Acetic Acid → 312904-18-0

Temperature

2.5 °C

In a 4 l 4-necked round bottom flask equipped with a thermometer, a mechanical stirrer, a Claisen condenser and an inert gas supply 278.0 g of (3R,4R,5S)-5-allylamino-4-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester obtained according to (d) were dissolved at room temperature with stirring under argon in 2800 ml of tert.-butyl methyl ether. From the red solution 1400 ml of tert.-butyl methyl ether were distilled. Again 1400 ml of tert.-butyl methyl ether were added and distilled off. The red solution was cooled to 0-5° C. and treated with 512 ml of acetic acid (9.0 mol) whereby the temperature rose to about 23° C. After cooling to 0° C.-5° C. 58.1 ml of methanesulfonic acid (d=1.482, 0.90 mol) were added dropwise in the course of 27 min followed by 84.7 ml of acetic anhydride (d=1.08, 0.90 mol) added dropwise in the course of 40 min keeping the temperature in the range of 0° C. to 5° C. The brown reaction mixture was stirred without cooling for 14 h then treated with vigorous stirring with 1400 ml of water (deionized) for 30 min and the brown organic phase was extracted with 450 ml of 1M aqueous methanesulfonic acid. The combined aqueous phases (pH=1.6) were treated with stirring with about 694 ml of 50% aqueous potassium hydroxide until pH=10.0 was reached, keeping the temperature in the range of 10 to 25° C. The brown, turbid mixture was extracted first with 1000 ml then with 400 ml, in total with 1400 ml of tert.-butyl methyl ether, the combined organic extracts were stirred over 32 g of charcoal and filtered. The filter cake was washed with about 200 ml tert.-butyl methyl ether and the combined filtrates were evaporated in a rotary evaporator at 47° C./380 to 10 mbar to yield 285.4 g of brown-red, amorphous crystals which were dissolved with stirring in a mixture of 570 ml of tert.-butyl methyl ether and 285 ml of n-hexane at 50° C. The brown solution was cooled in 45 min with stirring to −20° C. to −25° C. and stirred for 5 h whereby brown crystals precipitated. The suspension was filtered over a pre-cooled (−20° C.) glass filter funnel and the filter cake was washed with a pre-cooled (−20° C.) mixture of 285 ml of tert.-butyl methyl ether and 143 ml of n-hexane and dried in a rotary evaporator at 48° C.<10 mbar to yield 200.33 g (83%) of (3R,4R,5S)-4-acetylamino-5-allylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid ethyl ester; m.p. 100.2° C.-104.2° C.

1. dissolutionwere dissolved at room temperature
2. distillationFrom the red solution 1400 ml of tert.-butyl methyl ether were distilled
3. additionAgain 1400 ml of tert.-butyl methyl ether were added
4. distillationdistilled off
5. customrose to about 23° C
6. temperatureAfter cooling to 0° C.-5° C
7. additionadded dropwise in the course of 40 min
8. customin the range of 0° C. to 5° C
9. temperaturewithout cooling for 14 h
10. additionthen treated
11. extractionthe brown organic phase was extracted with 450 ml of 1M aqueous methanesulfonic acid
12. additionThe combined aqueous phases (pH=1.6) were treated
13. stirringwith stirring with about 694 ml of 50% aqueous potassium hydroxide until pH=10.0
14. customin the range of 10 to 25° C
15. extractionThe brown, turbid mixture was extracted first with 1000 ml
16. stirringwith 400 ml, in total with 1400 ml of tert.-butyl methyl ether, the combined organic extracts were stirred over 32 g of charcoal
17. filtrationfiltered
18. washThe filter cake was washed with about 200 ml tert.-butyl methyl ether
19. customthe combined filtrates were evaporated in a rotary evaporator at 47° C./380 to 10 mbar
20. customto yield 285.4 g of brown-red, amorphous crystals which
21. dissolutionwere dissolved
22. temperatureThe brown solution was cooled in 45 min
23. stirringwith stirring to −20° C. to −25° C.
24. stirringstirred for 5 h whereby brown crystals
25. customprecipitated
26. filtrationThe suspension was filtered over
27. temperaturea pre-cooled (−20° C.) glass
28. filtrationfilter funnel
29. washthe filter cake was washed with
30. temperaturea pre-cooled
31. addition(−20° C.) mixture of 285 ml of tert.-butyl methyl ether and 143 ml of n-hexane
32. customdried in a rotary evaporator at 48° C.<10 mbar

ORD record

ord-d0355d72053f44d6b40a9baa22866a3b

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07514580B2