This compound has been obtained by three related ways: 1. The lithiation of N-(1-ethylpyrrolidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (I) with n-BuLi gives the dilithium salt (II), which by reaction with tosyl azide yields 6-azido-N-(1-ethylpyrrolidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (III). The reduction of the azido group of (III) with SnCl2 yields the corresponding amino derivative (IV), which is finally brominated with Br2 to afford the target compound. 2. The reaction of N-(3,4-dimethoxyphenyl)carbamic acid tert-butyl ester (V) with n-BuLi and CO2 gives 6-(tert-butoxycarbonyl)-2,3-dimethoxybenzoic acid (VI), which is condensed with (S)-1-ethylpyrrolidin-2-ylmethylamine (VII) by means of SOCl2, yielding the already reported 2-aminobenzamide (IV). 3. The intermediate carboxylic acid (VI) can also be first brominated with Br2 to give 5-bromo-6-(tert-butoxycarbonyl)-2,3-dimethoxybenzoic acid (VIII), which is finally condensed with (S)-1-ethylpyrrolidin-2-ylmethylamine (VII) by means of SOCl2, yielding the target compound.
The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-bromo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.
The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-iodo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.
The lithiation of N-(1-ethylpyrroidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (I) with n-BuLi gives the dilithium salt (II), which by treatment with butyl borate, H2O2 and ammonium chloride yields N-(1-ethylpyrrolidin-2(S)-ylmethyl)-6-hydroxy-2,3-dimethoxybenzamide (III). Finally, this compound is iodinated with 123INa and chloramine T.