| Identification | Back Directory | [Name]
alfa1-[[1,1-Dimethylethylamino]methyl]-4-hydroxy-1-(S),3-benzene dimethanol Hydrochlorid | [CAS]
50293-90-8 | [Synonyms]
Xopenex
Zopenex
Unii-wdq1526qjm
Salbutamol (R)-Isomer HCl
Levalbuterol hydrochloride
LevosalbutaMol Hydrochloride
(-)-Salbutamol hydrochloride
(R)-Salbutamol hydrochloride
LEVALBUTEROL HCL (SALBUTAMOL HCL)
Levalbuterol Hydrochloride (200 mg)
Levosalbutamol HCl (Levosalbutamol)
(R)-Salbutamol HCl ((R)-Albuterol HCl)
Zopenex [common misspelling of xopenex]
(R)-4-(2-(tert-butylamino)-1-hydroxyethyl)
Salbutamol Impurity 14（Salbutamol (R)-Isomer HCl）
SALBUTAMOL (HYDROCHLORIDE);LEVALBUTEROL;(-)-SALBUTAMOL;(R)-SALBUTAMOL
(R)-4-(2-(tert-butylamino)-1-hydroxyethyl)-2-(hydroxymethyl)phenol hydrochloride
4-[(1R)-2-(TERT-BUTYLAMINO)-1-HYDROXYETHYL]-2-(HYDROXYMETHYL)PHENOL HYDROCHLORIDE
2-(hydroxymethyl)-4-[(1R)-1-hydroxy-2-(tert-butylamino)ethyl]phenol hydrochloride
fa1-[[1,1-DiMethylethylaMino]Methyl]-4-hydroxy-1-(S),3-benzene diMethanol Hydrochlorid
(α1R)-α1-[[(1,1-DiMethylethyl)aMino]Methyl]-4-hydroxy-1,3-benzenediMethanol Hydrochloride
1,3-Benzenedimethanol, a1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-,hydrochloride (1:1), (a1R)-
2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(2-methyl-2-propanyl)amino ]ethyl}phenol hydrochloride (1:1)
1,3-Benzenedimethanol, alpha1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-, hydrochloride, (alpha1R)- | [Molecular Formula]
C13H22ClNO3 | [MDL Number]
MFCD08067728 | [MOL File]
50293-90-8.mol | [Molecular Weight]
275.772 |
| Chemical Properties | Back Directory | [Melting point ]
169-171°C | [alpha ]
D20 -32.2° (c = 0.1 in water) | [storage temp. ]
2-8°C | [solubility ]
H2O: ≥15mg/mL | [form ]
powder | [color ]
white to tan | [Optical Rotation]
[α]/D -25 to -35°, c = 0.1 in H2O | [Water Solubility ]
H2O: ≥15mg/mL | [InChI]
InChI=1/C13H21NO3.ClH/c1-13(2,3)14-7-12(17)9-4-5-11(16)10(6-9)8-15;/h4-6,12,14-17H,7-8H2,1-3H3;1H/t12-;/s3 | [InChIKey]
OWNWYCOLFIFTLK-ZLBVLXFENA-N | [SMILES]
c1(CO)cc([C@@H](O)CNC(C)(C)C)ccc1O.Cl |&1:5,r| |
| Hazard Information | Back Directory | [Description]
Salbutamol is an agonist of the β2-adrenergic receptor (β2-AR; Kd = 759 nM in a radioligand binding assay using CHO cells expressing the human receptor).1 It is selective for β2-ARs over β1- and β3-ARs (Kds = 46.8 and 21.9 μM, respectively). Salbutamol (25-50 μg/kg, i.v.) reduces acetylcholine-induced bronchospasm in anesthetized guinea pigs.2 It also reduces response of bronchial muscle to efferent vagal stimulation in anesthetized cats and dogs when administered at doses ranging from 1 to 2.5 and 10 to 20 μg/kg, respectively. Nebulized salbutamol reduces transpulmonary pressure in recurrent airway obstruction-affected horses (EC50 = 39.7 μg).3 Formulations containing salbutamol have been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). | [Chemical Properties]
Off-White Solid | [Originator]
Xopenex,Sepracor Inc.,USA | [Uses]
Antiasthmatic | [Uses]
bronchodilator, tocolytic | [Uses]
The R-enantiomer | [Uses]
β2-agonist, bronchodilator | [Manufacturing Process]
Preparation of 5-glyoxyloyl-salicylic acid methyl ester hydrate using aqueous
HBr
To a 3-neck flask immersed in an oil bath containing a solution of 40 g (0.206
mole) methyl 5-acetylsalicylate in 6 ml methylene chloride is charged with 82
ml of isopropanol. The solution is distilled to remove excess methylene
chloride. When the internal temperature reaches 77°C, 126 ml (1.77 mole or
8.6 equivalents) of DMSO is added to the reaction mixture and the
temperature of the mixture is increased to a temperature of 85° to 90°C.
Then 33 ml (0.29 mole or 1.4 equivalents) of HBr (aqueous, 48%) is added to
the mixture over a period of 20 minutes (exothermic), and the bath
temperature is maintained at 95° to 100°C. As the addition of HBr nears
completion distillation is initiated and dimethysulfide and isopropanol are
distilled off. The mixture is stirred and the volume of the distillate monitored.
