Reacción #489508

Ecuación de reacción

cesium carbonate

chloroiodomethane

tetrahydrofuran

3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

→

2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Rendimiento 63.0%

Disolventes

N,N-dimethylformamide

N,N-dimethylformamide

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawas maintained between 0 and 5° C
2. 2
   Temperaturaheated at 20-25° C. for 18.5 h
3. 3
   FiltraciónThe mixture was filtered
4. 4
   Filtraciónfiltered again
5. 5
   Concentraciónconcentrated to a volume of 110 L under reduced pressure at a temperature <60° C
6. 6
   TemperaturaThe mixture was cooled to 20-25° C.
7. 7
   Otropurified water (1200.8 kg)
8. 8
   workup.ADDITIONwas added at a rate of 343.1 kg/h
9. 9
   TemperaturaThe mixture was cooled to 0-5° C.
10. 10
    Filtraciónfiltered
11. 11
    Filtraciónfiltered
12. 12
    Secadodried at a temperature <60° C. until the water content
13. 13
    workup.ADDITIONA 200 L reactor was charged with tetrahydrofuran (98.0 kg)
14. 14
    FiltraciónThe partially-dried filter cake (−11.0 kg)
15. 15
    workup.ADDITIONwas added to the 200 L reactor by means of a solid addition funnel
16. 16
    TemperaturaThe mixture was heated
17. 17
    Temperaturaat reflux for 4.5 h
18. 18
    Temperaturacooled to 10-15° C.
19. 19
    workup.STIRRINGstirred for 3.5 h at 10-15° C
20. 20
    FiltraciónThe mixture was filtered
21. 21
    Lavadothe filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg)
22. 22
    Otrodried in a tray dryer at a temperature <55° C.

Procedimiento

A 2000 L stainless steel crystallizer was charged with N,N-dimethylformamide (113.7 kg) and tetrahydrofuran (1070.9 kg). The contents were cooled to 0-5° C. and 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (12.0 kg, 42.4 mol) was added, followed by cesium carbonate (30.4 kg, 93.3 mol). A solution of chloroiodomethane (9.4 kg, 53.7 mol) in N,N-dimethylformamide (16.9 kg) was added at a rate of 39.5 kg/h such that the temperature of the reaction mixture was maintained between 0 and 5° C. The reaction mixture was stirred at 0-5° C. for 2 h and heated at 20-25° C. for 18.5 h. The mixture was filtered and the filter cake was suspended in tetrahydrofuran (26.4 kg) and filtered again. The combined filtrates were combined and concentrated to a volume of 110 L under reduced pressure at a temperature <60° C. The mixture was cooled to 20-25° C. and purified water (1200.8 kg) was added at a rate of 343.1 kg/h. The mixture was cooled to 0-5° C. and filtered. The filter cake was suspended in water (310.5 kg), filtered and dried at a temperature <60° C. until the water content was 10.6% by weight by Karl-Fisher titration. A 200 L reactor was charged with tetrahydrofuran (98.0 kg). The partially-dried filter cake (−11.0 kg) was added to the 200 L reactor by means of a solid addition funnel. The mixture was heated at reflux for 4.5 h, cooled to 10-15° C. and stirred for 3.5 h at 10-15° C. The mixture was filtered and the filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg) and dried in a tray dryer at a temperature <55° C. to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (6.88 kg, 63%) as a pale yellow solid: purity (HPLC-UV at 210 nm) 98.3%; mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.58 (br s, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.47 (s, 1H), 6.16 (s, 1H), 4.74, 4.60 (ABq, JAB=9.2 Hz, 2H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 178.4, 154.7, 144.0, 141.8, 137.8, 132.6, 128.7, 123.8, 122.3, 121.5, 111.1, 109.8, 98.7, 79.5, 64.2, 63.6, 57.7; MS (ES+) m/z 295.9 (M+1).

Fuente