沙丁胺醇半硫酸盐

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

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

实验步骤: Albuterol has been prepared, see Irish Patent Specification No. 31391, Aug. 9, 1972, starting from the appropriate acetophenone derivative methyl-5-(bromoacetyl-2-hydroxybenzoate, by condensation with N-(1,1-dimethylethyl)benzenemethanamine in the presence of base to form the ketonic ester, methyl-5[[(1,1-dimethylethyl)(phenylmethyl)-amino]acetyl]-2-hydroxybenzoate. The ketonic ester is reduced with lithium aluminum hydride in tetrahydrofuran under nitrogen to yield α1 -[[(1,1-dimethylethyl)-(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol which is subsequently debenzylated with hydrogen in the presence of palladium on carbon catalyst to produce albuterol.

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

实验步骤: A mixture of (R)-4-benzyl albuterol from Example-3 (6.6 g, 20 mmol) and 10% Pd/C (1.32 g) in 50 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 2-3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give crude (R)-albuterol (compound IIIa). The crude albuterol (20 mmol) is dissolved in 20 mL of ethanol and treated with anhydrous HCl in ether (1.0M, 19 mL, 0.95 eq) at 0°-5° C. After 30 min at room temperature, 20 mL of methyl t-butyl ether (MTBE) is added to the mixture and the resulting mixture is stirred at room temperature for 30 min and at 0°-5° C. for 2 hours. The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration and recrystallized from 52 mL of ethanol and 26 mL of MTBE to give pure (R)-albuterol hydrochloride as a white powder (4.6 g, 83.5% yield, 99.6% ee, 99.3% purity). The catalyst is removed by filtration the filtrate is concentrated to give crude (R)-albuterol (compound IIIa) The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration recrystallized from 52 mL of ethanol and 26 mL of MTBE

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

实验步骤: A mixture of (R)-4-benzyl albuterol from Example-3 (6.6 g, 20 mmol) and 10% Pd/C (1.32 g) in 50 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 2-3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give crude (R)-albuterol (compound IIIa). The crude albuterol (20 mmol) is dissolved in 20 mL of ethanol and treated with anhydrous HCl in ether (1.0M, 19 mL, 0.95 eq) at 0°-5° C. After 30 min at room temperature, 20 mL of methyl t-butyl ether (MTBE) is added to the mixture and the resulting mixture is stirred at room temperature for 30 min and at 0°-5° C. for 2 hours. The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration and recrystallized from 52 mL of ethanol and 26 mL of MTBE to give pure (R)-albuterol hydrochloride as a white powder (4.6 g, 83.5% yield, 99.6% ee, 99.3% purity). The catalyst is removed by filtration the filtrate is concentrated to give crude (R)-albuterol (compound IIIa) The white solid (R)-albuterol hydrochloride (compound IIIb) is collected by filtration recrystallized from 52 mL of ethanol and 26 mL of MTBE

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

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

实验步骤: In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: (i) fitting a high density polyethylene (HDPE) or stainless steel formulation tank with a bottom drain and peristaltic recirculation system (for HDPE) or tri-blender (for stainless steel) for mixing; (ii) filling the tank with approximately 90% of the required amount of Purified Water USP at a temperature of between 18° C. to 25° C.; while mixing, (iii) adding sulfuric acid, Sodium Chloride USP, and at least a therapeutically effective pediatric amount of Albuterol Sulfate USP to the tank; (iv) continue mixing until all chemical components are dissolved; (v) adding Purified Water USP to adjust the final volume, if necessary, thus producing an albuterol mixture. In an alternative embodiment, the inhalation solution of the present invention may be prepared for mixing of between 18° C. to 25° C. while mixing are dissolved Purified Water USP

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The Albuterol Resin Complex was prepared by first dissolving 286 g of albuterol sulfate in 8 liters of purified water, and then slowly adding 1837 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 30%. KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and continued drying under 50° C. until the moisture content was between 4-6%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 1837 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D of 640 g was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried at 50° C. in a VWR™ convection oven to the moisture content around 25% The semi-dried granules were then milled through a 40 mesh screen continued drying under 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

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

实验步骤: In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: (i) fitting a high density polyethylene (HDPE) or stainless steel formulation tank with a bottom drain and peristaltic recirculation system (for HDPE) or tri-blender (for stainless steel) for mixing; (ii) filling the tank with approximately 90% of the required amount of Purified Water USP at a temperature of between 18° C. to 25° C.; while mixing, (iii) adding sulfuric acid, Sodium Chloride USP, and at least a therapeutically effective pediatric amount of Albuterol Sulfate USP to the tank; (iv) continue mixing until all chemical components are dissolved; (v) adding Purified Water USP to adjust the final volume, if necessary, thus producing an albuterol mixture. In an alternative embodiment, the inhalation solution of the present invention may be prepared for mixing of between 18° C. to 25° C. while mixing are dissolved Purified Water USP