반응 #75375

반응 방정식

sodium hydroxide

thiophenol

hydrochloric acid

sodium nitrite

3-sulphamoyl-4-chloro-5-(β-chloro-β-cyanoethyl)-benzoic acid

hydrochloric acid

3-sulphamoyl-4-chloro-5-aminobenzoic acid

acrylonitrile

→

3-Sulphamoyl-4-phenylthio-5-[γ-(1-pyrrolyl)-propyl]-benzoic acid

용매

water

acetic acid

water

hexamethylphosphoric acid triamide

water

acetone

반응 조건

후처리

1. 1
   온도the resulting slurry is cooled to +3° C.
2. 2
   workup.WAITAfter a further 15 minutes
3. 3
   여과flocks are filtered off
4. 4
   온도the filtrate is cooled to +5° C., whereupon a dark resin
5. 5
   기타the supernatant solution is decanted off from the resin and latter
6. 6
   추출is extracted with sodium bicarbonate solution
7. 7
   기타the acid is precipitated
8. 8
   추출extract
9. 9
   기타For further purification
10. 10
    여과the dried ethyl acetate solution is filtered through a column
11. 11
    workup.ADDITIONcontaining 35 g of silica gel
12. 12
    기타the filtrate is evaporated in vacuo
13. 13
    workup.ADDITIONthe temperature slowly rising during the addition
14. 14
    workup.WAITAfter 20 minutes
15. 15
    온도the temperature is raised to 90°-100° for 45 minutes
16. 16
    여과the resulting suspension is then filtered
17. 17
    세척the precipitate is washed with glacial acetic acid
18. 18
    기타the filtrate is evaporated in vacuo
19. 19
    추출extracted with ethyl acetate
20. 20
    농축the resulting solution is concentrated to a smaller volume
21. 21
    기타crystallised
22. 22
    workup.ADDITIONThis compound (72 g=0.25 mol) is added, under nitrogen blanketing gas, to a thiophenolate solution
23. 23
    workup.DISSOLUTIONthe resulting suspension is dissolved
24. 24
    기타spontaneously rising to above 100°
25. 25
    기타is kept at 110°
26. 26
    온도(reflux) for a further 5 hours
27. 27
    추출extracted three times with ethyl acetate
28. 28
    기타the ethyl acetate layer is separated off
29. 29
    세척washed twice with sodium chloride solution
30. 30
    추출is twice extracted
31. 31
    workup.STIRRINGby shaking with saturated sodium bicarbonate solution
32. 32
    추출twice extracted
33. 33
    workup.STIRRINGby shaking with water (excess thiophenol
34. 34
    기타the precipitate which has separated out
35. 35
    세척the ethyl acetate layer is washed with water
36. 36
    기타dried
37. 37
    여과filtered
38. 38
    기타the filtrate is evaporated
39. 39
    기타On grinding with a little ethyl acetate, 3-sulphamoyl-4-phenylthio-5-[β-cyanoethyl]-benzoic acid
40. 40
    기타crystallises

실험 절차

The starting material is accessible by the following route: 4.8 ml of concentrated hydrochloric acid and 20 ml of water are added to 3-sulphamoyl-4-chloro-5-aminobenzoic acid (P. W. Feit, H. Bruun and C. Kaergaard-Nielsen, J. Med. Chem. 13, 1,071 (1970); 5.01 g=20 mmols) and the resulting slurry is cooled to +3° C. and diazotised with 20 ml of 1 N sodium nitrite solution at 0°-5°, after which, after a total of 30 minutes, a solution of acrylonitrile (1.4 g=1.74 ml=26 mmols) in acetone (25 ml) is added to the suspension, which has become mobile, and solid CuCl2.2H2O (1 g) is added to the resulting yellow solution, carefully at first and then all at once, and the mixture is heated slowly to 35° C., with vigorous stirring, whereupon a vigorous evolution of nitrogen starts fairly suddenly; this has ended after about 15 minutes. After a further 15 minutes, flocks are filtered off and the filtrate is cooled to +5° C., whereupon a dark resin settles on the base of the flask, the supernatant solution is decanted off from the resin and latter is ground with 30 ml of water. After it has been taken up in 200 ml of ethyl acetate the acid is extracted with sodium bicarbonate solution and the acid is precipitated by acidifying the extract and is taken up in ethyl acetate again. For further purification, the dried ethyl acetate solution is filtered through a column containing 35 g of silica gel, the filtrate is evaporated in vacuo and the residue is further processed. The above crude product comprising 3-sulphamoyl-4-chloro-5-(β-chloro-β-cyanoethyl)-benzoic acid (2.7 g=8.35 mmols) is dissolved in glacial acetic acid and a total of 1.5 g of zinc dust is added in portions at room temperature, with stirring, the temperature slowly rising during the addition. After 20 minutes, the temperature is raised to 90°-100° for 45 minutes, the resulting suspension is then filtered and the precipitate is washed with glacial acetic acid and the filtrate is evaporated in vacuo. The residue is acidified with hydrochloric acid and extracted with ethyl acetate and the resulting solution is concentrated to a smaller volume and crystallised. The resulting 3-sulphamoyl-4-chloro-5-(β-cyanoethyl)-benzoic acid melts at 224°-228° C. This compound (72 g=0.25 mol) is added, under nitrogen blanketing gas, to a thiophenolate solution prepared from solid sodium hydroxide (25 g=0.625 mol), water (30 ml) and thiophenol (68.8 g=63.7 ml=0.625 mol) and the resulting suspension is dissolved by adding 150 ml of hexamethylphosphoric acid triamide, the temperature spontaneously rising to above 100°. The mixture is kept at 110° (reflux) for a further 5 hours and is then poured into 300 ml of water, rendered strongly acid (Congo red) with 6 N hydrochloric acid and extracted three times with ethyl acetate, the ethyl acetate layer is separated off and washed twice with sodium chloride solution and is twice extracted by shaking with saturated sodium bicarbonate solution and twice extracted by shaking with water (excess thiophenol remains in the ethyl acetate phase), the combined bicarbonate and water phases are acidified, the precipitate which has separated out is again taken up in ethyl acetate, the ethyl acetate layer is washed with water, dried and filtered and the filtrate is evaporated. On grinding with a little ethyl acetate, 3-sulphamoyl-4-phenylthio-5-[β-cyanoethyl]-benzoic acid crystallises; pale yellow crystals from ethyl acetate/ether, melting point 179°-181° C.

출처