Reacción #55352

Ecuación de reacción

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

Rendimiento 56.4%

Disolventes

dimethylformamide

methylene chloride

methylene chloride

ethyl acetate

methylene chloride

methylene chloride

Condiciones de reacción

Tratamiento posterior

1. 1
   FiltraciónThe insoluble product (dicyclohexylurea) is filtered off
2. 2
   Lavadowashed with methylene chloride (2×10 cc.)
3. 3
   ConcentraciónThe filtrate is concentrated to dryness under reduced pressure
4. 4
   Otrothe residue obtained
5. 5
   Filtracióna 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
   Otrothe product which has crystallised
9. 9
   Filtraciónis filtered off
10. 10
    Lavadowashed with ethyl acetate (3×2 cc.)
11. 11
    OtroAfter drying
12. 12
    Otrothe product obtained (4.9 g.)
13. 13
    FiltraciónThe solution is filtered through silica gel (100 g.)
14. 14
    LavadoElution
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
    LavadoElution
18. 18
    workup.ADDITIONa mixture of methylene chloride and methanol (98-2 by volume; 200 cc.)
19. 19
    Concentraciónconcentrated to dryness under reduced pressure (20 mm.Hg)
20. 20
    OtroAfter recrystallisation from acetonitrile
21. 21
    Otrodrying
22. 22
    Otrois obtained
23. 23
    FiltraciónThe insoluble product is filtered off
24. 24
    Lavadowashed with water (3×10 cc.)
25. 25
    OtroAfter drying

Procedimiento

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.

Fuente