2-(2-(2-Chloroethoxy)ethoxy)ethanol → 2-{2-[2-(2-Hydroxyethoxy)ethoxy]ethyl}-1H-isoindole-1,3(2H)-dione

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Reaction Steps

A process for preparing (-)-2-{[2-(2-Amino-ethoxy)ethoxy]methyl}-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, the compound of formula XXIV: ##STR77## wherein 2-[2-(2-chloroethoxy)ethoxy]ethanol is condensed with potassium phthalimide, in dimethylformamide in the heated state, to form 2-[2-(2-phthalimido-ethoxy)ethoxy]ethanol, the compound of formula XIV: ##STR78## which is converted by means of Jones reagent to 2-[2-(2-phthalimidoethoxy)ethoxy] acetic acid, the compound of formula XV ##STR79## which is treated with carbonyldiimidazole and Meldrum's acid in the presence of pyridine in methylene chloride to obtain the compound of formula XVI: ##STR80## which is then reacted with (R)-2-phenyl-2-methoxyethanol, the compound of formula XVII ##STR81## to obtain the β-keto ester of formula XVIII ##STR82## which is condensed in the presence of ammonium formate in ethanol with a benzylidene compound of formula XIX ##STR83## to obtain (4R,4'R/4S,4'R)-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XX ##STR84## and then: either: this compound is subjected to the action of aqueous sodium bicarbonate solution to obtain (4R,4'R/4S,4'R)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}methyl]-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-1,4-dihydropyridine, the compound of formula XXI: ##STR85## which is treated after separation by HPLC in the heated state with a mixture of glyme and sodium ethylate to obtain a mixture containing (-)-2-[{2-[2-(2-carboxyphenylcarboxamido)ethoxy]ethoxy}-methyl]-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, the compound of formula XXII: ##STR86## and its homolog substituted at the 5-position with an ethoxycarbonyl radical, or: the compound of formula XX is separated by chromatography on a silica column, using a mixture of methylene chloride and ethyl acetate (95:5 V/V) as eluant, to obtain the less polar isomer of 4-(2,3-dichlorophenyl)-5-methoxycarbonyl-3-(2-methoxy-2-phenylethoxycarbonyl)-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, which is then subjected to the action of sodium ethanolate in the presence of glyme in solution in ethanol to obtain a mixture containing the compound of formula XXII and its homolog substituted at the 5-position with an ethoxycarbonyl radical, which is then subjected to the action of carbonyldiimidazole in solution in a halogenated alkane at room temperature to obtain a mixture containing (-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, the compound of formula XXIII: ##STR87## and its homolog substituted at the 5-position with an ethoxycarbonyl radical, which mixture is then separated by (reverse phase) HPLC to obtain (-)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-{[2-(2-phthalimidoethoxy)ethoxy]methyl}-1,4-dihydropyridine, which is then brought to reflux in ethanol in the presence of hydrazine hydrate to give the compound of formula XXIV, which can then be salified with a pharmaceutically-compatible organic or inorganic acid.

Provenance & Evidence