Isatin → HCID 58224171, compound

HRID 2095083Notes

Reaction equation

HRID 2095083 reaction equation
[CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C([Mg]Cl)(C)C.[NH:16]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[C:17]1=[O:18].[Cl-].[NH4+]>O.O1CCCC1>[OH:20][C:19]1([C:8]2[C:7]([OH:10])=[CH:6][C:4]3[O:5][CH2:1][O:2][C:3]=3[CH:9]=2)[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][C:17]1=[O:18]

Participants

7

Reactant 4

HCID 7054IsatinHCID 25517Ammonium ChlorideHCID 68289SesamolHCID 178418918HCID 178418918, compound

Product 1

HCID 58224171HCID 58224171, compoundYield 103.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
2 °C

Procedure

A 630 L reactor was charged with sesamol (42.6 kg, 299 mol). Tetrahydrofuran (400 kg) was added and the resultant solution was cooled to 1° C. over 42 minutes. Isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 173 kg, 337 mol) was added over 2 h such that the internal temperature was kept between 0 and 4° C. Once the addition was complete, the internal temperature was lowered to −5° C. and isatin (37.9 kg, 250 mol) was added in four portions. The reaction mixture was stirred for 2.75 h at 1 to 3° C. A 1000 L reactor was charged with ammonium chloride (72 kg), followed by deionized water (356 kg). The mixture was stirred at 15° C. until the solid had completely dissolved and the resultant solution was cooled to 1° C. over 1 h. The contents of the 630 L reactor were transferred to the 1000 L reactor over 1 h such that the internal temperature remained between 3 and 4° C. The 630 L reactor was rinsed with toluene (133 kg) and the rinse solution added to the 1000 L reactor. The contents of the 1000 L reactor were allowed to warm to 20-25° C. over 29 minutes and were stirred for a further 15 minutes. The stirring was stopped and the contents of the reactor held at 25° C. for 15 minutes, allowing the phases to separate. The aqueous phase was removed and a solution of sodium chloride (42 kg) in deionized water (218 kg) was added over 25 minutes at an internal temperature of 22-24° C. The stirring was stopped and the mixture held at 25° C. for 1 h, allowing the phases to separate. The organic phase was degassed for 0.5 h with nitrogen and toluene (89 kg) was added. A 300 mbar vacuum was applied to the reactor and the reactor's external temperature was set to 50-60° C. Volatile components of the mixture were removed by distillation over a period of 12 h such that 670 L of distillate were collected. The reactor's external temperature was set to 20-25° C. An orange precipitate was deposited upon cooling. Toluene (114 kg) was added and the suspension stirred for 10 minutes. The solid was collected by filtration, washed with tert-butyl methyl ether (171 kg) and heptane (85 kg) and dried at 55-60° C. under a reduced pressure of 170 to 4 mbar over a period of 10.5 h to afford 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (73.5 kg, quantitative yield) as a pale pink solid: purity (HPLC-UV at 300 nm) 99.3% a/a; 1H NMR (300 MHz, DMSO-d6) δ10.18 (s, 1H), 9.08 (s, 1H), 7.21-7.07 (m, 2H), 6.88-6.74 (m, 3H), 6.38 (br s, 1H), 6.23 (s, 1H), 5.92 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 148.4, 146.6, 143.0, 139.4, 133.2, 128.6, 123.8, 121.1, 120.1, 109.0, 106.8, 100.8, 97.4, 75.1.

Workup

  1. customwas kept between 0 and 4° C
  2. additionOnce the addition
  3. customwas lowered to −5° C.
  4. stirringThe mixture was stirred at 15° C. until the solid
  5. dissolutionhad completely dissolved
  6. waitThe contents of the 630 L reactor were transferred to the 1000 L reactor over 1 h such that the internal temperature
  7. customremained between 3 and 4° C
  8. washThe 630 L reactor was rinsed with toluene (133 kg)
  9. additionthe rinse solution added to the 1000 L reactor
  10. temperatureto warm to 20-25° C. over 29 minutes
  11. stirringwere stirred for a further 15 minutes
  12. waitthe contents of the reactor held at 25° C. for 15 minutes
  13. customto separate
  14. customThe aqueous phase was removed
  15. additiona solution of sodium chloride (42 kg) in deionized water (218 kg) was added over 25 minutes at an internal temperature of 22-24° C
  16. waitthe mixture held at 25° C. for 1 h
  17. customto separate
  18. customThe organic phase was degassed for 0.5 h with nitrogen and toluene (89 kg)
  19. additionwas added
  20. customwas set to 50-60° C
  21. customVolatile components of the mixture were removed by distillation over a period of 12 h such that 670 L of distillate
  22. customwere collected
  23. customwas set to 20-25° C
  24. temperatureupon cooling
  25. additionToluene (114 kg) was added
  26. stirringthe suspension stirred for 10 minutes
  27. filtrationThe solid was collected by filtration
  28. washwashed with tert-butyl methyl ether (171 kg) and heptane (85 kg)
  29. customdried at 55-60° C. under a reduced pressure of 170 to 4 mbar over a period of 10.5 h

Sources & evidence

ORD record
ord-7fe20802a30547bfa04bf16166e62d68
Source dataset
uspto-grants-2013_05
Patent number
US08445696B2

Reaction notes

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