2,3-Dihydroxybutanedioic Acid → (R)-N-(2-(2-(10H-phenothiazin-10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester

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Reaction Steps

A well-stirred mixture of the above alcohol (1.5 g, 5.2 mmol), triethylamine (1.8 ml) and toluene (20 ml) placed under an atmosphere of nitrogen was cooled on an ice-bath. A solution of methanesulfonyl chloride (1.5 g, 10.4 mmol) in toluene (5 ml) was added within 15 minutes. Stirring was continued for 45 minutes on an ice-bath and then for 30 minutes at room temperature. Water (15 ml) was added and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with toluene (20 ml). The combined organic extracts were washed with a 5% sodium bicarbonate solution, brine and then dried over sodium sulphate. The solvent was evaporated in vacuo to give an oil, which was dissolved in toluene (30 ml). To this solution was added potassium carbonate (2.5 g, 18.3 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (3.2 g, 10.4 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solid washed with a small portion of toluene. The solvent was evaporated from the filtrate in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate (30 ml) and water (30 ml). A 34% aqueous solution of tartaric acid was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate (15 ml). To the combined organic phases were added water (10 ml) and a 34% aqueous solution of tartaric acid (3.5 ml). The phases were separated and the organic phase was extracted with a mixture of water (10 ml) and a 34% aqueous solution of tartaric acid (2 ml). The acidic aqueous phases are combined and washed with ethyl acetate (15 ml). All the organic phases were discarded and to the acidic aqueous phase was added ethyl acetate (50 ml) and water (50 ml). A 4 N sodium hydroxide solution was added until pH 8.5 and the phases were separated. The aqueous phase was extracted with ethyl acetate (15 ml) and the combined organic phases were washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 0.8 g of (R)-N-(2-(2-(10H-phenothiazin-10-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1 ).

Provenance & Evidence