Reaktion #50321

Reaktionsgleichung

sodium isopropoxide

sodium isopropoxide

THF

3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride

3-Chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride

THF

sodium bicarbonate

→

title compound

5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid

Lösungsmittel

heptane

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeTo a 12 L 3-necked round-bottomed flask fitted with a mechanical stirrer
2. 2
   Sonstigeto rise to 60° C
3. 3
   Waschenis rinsed with THF (275 mL)
4. 4
   workup.ADDITIONthe rinse is added to the 12 L reaction flask
5. 5
   TemperaturThe mixture is heated
6. 6
   Temperaturunder reflux for 7 hours
7. 7
   TemperaturAfter cooling to 5° C. to 10° C.
8. 8
   workup.ADDITIONconcentrated hydrochloric acid (85 mL) is added
9. 9
   workup.STIRRINGthe dark mixture stirred for 1 hour
10. 10
    Sonstigeto give a final pH of 1.5
11. 11
    FiltrationThe reaction is filtered
12. 12
    Filtrationthrough filter paper
13. 13
    Waschenthe filter cake is washed with THF (200 mL)
14. 14
    workup.ADDITIONThe clear filtrates are charged to a 12 L 3-necked round-bottomed flask
15. 15
    Sonstigefitted with a mechanical stirrer
16. 16
    Temperatura thermometer, and a distillation head with reflux condenser
17. 17
    workup.DISTILLATIONTHF is distilled out of the flask under low vacuum to a batch temperature of 50° C
18. 18
    workup.ADDITIONHeptane (3.1 L) is charged to the flask
19. 19
    Temperaturthe slurry is cooled to 5° C.
20. 20
    Filtrationfiltered
21. 21
    Filtrationthrough filter paper
22. 22
    WaschenThe filter cake is washed with heptane (300 mL)
23. 23
    Waschenthe combined filtrates are washed with a sodium bicarbonate solution (3×390 mL)
24. 24
    Sonstigeprepared
25. 25
    Sonstigefitted with a mechanical stirrer
26. 26
    Temperatura thermometer, and a distillation head with reflux condenser
27. 27
    workup.DISTILLATIONheptane is distilled out of the flask under low vacuum to a batch temperature of 70° C
28. 28
    TemperaturUpon cooling
29. 29
    workup.ADDITIONIPA (815 mL) and a solution of potassium hydroxide (392 g) in deionized water (1570 mL) are charged to the 12 L flask
30. 30
    SonstigeThe distillation head is replaced with a reflux condenser
31. 31
    Temperaturthe dark solution is heated
32. 32
    Temperaturto reflux
33. 33
    workup.STIRRINGstirred for 4 hours
34. 34
    Temperaturcooled to room temperature
35. 35
    workup.STIRRINGstirred for 16 hours
36. 36
    workup.DISTILLATIONis distilled out at atmospheric pressure to a batch temperature of 95° C
37. 37
    workup.ADDITIONDeionized water (1570 mL) is added to the solution which
38. 38
    Temperaturis then cooled to 5° C. to 10° C.
39. 39
    ExtraktionThe aqueous solution is extracted with methyl isobutyl ketone (MIBK) (2×500 mL)
40. 40
    Extraktionthe combined MIBK extracts are extracted with deionized water (300 mL)
41. 41
    workup.STIRRINGstirred with PWA carbon (50 g) at room temperature for 16 hours
42. 42
    FiltrationThe solution is filtered
43. 43
    Filtrationthrough filter paper
44. 44
    Waschenthe filter cake is washed with deionized water (2×300 mL)
45. 45
    SonstigeThe pale yellow filtrates are transferred to a 12 L 3-necked round-bottomed flask
46. 46
    Sonstigefitted with a mechanical stirrer
47. 47
    TemperaturWith agitation, the solution is cooled to 5° C. to 10° C.
48. 48
    workup.ADDITIONconcentrated hydrochloric acid (70 mL) is added
49. 49
    Sonstigeto give a final pH of 2
50. 50
    workup.STIRRINGThe slurry is stirred for 2 hours at 5° C. to 10° C.
51. 51
    Sonstigethe crude product is collected
52. 52
    Filtrationon filter paper
53. 53
    Waschenwashed with deionized water (3×400 mL)
54. 54
    SonstigeThe off-white product is dried in a vacuum oven at 50° C.

Vorschrift

To a 12 L 3-necked round-bottomed flask fitted with a mechanical stirrer, a thermometer, an addition funnel and a reflux condenser with a nitrogen inlet are charged 3-chloro-5-methoxybenzo[b]thiophene-2-carbonyl chloride (Example 1) (336 g) and THF (2.3 L). The solution of sodium isopropoxide from above is charged to the THF solution of the acid chloride in four portions causing the temperature of the reaction mixture to rise to 60° C. The flask which contains the sodium isopropoxide is rinsed with THF (275 mL) and the rinse is added to the 12 L reaction flask. The mixture is heated under reflux for 7 hours and then cooled to room temperature and stirred for 12 hours. After cooling to 5° C. to 10° C., concentrated hydrochloric acid (85 mL) is added and the dark mixture stirred for 1 hour to give a final pH of 1.5. The reaction is filtered through filter paper and the filter cake is washed with THF (200 mL). The clear filtrates are charged to a 12 L 3-necked round-bottomed flask fitted with a mechanical stirrer, a thermometer, and a distillation head with reflux condenser and THF is distilled out of the flask under low vacuum to a batch temperature of 50° C. Heptane (3.1 L) is charged to the flask and the slurry is cooled to 5° C. and filtered through filter paper. The filter cake is washed with heptane (300 mL) and the combined filtrates are washed with a sodium bicarbonate solution (3×390 mL) prepared by dissolving sodium bicarbonate (47 g) in deionized water (1170 mL). The heptane solution is charged to a 12 L 3-necked round-bottomed flask fitted with a mechanical stirrer, a thermometer, and a distillation head with reflux condenser and heptane is distilled out of the flask under low vacuum to a batch temperature of 70° C. Upon cooling, IPA (815 mL) and a solution of potassium hydroxide (392 g) in deionized water (1570 mL) are charged to the 12 L flask. The distillation head is replaced with a reflux condenser and the dark solution is heated to reflux and stirred for 4 hours and then cooled to room temperature and stirred for 16 hours. The reflux condenser is again replaced with a distillation head and IPA is distilled out at atmospheric pressure to a batch temperature of 95° C. Deionized water (1570 mL) is added to the solution which is then cooled to 5° C. to 10° C. and adjusted to pH 8 using concentrated hydrochloric acid (480 mL). The aqueous solution is extracted with methyl isobutyl ketone (MIBK) (2×500 mL) and the combined MIBK extracts are extracted with deionized water (300 mL). The aqueous solutions are combined and stirred with PWA carbon (50 g) at room temperature for 16 hours. The solution is filtered through filter paper coated with supercel and the filter cake is washed with deionized water (2×300 mL). The pale yellow filtrates are transferred to a 12 L 3-necked round-bottomed flask fitted with a mechanical stirrer and a thermometer. With agitation, the solution is cooled to 5° C. to 10° C. and concentrated hydrochloric acid (70 mL) is added to give a final pH of 2. The slurry is stirred for 2 hours at 5° C. to 10° C. and the crude product is collected on filter paper and washed with deionized water (3×400 mL). The off-white product is dried in a vacuum oven at 50° C. to afford 215.1 g of the title compound; High Pressure Liquid Chromatography (HPLC): 99.72% (w/w); 98.93% (by area).

Quelle