Hydrochloric Acid → HCID 67121322, compound

HRID 1805895Notes

Reaction equation

HRID 1805895 reaction equation
[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=O)O[C:8](=O)[C:4]=2[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14].[ClH:17].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:17].[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:8]2

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 6363IsopropylamineHCID 312751,4-DioxaneHCID 665904-Bromophthalic anhydride2×

Product 1

HCID 67121322HCID 67121322, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
20 °C

Procedure

5-bromo-2-benzofuran-1,3-dione (1 wt) was suspended in toluene (5 vol) with stirring under nitrogen. Isopropylamine (1.1 eq, 0.416 vol) was then added dropwise over 10-30 mins at such a rate as to maintain the temperature between 15-25° C. (exothermic addition). The batch was stirred for a further 30 mins at 15-25° C. once the addition was complete, before heating to reflux under Dean-Stark conditions. The batch was held at reflux for 5-8 hrs until residual 5-bromo-2-benzofuran-1,3-dione by HPLC is <1% a/a uncorrected, then the batch was concentrated atmospherically to ca 2.5 vols2. Added toluene (3 vols) and reconcentrated atmospherically to ca 2.5 vols. Batch then cooled to 55-60° C., diluted with THF (1.5 vols), and then further cooled to 15-25° C. This was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol) and the resultant solution was stirred at 20-30° C. for ca 30 mins. The batch was then heated to 48-52° C., and held thus for 16-24 hrs until complete by HPLC, before cooling back to 15-25° C. The reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins maintaining an internal temp of 15-30° C. (initially effervescent, evolves hydrogen). Once the addition was complete, the batch was heated to 60-63° C., and held thus for 1-1.5 hrs before cooling to 15-25° C. Ethyl acetate (6 vols) was added and the resultant biphase was shaken, settled and separated1. Organics back-extracted with 2N HCl (3 vols) before being discarded. The combined aqueous liquors were then neutralized to pH>12 with 40% w/v aq NaOH (approx 3.9 vols). Overlain with ethyl acetate (6 vols) then the resultant biphase was shaken, settled and separated. Aqueous back extracted with ethyl acetate (3 vols) before being discarded. The organics were combined and washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols. Ethyl acetate (8 vols) was added and the batch was reconcentrated in vacuo to ca 4 vols. Ethyl acetate (9 vols) was added and the batch was adjusted to 0±3° C. 4M HCl in dioxane (0.89 eq, 0.98 vol) was then added slowly maintaining the batch temp within the range 0±3° C. The batch was then aged within this range for 30 min before product was collected by vacuum filtration. Washed with chilled ethyl acetate (<5° C., 2×2 vols) and dried o/n in vacuo at 30° C. to constant weight.

Workup

  1. addition(exothermic addition)
  2. stirringThe batch was stirred for a further 30 mins at 15-25° C. once
  3. additionthe addition
  4. temperaturebefore heating
  5. temperatureto reflux under Dean-Stark conditions
  6. concentrationthe batch was concentrated atmospherically to ca 2.5 vols2
  7. temperatureBatch then cooled to 55-60° C.
  8. additiondiluted with THF (1.5 vols)
  9. temperaturefurther cooled to 15-25° C
  10. additionThis was added to a solution of borane-THF complex (1.0M, 4 eq, 14.1 vol)
  11. temperatureThe batch was then heated to 48-52° C.
  12. temperatureuntil complete by HPLC, before cooling back to 15-25° C
  13. customThe reaction was quenched inversely into aqueous hydrochloric acid (2N, 9 vol) over at least 30 mins
  14. temperaturemaintaining an internal temp of 15-30° C. (initially effervescent
  15. additionOnce the addition
  16. temperaturethe batch was heated to 60-63° C.
  17. waitheld thus for 1-1.5 hrs
  18. temperaturebefore cooling to 15-25° C
  19. additionEthyl acetate (6 vols) was added
  20. stirringthe resultant biphase was shaken
  21. extractionOrganics back-extracted with 2N HCl (3 vols)
  22. stirringOverlain with ethyl acetate (6 vols) then the resultant biphase was shaken
  23. customseparated
  24. extractionAqueous back extracted with ethyl acetate (3 vols)
  25. washwashed with saturated brine (2×2 vols)
  26. concentrationbefore being concentrated in vacuo to ca 4 vols
  27. additionEthyl acetate (8 vols) was added
  28. additionEthyl acetate (9 vols) was added
  29. customwas adjusted to 0±3° C
  30. temperaturemaintaining the batch temp within the range 0±3° C
  31. waitThe batch was then aged within this range for 30 min before product
  32. filtrationwas collected by vacuum filtration
  33. washWashed with chilled ethyl acetate (<5° C., 2×2 vols)
  34. customdried o/n in vacuo at 30° C. to constant weight

Sources & evidence

ORD record
ord-de2691f7e9e1449587e3ee1eecf1bbe9
Source dataset
uspto-grants-2013_01
Patent number
US08354539B2

Reaction notes

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