Tetrahydrofuran → Spiro[furo[2,3-g]-1,4-benzodioxin-8(7H),3'-[3H]indol]-2'(1'H)-one, 2,3-dihydro

HRID 2095088Notes

Reaction equation

HRID 2095088 reaction equation
O1CCC[CH2:2]1.[OH:6][C:7]1[C:8]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2([C:8]3[C:7](=[CH:16][C:11]4[O:12][CH2:13][CH2:14][O:15][C:10]=4[CH:9]=3)[O:6][CH2:2]2)[C:18]1=[O:26]

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 10796Cesium carbonateHCID 11644ChloroiodomethaneHCID 469415943-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Product 1

HCID 58224164Spiro[furo[2,3-g]-1,4-benzodioxin-8(7H),3'-[3H]indol]-2'(1'H)-one, 2,3-dihydroYield 63%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
2.5 °C

Procedure

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) δ10.58 (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) δ178.4, 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).

Workup

  1. temperaturewas maintained between 0 and 5° C
  2. temperatureheated at 20-25° C. for 18.5 h
  3. filtrationThe mixture was filtered
  4. filtrationfiltered again
  5. concentrationconcentrated to a volume of 110 L under reduced pressure at a temperature<60° C
  6. temperatureThe mixture was cooled to 20-25° C.
  7. custompurified water (1200.8 kg)
  8. additionwas added at a rate of 343.1 kg/h
  9. temperatureThe mixture was cooled to 0-5° C.
  10. filtrationfiltered
  11. filtrationfiltered
  12. dry with materialdried at a temperature<60° C. until the water content
  13. additionA 200 L reactor was charged with tetrahydrofuran (98.0 kg)
  14. filtrationThe partially-dried filter cake (−11.0 kg)
  15. additionwas added to the 200 L reactor by means of a solid addition funnel
  16. temperatureThe mixture was heated
  17. temperatureat reflux for 4.5 h
  18. temperaturecooled to 10-15° C.
  19. stirringstirred for 3.5 h at 10-15° C
  20. filtrationThe mixture was filtered
  21. washthe filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg)
  22. customdried in a tray dryer at a temperature<55° C.

Sources & evidence

ORD record
ord-08ad615624064a699b2d85d21563305b
Source dataset
uspto-grants-2013_05
Patent number
US08445696B2

Reaction notes

Loading…