Acetic Acid → HCID 118084365, compound

Temperature

22.5 °C

Into a solution of ethyl formate (123.9 L, 1538.9 mol) in MTBE (189 L) was added ethyl 4-chlorophenylacetate (120 kg, 604.1 mol). The mixture was stirred at 15-30° C. for 30 min and then a mixture of t-BuOK (136.8 kg, 1219.1 mol) in MTBE (1215.8 L) was added while maintaining the internal temperature below 5° C. The mixture was stirred between 0-10° C. for 1.5 h. The reaction mixture was added to an aqueous solution of hydrochloric acid (35%, 99.8 L in 560 L H2O) maintaining the internal temperature below 10° C. The mixture was stirred for 30 min between 0-10° C. until a final pH=2 was observed. The layers were separated and the organic layer was washed with 25% NaCl solution (496 L). The mixture was cooled to −5° C. and then isopropylamine (107.2 L, 1251.9 mol) and AcOH (70.5 L, 1233.3 mol) were slowly added maintaining the temperature <10° C. The mixture was stirred for 3 h at 0-10° C. and then the organic layer was washed with H2O (760 L), 15% aqueous Na2CO3 (424 L) and then 25% aqueous NaCl (650 L). The aqueous layer was separated and DMF (443 L) and DMAP (14.4 kg. 117.9 mol) were added to the organic solution. The mixture was then heated to 60-65° C. followed by slow addition of (Boc)2O (951.6 L, 4142 mol), DMF (228.6 L) and triethylamine (263.0 L, 1821.8 mol) over 24 h. After stirring ˜6 h, the mixture was cooled to room temperature and MTBE (1434 L), water (1010 L) and 10% aqueous citric acid (938 L) were added. The aqueous layer was separated and the mixture was washed by 25% aqueous NaCl (984 L). The organic layer was then concentrated via distillation to a minimum working volume (˜240 L) while maintaining the temperature below 50° C. The organic layer was then stirred for 5 h at 0-5° C. and filtered. The filter cake was washed with heptane (20.6 L) and dried to afford (E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (148.55 kg, 63% yield over three steps) as a white solid.

1. additionwas added
2. temperaturewhile maintaining the internal temperature below 5° C
3. stirringThe mixture was stirred between 0-10° C. for 1.5 h
4. temperaturemaintaining the internal temperature below 10° C
5. stirringThe mixture was stirred for 30 min between 0-10° C. until a final pH=2
6. customThe layers were separated
7. washthe organic layer was washed with 25% NaCl solution (496 L)
8. temperatureThe mixture was cooled to −5° C.
9. temperaturemaintaining the temperature <10° C
10. stirringThe mixture was stirred for 3 h at 0-10° C.
11. washthe organic layer was washed with H2O (760 L), 15% aqueous Na2CO3 (424 L)
12. customThe aqueous layer was separated
13. temperatureThe mixture was then heated to 60-65° C.
14. stirringAfter stirring ˜6 h
15. temperaturethe mixture was cooled to room temperature
16. customThe aqueous layer was separated
17. washthe mixture was washed by 25% aqueous NaCl (984 L)
18. concentrationThe organic layer was then concentrated via distillation to a minimum working volume (˜240 L)
19. temperaturewhile maintaining the temperature below 50° C
20. stirringThe organic layer was then stirred for 5 h at 0-5° C.
21. filtrationfiltered
22. washThe filter cake was washed with heptane (20.6 L)
23. customdried

ORD record

ord-5784f73acd9947eeac7e5fb733f6841e

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278917B2