After distillation of 82 ml of solvent, 20 ml of isopropanol is added slowly to
maintain a steady rate of distillation. After the reaction completed asdetermined by high performance liquid chromatography (HPLC), the reaction
mixture is quenched with 70 ml of 2.4 N H2SO4, the temperature of the
reaction mixture is allowed to drop to 75°C and residual isopropanol is
distilled off under vacuum. After a total of 165 ml distillate is collected, the
title compound begins to precipitate. A mixture of 30 ml of acetonitrile and 70
ml of water is added slowly at 75°C with stirring. After 30 minutes of stirring,
the reaction mixture is cooled to 15°C over a period of 90 minutes to
complete the precipitation. The reaction mixture is filtered and the cake is
washed with three 300 ml portions of water. The cake is dried in a draft oven
at 50°C for 16 hours to give 39.5 g of the title compound (85% yield).
Preparation of albuterol from 5-glyoxyloyl-salicylic acid methyl ester
To a solution of 5-glyoxyloylsalicylic acid methyl ester hydrate (50 g, 0.221
mol) in ethylene glycol diethyl ether, 440 mL is added tertiary butylamine
(16.2 g, 0.221 mol) at room temperature. The resulting light orange solution
is stirred for 5 min until a clear solution is formed. The clear solution is then
heated to reflux. Water and DME are distilled off azeotropically. After a total of
200 ml of distillate are collected, the solution is cooled to 25°C. The reaction
mixture is slowly added to a solution containing 49 mL (0.49 mol) of 10.0 M
borane-dimethyl sulfide in 220 mL of ethylene glycol diethyl ether (DME) at
70°C. The resulting reaction mixture is further refluxed for 2.5 hrs. After the
reaction is completed as monitored by HPLC, excess DME is removed via
vacuum distillation. The residue containing complexes of boron and
arylethanolamine is subsequently cooled to 0°C. Quenching of the residue
with 300 mL methanol gives the methylborate of arylethanolamine. The borate
is then removed by azeotropic distillation as trimethylborate, leaving behind
the desired arylethanolamine in the reaction mixture. An additional 300 ml of
methanol and acetic acid (85 mL) are added to ensure the complete removal
of trimethylborate via vacuum distillation to near dryness. The residue
containing the boron-free arylethanolamine is cooled to 25°C and
concentrated sulfuric acid (10.4 g, 0.221 mole) in water (64 mL) is added
following by 570 ml of isopropyl alcohol. Albuterol sulfate is precipitated out
as a white solid. After the reaction mixture is stirred at room temperature for
12 hrs and 0°C for 30 min the albuterol sulfate is filtered, washed with
isopropyl alcohol (two 50 mL portions) and dried at 50°C for 12 hrs to give
49.75 g of the title compound (78% yield) as racemate.
The optically pure albuterol may be prepared by resolving a mixture of
enantiomers methyl benzoate albuterol precursors which prepared by
procedures well known to persons skilled in the art. The starting material 4-
benzyl albuterol is commercially available from Cipla (Bombay, India).
(-)-D-Dibenzoyltartaric acid (D-DBTA) (32.2 g, 90 mmol, 1.0 eq) is added to a
hot solution of racemic 4-benzyl albuterol (29.6 g, 90 mmol, 1.0 eq) in 180
mL of anhydrous denatured ethanol (type 3A, denatured with 5 vol % 2-
propanol). The resulting solution is refluxed for 15 min and cooled to room
temperature over 40 min and seeded with 99% ee (R)-4-benzyl albuterol DDBTA salt. The mixture is cooled to 5°-10°C and stirred for 1 hour. The white
solid is collected by filtration and dried at 40°C and 28 inches of Hg for 1 hour
to give (R)-4-benzyl albuterol D-DBTA salt (31.8 g, 50% yield, 83.6% ee).
The solid is redissolved in 240 mL of ethanol at 55°-60°C and the solution is
cooled to room temperature and stirred at room temperature for 2 hours and
at 0°-5°C for 1 hour. The resulting solid is collected by filtration and dried at40°C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt
(22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204
mL of 5 wt % aq. Na2CO3 solution in 570 mL of ethyl acetate. The solid is
worked-up, and recrystallization from 30 mL of ethyl acetate and 30 mL of nheptane gives optically pure (R)-4-benzyl albuterol free base as a white
powder (10.1 g, 34.1% yield from racemic compound 99.6% ee and 99.8%
purity).
A mixture of (R)-4-benzyl albuterol as a free base (3.2 g, 9.73 mmol) and
10% Pd/C (0.64 g) in 24 mL of ethanol (denatured with 5 vol % 2-propanol)
is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room
temperature for 3 hours. The catalyst is removed by filtration and the filtrate
is concentrated to ca. 9 mL in volume containing crude (R)-albuterol and
treated with anhydrous HCl in ether (1.0 M, 9.5 mL, 0.98 eq) at 0°-5°C. After
30 min at room temperature, 9 mL of methyl t-butyl ether (MTBE) is added,
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 is collected by
filtration and recrystallized from 25 mL of ethanol and 12.5 mL of MTBE to
give pure (R)-albuterol hydrochloride (2.17 g, 80.9% yield, 99.6% purity),
white powder. | [Brand name]
Xopenex (Sepracor). | [Therapeutic Function]
Bronchodilator | [Biochem/physiol Actions]
Levalbuterol (levosalbutamol) is the more active isomer of albuterol. Levalbuterol is a β-adrenergic agonist; a bronchodilator used clinically to treat asthma and COPD.. | [References]
[1] C. HAWKINS G K. RELATIVE POTENCY OF (-)- AND (+-)-SALBUTAMOL ON GUINEA PIG TRACHEAL TISSUE[J]. ChemInform, 1973, 20 1. DOI: 10.1002/chin.197342241
[2] R B PENN. Comparison of R-, S-, and RS-albuterol interaction with human beta 1- and beta 2-adrenergic receptors.[J]. Clinical Reviews in Allergy & Immunology, 1996, 14 1: 37-45. DOI: 10.1007/bf02772201 |
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