Reacción #76304

Ecuación de reacción

para ethyl (4-chloro-1-oxobutyl)benzene acetic acid

ethyl benzeneacetic acid

para ethyl (4-chloro-1-oxobutyl)benzene acetic acid

LiOH

4-chlorobutyryl chloride

AlCl3

→

(cyclopropylcarbonyl)benzeneacetic acid

Rendimiento 11.0%

Disolventes

Methylene chloride

water

ethanol

methylene chloride

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawhile maintaining the pot temperature below 10° C
2. 2
   Temperaturamaintaining the pot temperature below 100° C
3. 3
   Temperaturaheated to 40° C
4. 4
   workup.WAITAfter 4 hours
5. 5
   Temperaturathe solution is cooled to room temperature
6. 6
   workup.ADDITIONpoured
7. 7
   OtroThe organic phase is separated
8. 8
   ExtracciónThe aqueous phase is extracted with two 1 L portions of methylene chloride
9. 9
   SecadoThe combined organics are dried (MgSO4)
10. 10
    Concentraciónconcentrated
11. 11
    workup.ADDITIONToluene (1 L) is added
12. 12
    Concentraciónthe solution is concentrated to ca. 500 mL
13. 13
    workup.ADDITIONEthanol (500 mL) is added
14. 14
    TemperaturaThe solution is heated to 70° C.
15. 15
    OtroHCl (g) is bubbled through for 20 minutes
16. 16
    OtroThe solution is sparged with N2
17. 17
    Concentraciónconcentrated
18. 18
    Otrogives
19. 19
    Temperaturais cooled with an ice bath
20. 20
    workup.WAITAfter 1 hour
21. 21
    Temperaturato warm to room temperature
22. 22
    workup.WAITAfter 18 hours
23. 23
    Concentraciónthe mixture is concentrated
24. 24
    workup.ADDITIONWater (400 mL) and conc. HCl are added (until pH 4)
25. 25
    workup.ADDITIONEthyl acetate (600 mL) is added
26. 26
    OtroThe organic phase is separated
27. 27
    Lavadowashed with brine
28. 28
    Secadodried (MgSO4)
29. 29
    TemperaturaThe solution is heated on a steam bath
30. 30
    workup.ADDITIONcharcoal (ca. 3 g) is added
31. 31
    FiltraciónThe mixture is filtered through Celite
32. 32
    Concentraciónconcentrated
33. 33
    workup.DISSOLUTIONThe residue is dissolved in ethyl acetate (300 mL)
34. 34
    Temperaturaheptane (600 mL) with heating
35. 35
    workup.ADDITIONSeed crystals are added
36. 36
    TemperaturaAfter cooling an organic oil
37. 37
    workup.ADDITIONHeptane (500 mL) is added
38. 38
    Temperaturathe mixture is heated
39. 39
    Temperaturato reflux
40. 40
    workup.ADDITIONtreated with charcoal (ca. 5 g)
41. 41
    Filtraciónfiltered
42. 42
    OtroA solid forms and is collected
43. 43
    workup.ADDITION4:1 mixture of para
44. 44
    OtroRecrystallization from ethyl acetate/heptane

Procedimiento

To a slurry of AlCl3 (210 g, 1.6 mol) in methylene chloride (200 mL) cooled in an ice bath is added 4-chlorobutyryl chloride (121 g) dropwise while maintaining the pot temperature below 10° C. After 10 minutes, ethyl benzeneacetic acid (118 g, 0.72 mol) is added dropwise maintaining the pot temperature below 100° C. The mixture is stirred at room temperature for 1 hour, then heated to 40° C. After 4 hours, the solution is cooled to room temperature and poured onto crushed ice (2 L). Methylene chloride (1 L) is added. The organic phase is separated. The aqueous phase is extracted with two 1 L portions of methylene chloride. The combined organics are dried (MgSO4) and concentrated. Toluene (1 L) is added and the solution is concentrated to ca. 500 mL. Ethanol (500 mL) is added. The solution is heated to 70° C. and HCl (g) is bubbled through for 20 minutes. The solution is sparged with N2 and concentrated. Chromatography through silica gel (2.5 L) using an ethyl acetate/heptane gradient gives a 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH (23.5 g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the 1:1 mixture of meta, para ethyl (4-chloro-1-oxobutyl)benzene acetic acid (50 g, 0.19 mol). The reaction becomes exothermic and is cooled with an ice bath. After 1 hour, the solution is allowed to warm to room temperature. After 18 hours, the mixture is concentrated. Water (400 mL) and conc. HCl are added (until pH 4). Ethyl acetate (600 mL) is added. The organic phase is separated, washed with brine and dried (MgSO4). The solution is heated on a steam bath and charcoal (ca. 3 g) is added. The mixture is filtered through Celite and concentrated. The residue is dissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating. Seed crystals are added. After cooling an organic oil appears. Heptane (500 mL) is added and the mixture is heated to reflux, treated with charcoal (ca. 5 g), filtered and seeded. A solid forms and is collected. 1H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallization from ethyl acetate/heptane gives 4 (cyclopropylcarbonyl)benzeneacetic acid (4.3 g, 11%).

Fuente