N. Mealy, P. Leeson, M. Bayes
2001
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Drugs of The Future
Abstract
Nolomirole is synthesized by acylation of (′)-6-(methylamino)-5,6,7,8--tetrahydronaphthalene-1,2-diol, CHF-1024 (I) with isobutyryl chloride (II) in THF (1). Scheme 1. CHF-1024 (I) is obtained by several related ways: 1) Reductocondensation of 5,6-dimethoxy-2-tetralone (III) wth methylamine (IV) by means of LiBH 4 or NaBH 4 gives N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V), which is treated with 48% HBr at 110 °C (1). 2) The condensation of 2,3-dimethoxybenzaldehyde (VI) with pyruvic acid (VII) by means of KOH in ethanol/water gives 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII), which is reductocondensed with methylamine (IV) by means of H 2 over Pd/C in ethanol/ acetic acid to yield 4-(2.3-dimethoxyphenyl)-2-methylamino)butyric acid (IX). Reaction of acid (IX) with benzyl chloroformate (X) and NaOH in water affords the carbamate (XI), which is treated with refluxing SOCl 2 to provide 4-[2-(2,3-dimethoxyphenyl)ethyl]-3-methyloxazolidine-2,5-dione (XII). Reaction of oxazolidinone (XII) with AlCl 3 in dichloromethane provides 5,6-dimethoxy-2-(methyl-amino)-1,2,3,4-tetrahydronaphthalen-1--one (XIII), which is reduced with H 2 over Pd/C in ethanol containing some methanolic HCI in an autoclave at 80 °C to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-amine (V). Finally, this compound is demethylated by treatment with AlCl 3 in hot toluene (2). Scheme 2. 3) Alternatively, 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII) can first be demethylated with 48% HBr to give 5,6-dihydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIV), which is then reduced by means of H 2 over Pd/C in an autoclave as before (2). Scheme 2. 4) Condensation of 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII) with methyl carbamate (XV) by means of TsOH in refluxing toluene gives the substituted furanone (XVI), which is hydrogenated with H 2 over Pd/C in hot ethanol to yield 4-(2,3-dimethoxyphenyl)-2-(methoxy-carbonylamino)butyric acid (XVII). Cyclization of acid (XVII) by means of polyphosphoric acid (PPA) at 60°C affords tetralone (XVIII), which is reduced with H 2 over Pd/C in an autoclave as before to provide N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic acid methyl ester (XIX). Finally, the carbamoyl group of (XIX) is reduced with LiAlH 4 in hot THF to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-amine (V) (2). Scheme 3.