Реакция #1009350

Уравнение реакции

isopropylamine

AcOH

t-BuOK

ethyl formate

ethyl 4-chlorophenylacetate

hydrochloric acid

(Boc)2O

triethylamine

citric acid

water

→

(E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate

Выход 63.0%

Растворители

MTBE

MTBE

DMF

DMF

MTBE

Условия реакции

Обработка

1. 1
   workup.ADDITIONwas added
2. 2
   Температураwhile maintaining the internal temperature below 5° C
3. 3
   workup.STIRRINGThe mixture was stirred between 0-10° C. for 1.5 h
4. 4
   Температураmaintaining the internal temperature below 10° C
5. 5
   workup.STIRRINGThe mixture was stirred for 30 min between 0-10° C. until a final pH=2
6. 6
   ДругоеThe layers were separated
7. 7
   Промывкаthe organic layer was washed with 25% NaCl solution (496 L)
8. 8
   ТемператураThe mixture was cooled to −5° C.
9. 9
   Температураmaintaining the temperature <10° C
10. 10
    workup.STIRRINGThe mixture was stirred for 3 h at 0-10° C.
11. 11
    Промывкаthe organic layer was washed with H2O (760 L), 15% aqueous Na2CO3 (424 L)
12. 12
    ДругоеThe aqueous layer was separated
13. 13
    ТемператураThe mixture was then heated to 60-65° C.
14. 14
    workup.STIRRINGAfter stirring ˜6 h
15. 15
    Температураthe mixture was cooled to room temperature
16. 16
    ДругоеThe aqueous layer was separated
17. 17
    Промывкаthe mixture was washed by 25% aqueous NaCl (984 L)
18. 18
    КонцентрированиеThe organic layer was then concentrated via distillation to a minimum working volume (˜240 L)
19. 19
    Температураwhile maintaining the temperature below 50° C
20. 20
    workup.STIRRINGThe organic layer was then stirred for 5 h at 0-5° C.
21. 21
    Фильтрацияfiltered
22. 22
    ПромывкаThe filter cake was washed with heptane (20.6 L)
23. 23
    Другоеdried

Методика

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.

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