反应详情

温度

-5 °C

A 0.5-1, 5-necked, round-bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel and a nitrogen inlet/outlet was charged with diisopropylamine (45.52 g) and tetrahydrofuran (175 ml). After cooling to -5° C., a 2.49 m solution of freshly titrated n-butyllithium in hexanes (176.7 ml) was added while maintaining the temperature at -5° C. to 21° C. This mixture was allowed to stir at 21° C. for 45 minutes and was then cooled to -5° C. This cooled solution was added to a tetrahydrofuran (700 ml, -5° C.) slurry of [R-(R*,R*)]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-α-aminoacetamide monohydrate (50 g) and lithium chloride (57.21 g, was dried in vacuo at 130° C. for 6 hours and then at 100° C. for 18 hours prior to use) maintaining the temperature in the range -7° to 7° C. After the addition was complete, the mixture was stirred for an additional hour at 0° to 3° C. 2-(3-Iodopropyl)-1,3-dioxolane (51.72 g) was added to the reaction mixture as a tetrahydrofuran (50 ml) solution over 15 minutes with agitation. The reaction was stirred for 3 hours at 0° C. until it was determined to be complete (HPLC analysis). The reaction was quenched by the addition of water (450 ml) and the tetrahydrofuran/hexane phase was separated from the lower aqueous phase and set aside. The pH of the aqueous phase was adjusted from about 11 to about 8 by the addition of concentrated hydrochloric acid (10 ml) and then extracted with methylene chloride (2×250 ml). The methylene chloride phases were combined and concentrated in vacuo (bath temperature less than or equal to 40° C.) to afford [αS-[R*(1S*,2S*)]]-α-amino-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-1,3-dioxolane-2-pentanamide as an oil (60 g). The oil was dissolved in water (300 ml) with heating and was refluxed for 12 hours until it was judged to be complete (HPLC analysis). After cooling, the reaction mixture was extracted with methylene chloride (2×250 ml) and the rich aqueous phase was concentrated in vacuo to afford the crude product as a yellow solid. The yellow solid was recrystallized from aqueous ethanol (water 75 ml, absolute ethanol 500 ml) and dried in vacuo to give 18.8 g of desired product as a white crystalline solid.

1. customA 0.5-1, 5-necked, round-bottom flask, equipped with an overhead stirrer
2. additionthermocouple, addition funnel and a nitrogen inlet/outlet
3. temperaturewhile maintaining the temperature at -5° C. to 21° C
4. temperaturewas then cooled to -5° C
5. customwas dried in vacuo at 130° C. for 6 hours
6. waitat 100° C. for 18 hours
7. temperaturemaintaining the temperature in the range -7° to 7° C
8. additionAfter the addition
9. stirringthe mixture was stirred for an additional hour at 0° to 3° C
10. addition2-(3-Iodopropyl)-1,3-dioxolane (51.72 g) was added to the reaction mixture as a tetrahydrofuran (50 ml) solution over 15 minutes with agitation
11. stirringThe reaction was stirred for 3 hours at 0° C. until it
12. customThe reaction was quenched by the addition of water (450 ml)
13. customthe tetrahydrofuran/hexane phase was separated from the lower aqueous phase
14. additionThe pH of the aqueous phase was adjusted from about 11 to about 8 by the addition of concentrated hydrochloric acid (10 ml)
15. extractionextracted with methylene chloride (2×250 ml)
16. concentrationconcentrated in vacuo (bath temperature less than or equal to 40° C.)