Ethanolamine → (3R,4S,5R)-ethyl 5-amino-4-hydroxy-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate

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Reaction Conditions

Reaction Steps

In a 2.5 l 4-necked round bottom flask equipped with a reflux condenser, a thermometer, a mechanical stirrer and an inert gas supply 312.8 g of (3R,4S,5R)-5-allylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (a) were dissolved at room temperature and stirring under argon in 1560 ml of ethanol. To the clear, dark yellow solution were added 66.2 ml of ethanolamine (d=1.015, 1.10 mol) and 31.3 g of palladium on charcoal 10%. The black suspension was heated to 78° C. in the course of 25 min and refluxed for 3 h. The suspension was cooled below 40° C., filtered through a filter paper and the filter cake was washed with 100 ml of ethanol. The combined orange filtrates were cooled to 0 to 5° C., treated with 59.0 ml of sulfuric acid (d=1.83, 1.10 mol) keeping the temperature below 30° C. The yellow suspension (pH=2.5) was evaporated in a rotary evaporator at 48° C./160 to 50 mbar and the remaining oily, yellow crystals (956 g) were dissolved in 1000 ml of deionized water and the orange solution was extracted with a mixture of 500 ml of tert.-butyl methyl ether and 500 ml of n-hexane. The organic phase was extracted with 260 ml of 0.5M aqueous sulfuric acid and the combined aqueous phases (pH=2.3) were cooled to 10° C. and treated with stirring with about 128 ml of 50% aqueous potassium hydroxide until pH=9.5 was reached keeping the temperature in the range of 5° C. to 20° C. The organic phase was separated and the aqueous phase was extracted first with 1000 ml, then twice with 500 ml, in total with 2000 ml of tert.-butyl methyl ether. The combined organic extracts were dried over 1000 g of sodium sulfate and filtered. The filter cake was washed with about 300 ml of tert.-butyl methyl ether and the combined filtrates were evaporated in a rotary evaporator at 48° C./360 to 20 mbar and dried at 48° C./15 mbar for 2 h to yield crude (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (271.4 g) as a red oil containing about 4% of the 4-amino-5-hydroxy isomer.

Provenance & Evidence