반응 #55352

반응 방정식

acrylic acid

N,N'-dicyclohexylcarbodiimide

6-(5-chloropyrid-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine

→

5-(4-acryloylpiperazin-1-yl)carbonyloxy-6-(5-chloropyrid-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrate

수율 56.4%

용매

dimethylformamide

methylene chloride

methylene chloride

ethyl acetate

methylene chloride

methylene chloride

반응 조건

후처리

1. 1
   여과The insoluble product (dicyclohexylurea) is filtered off
2. 2
   세척washed with methylene chloride (2×10 cc.)
3. 3
   농축The filtrate is concentrated to dryness under reduced pressure
4. 4
   기타the residue obtained
5. 5
   여과a small amount of insoluble matter is filtered off
6. 6
   workup.WAITThe filtrate is left
7. 7
   workup.WAITto stand for 18 hours at a temperature of about 20° C.
8. 8
   기타the product which has crystallised
9. 9
   여과is filtered off
10. 10
    세척washed with ethyl acetate (3×2 cc.)
11. 11
    기타After drying
12. 12
    기타the product obtained (4.9 g.)
13. 13
    여과The solution is filtered through silica gel (100 g.)
14. 14
    세척Elution
15. 15
    workup.ADDITIONa mixture of methylene chloride and methanol (99-1 by volume; 300 cc.)
16. 16
    workup.ADDITIONa mixture of methylene chloride and methanol (98-2 by volume; 300 cc.)
17. 17
    세척Elution
18. 18
    workup.ADDITIONa mixture of methylene chloride and methanol (98-2 by volume; 200 cc.)
19. 19
    농축concentrated to dryness under reduced pressure (20 mm.Hg)
20. 20
    기타After recrystallisation from acetonitrile
21. 21
    기타drying
22. 22
    기타is obtained
23. 23
    여과The insoluble product is filtered off
24. 24
    세척washed with water (3×10 cc.)
25. 25
    기타After drying

실험 절차

A solution of acrylic acid (1.19 g.) in anhydrous methylene chloride (10 cc.) followed by a solution of N,N'-dicyclohexylcarbodiimide (3.4 g.) in anhydrous methylene chloride (30 cc.) are added successively, at a temperature of about 20° C., to a suspension of 6-(5-chloropyrid-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (5.6 g.) in anhydrous methylene chloride (100 cc.). The mixture is stirred for 1 hour at a temperature of about 20° C. The insoluble product (dicyclohexylurea) is filtered off and washed with methylene chloride (2×10 cc.). The filtrate is concentrated to dryness under reduced pressure and then the residue obtained is taken up in ethyl acetate (25 cc.) and a small amount of insoluble matter is filtered off. The filtrate is left to stand for 18 hours at a temperature of about 20° C. and the product which has crystallised is filtered off and washed with ethyl acetate (3×2 cc.). After drying, the product obtained (4.9 g.) is dissolved in methylene chloride (100 cc.). The solution is filtered through silica gel (100 g.) contained in a column of diameter 3 cm. Elution is carried out using pure methylene chloride (400 cc.), a mixture of methylene chloride and methanol (99-1 by volume; 300 cc.) and a mixture of methylene chloride and methanol (98-2 by volume; 300 cc.). These eluates are discarded. Elution is then carried out using a mixture of methylene chloride and methanol (98-2 by volume; 200 cc.) and the corresponding eluates are combined and concentrated to dryness under reduced pressure (20 mm.Hg). After recrystallisation from acetonitrile and drying, a product (2.3 g.), which is solvated with acetonitrile, is obtained. This product is dissolved in dimethylformamide (37 cc.) at a temperature of about 50° C. and the solution is poured into ice-water (370 cc.). The insoluble product is filtered off and washed with water (3×10 cc.). After drying, 5-(4-acryloylpiperazin-1-yl)carbonyloxy-6-(5-chloropyrid-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrate (2.08 g.), which melts at about 202°-204° C., is obtained.

출처