.alpha..sup.1 -[[(1,1-Dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol, a substance known as albuterol and salbutamol, is a potent long-lasting .beta.-adrenoceptor stimulant that is orally effective and shows highly selective action on bronchial smooth muscle. Albuterol is indicated for the relief of bronchospasm in patients with reversible airway disease.
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 .alpha.1-[[(1,1-dimethylethyl)-(phenylmethyl)amino]methyl]-4-hydroxy-1,3-b enzenedimethanol which is subsequently debenzylated with hydrogen in the presence of palladium on carbon catalyst to produce albuterol.
We have found that albuterol can be conveniently prepared in good yield by reacting 5-(halo acetyl)-2-hydroxybenzaldehyde with 1,1-dimethylethanamine followed by reduction of the intermediate ketone compound, 5-[[(1,1-dimethylethyl)amino]acetyl]-2hydroxybenzaldehyde. The synthesis does not require protection of any of the reactive functional groups on either of the reactants, for example the hydroxy or aldehyde function of the 2-hydroxybenzaldehyde starting material or the amino function of the 1,1dimethylethanamine.
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