1-Butanol → Mono-2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl)piperazinium-1-yl]ethoxy)ethanol trans-butenedioate

HRID 2246818Notes

Reaction equation

HRID 2246818 reaction equation
Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[OH:17]CCO[CH:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22].[C:29](=[O:32])([O-:31])[O-].[K+].[K+].[I-].[K+].Cl.[CH2:38]([OH:42])[CH2:39][CH2:40]C>C(O)C.C1(C)C=CC=CC=1>[CH:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[N:3]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([CH2:21][CH2:22][O:42][CH2:38][CH2:29][OH:32])[CH2:28][CH2:27]3)[C:8]=2[CH:9]=1.[CH:39](/[C:38]([OH:42])=[O:17])=[CH:40]\[C:29]([OH:31])=[O:32]

Participants

9

Reactant 6

HCID 2631-ButanolHCID 313Hydrochloric AcidHCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 1058648111-Chlorodibenzo(b,f)(1,4)thiazepineHCID 193588281-(2-Hydroxyethoxy)ethylpiperazine

Product 1

HCID 6918224Mono-2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl)piperazinium-1-yl]ethoxy)ethanol trans-butenedioate

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 1140TolueneSolvent

Procedure

A 2 liter round bottom flask equipped with stirring rod, thermo pocket, reflux condenser and nitrogen inlet was charged with 50 gm (0.2 moles) of 11-chlorodibenzo[b,f][1,4]-thiazepine and 500 cc n-butanol and the mixture was stirred for 15 min. at room temperature. The resulting solution was combined with 39 gm (0.22 mole) of 1-(2-hydroxyethoxy)ethylpiperazine, 56.2 gm (0.40 mole) of potassium carbonate and 16.89 gm (0.10 mole) of potassium iodide. The reaction mixture was heated at gentle reflux for 12 hrs and a sample of the reaction mixture was analyzed by HPLC. The analysis revealed that starting material remains less than 1%. The reaction mixture was cooled to room temperature and treated with 1000 cc 1N hydrochloric acid solution to get a pH in between 1 to 2. The layers (aqueous and nonaqueous reaction solvent) were separated and the aqueous layer was extracted with 500 cc toluene and pH was adjusted to about 8 to 9 by addition of sodium carbonate. The layer s were separated and aqueous layer was again extracted with 500 cc toluene. The organic layers (n-butanol and toluene) were combined and washed with 2×500 cc of water. The solvent was distilled under vacuum at 70 to 80° C. to obtain an oil. To this oil 50 to 75 cc. toluene was added with 750 to 1000 cc absolute ethanol and activated carbon 5 to 6 gm, and heated to reflux for 90 min. The mixture was cooled to 55 to 60° C. and filtered. The filtrate was further cooled to 25 to 30° C. and fumaric acid 7 to 7.5 gm was added with stirring. The mixture was heated to reflux for 120 min, cooled slowly to 25 to 30° C., maintained for 120 min, filtered, and washed with 125 to 150 cc. of absolute ethanol. The wet material obtained was dried under vacuum at 50 to 60° C. to produce quetiapine fumarate (40 to 45 gm).

Workup

  1. customA 2 liter round bottom flask equipped
  2. temperaturethermo pocket, reflux condenser and nitrogen inlet
  3. stirringthe mixture was stirred for 15 min. at room temperature
  4. temperatureThe reaction mixture was heated
  5. temperatureat gentle reflux for 12 hrs
  6. customto get a pH in between 1 to 2
  7. customThe layers (aqueous and nonaqueous reaction solvent) were separated
  8. extractionthe aqueous layer was extracted with 500 cc toluene and pH
  9. additionwas adjusted to about 8 to 9 by addition of sodium carbonate
  10. customThe layer s were separated
  11. extractionaqueous layer was again extracted with 500 cc toluene
  12. washwashed with 2×500 cc of water
  13. distillationThe solvent was distilled under vacuum at 70 to 80° C.
  14. customto obtain an oil
  15. temperatureheated
  16. temperatureto reflux for 90 min
  17. temperatureThe mixture was cooled to 55 to 60° C.
  18. filtrationfiltered
  19. temperatureThe filtrate was further cooled to 25 to 30° C.
  20. additionfumaric acid 7 to 7.5 gm was added
  21. stirringwith stirring
  22. temperatureThe mixture was heated
  23. temperatureto reflux for 120 min
  24. temperaturecooled slowly to 25 to 30° C.
  25. temperaturemaintained for 120 min
  26. filtrationfiltered
  27. washwashed with 125 to 150 cc
  28. customThe wet material obtained
  29. customwas dried under vacuum at 50 to 60° C.

Sources & evidence

ORD record
ord-74a18f06174f4a8d921d3e2b0df22269
Source dataset
uspto-grants-2010_03
Patent number
US07687622B2

Reaction notes

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