentration of the product During solvent evaporation, progressive formation of a white precipitate The solid is filtered by washing with cold absolute ethanol

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of nebivolol (48.5 gm) and methanol (950 ml) was refluxed for 30 minutes and then subjected to carbon treatment. The resulting mass was cooled to 0-10° C., hydrochloric acid (6.5 ml) was slowly added during 30 minutes and then stirred for 4 hours at 0-10C. Filtered the material, washed with 50 ml of methanol and dried at 50-60° C. to give 27.5 gm of Nebivolol hydrochloride salt (HPLC purity: 99.5%). was refluxed for 30 minutes Filtered the material washed with 50 ml of methanol dried at 50-60° C.

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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)

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

Procedure: In a preferred embodiment the said form is obtained by conventional spray drying technique using a LabPlant SPD-005® spray drier. Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution or adjust pH below 2.0 of nebivolol base solution/suspension in alcohol using aqueous HCl/Alcoholic HCl/HCl gas, which is then spray dried for a period of 2 to 5 hours, and further isolating nebivolol hydrochloride Form T1. In a preferred embodiment the said form is obtained by conventional spray drying technique Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution is then spray dried for a period of 2 to 5 hours

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

Procedure: Nebivolol free base (3.30 g, 8.70 mmol) is suspended in absolute ethanol (100 mL) and heated to fall until complete dissolution. To this solution, 1.25 M ethanolic HCl (7.5 mL) is added. The obtained solution is concentrated under reduced pressure, until obtaining a 15% concentration of the product. During solvent evaporation, progressive formation of a white precipitate is observed. The solid is filtered by washing with cold absolute ethanol, to obtain 3.10 g of nebivolol hydrochloride salt. heated to fall until complete dissolution The obtained solution is concentrated under reduced pressure until obtaining a 15% concentration of the product During solvent evaporation, progressive formation of a white precipitate The solid is filtered by washing with cold absolute ethanol

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

Procedure: (±)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (142 g) was converted into the hydrochloric acid salt in ethanol (1000 ml). The crystals were filtered off and crystallized from ethanol. The second fraction of the crystallization was recrystallized from ethanol, yielding 10.3 g (6.6%) of (±)-[2R*[1S*,5S*(S*)]]-α,α'[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]hydrochloride; mp. 224.9° C. nebivolol hydrochloride (crystalline compound 1). The crystals were filtered off crystallized from ethanol The second fraction of the crystallization was recrystallized from ethanol

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

Procedure: In a preferred embodiment the said form is obtained by conventional spray drying technique using a LabPlant SPD-005® spray drier. Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution or adjust pH below 2.0 of nebivolol base solution/suspension in alcohol using aqueous HCl/Alcoholic HCl/HCl gas, which is then spray dried for a period of 2 to 5 hours, and further isolating nebivolol hydrochloride Form T1. In a preferred embodiment the said form is obtained by conventional spray drying technique Nebivolol hydrochloride is dissolved in alcohol such as methanol under heating to obtain a clear solution is then spray dried for a period of 2 to 5 hours