Abstract
The preparation of N-[(2-bromo-5-hydroxy-4-methoxyphenyl)methyl]-N-[(4-hydroxyphenyl)methyl]formamide (5) and 2-bromo-5-hydroxy-α-[(4-hydroxyphenyl)methyl]-4-methoxypropaneamide (10) is reported.
Highlights
One of the key steps of the industrial synthesis [1] of the anti-Alzheimer drug galanthamine (Reminyl®, Nivalin®) [2] comprises a K3[Fe(CN)6] induced phenol oxidation tandem cyclization [3]. In this reaction the 5-6-6-7 ring system is formed in one step starting from a suitable norbelladine derivative
We tried to extend this cyclization reaction towards the construction of 5-6-6-6 ring systems and prepared both N-[(2-bromo-5-hydroxy-4-methoxyphenyl)methyl]-N-[(4-hydroxyphenyl)methyl]formamide (5) and 2-bromo-5-hydroxy-α-[(4-hydroxyphenyl)methyl]-4-methoxypropaneamide (10) as necessary intermediates. These intermediates were subjected to the conditions of the tandem cyclization [1], the desired ring contracted galanthamine analog could not be obtained
Reductive amination of 4-hydroxybenzaldehyde with the free base of 2 using sodium borohydride gave rise to the secondary amine (3) with 84% yield, which was reacted with ethyl formate in presence of catalytic amount of 4-(N,N-dimethylamino)pyridine to give the amide (4) with 74% yield
Summary
One of the key steps of the industrial synthesis [1] of the anti-Alzheimer drug galanthamine (Reminyl®, Nivalin®) [2] comprises a K3[Fe(CN)6] induced phenol oxidation tandem cyclization [3]. For the synthesis of diphenol compound (5) 1-bromo-2-(chloromethyl)-5-methoxy-4-(1methylethoxy)benzene (1) [4] was converted into an amine by reaction with potassium phthalimide with subsequent hydrazinolysis and isolated as hydrochloride salt (2) with 79% yield.
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