Zamicastat hydrochloride → 1-((3R)-6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-1,3-dihydro-5-(2-((phenylmethyl)amino)ethyl)-2H-imidazole-2-thione

HRID 538942Notes

Reaction equation

HRID 538942 reaction equation
Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]1[N:16]([C@@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([F:28])[CH:22]=[C:23]([F:27])[CH:24]=3)[O:19][CH2:18]2)[C:15](=[S:29])[NH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH2:2]([NH:9][CH2:10][CH2:11][C:12]1[N:16]([C@@H:17]2[CH2:26][C:25]3[C:20](=[C:21]([F:28])[CH:22]=[C:23]([F:27])[CH:24]=3)[O:19][CH2:18]2)[C:15](=[S:29])[NH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1

Participants

3

Reactant 1

HCID 25156755Zamicastat hydrochloride

Product 1

HCID 250526301-((3R)-6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-1,3-dihydro-5-(2-((phenylmethyl)amino)ethyl)-2H-imidazole-2-thioneYield 90.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
47.29999923706055 °C

Procedure

A 250 L reactor was charged with 10.22 kg of purified (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride, 113.0 kg of Methanol was added and the reaction mixture was heated to 47.3° C. with stirring at 120 rpm. A resulting clear brown solution was filtered warm through a GAF filter into a 200 L drum and the filter was flushed with 8.0 kg of Methanol. The reactor was cleaned with 45.0 kg of Methanol, the filtered Methanol solution was transferred from the 200 L drum into the 250 L reactor and the solution was heated to 46.3° C. with stirring at 120 rpm. At this temperature 23.5 kg of water was added during 10 min, the solution was heated to 64.3° C. during 60 min (reflux) and 26.1 kg of a solution of 1.2 kg sodium hydroxide in 30.6 kg water was added at 64.5-65.3° C. during 90 min (reflux; exotherm). The resulting beige suspension was stirred at 65.2-66.9° C. during 45 min, cooled 58-60° C. and sampled for pH-control (pH 11). The suspension was cooled to 24.8° C. during 1 h 55 min, stirred at this temperature during 13 h. The suspension was transferred into the centrifuge (filter cloth type: Lanz Anliker PP20) and centrifuged in one portion. The 250 L reactor was charged with 20.0 kg water and 16.0 kg of Methanol and stirred at 23.0° C. during 10 min. The filter cake was washed with the methanol mixture, the wet product (8.84 kg) was transferred to the tray dryer and dried at 52.2° C. and 290-1 mbar during 68 h 44 min to give 8.45 kg of (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione.

Workup

  1. additionwas added
  2. filtrationA resulting clear brown solution was filtered
  3. temperaturewarm through a GAF
  4. filtrationfilter into a 200 L drum
  5. customthe filter was flushed with 8.0 kg of Methanol
  6. temperaturethe solution was heated to 46.3° C.
  7. stirringwith stirring at 120 rpm
  8. additionAt this temperature 23.5 kg of water was added during 10 min
  9. temperaturethe solution was heated to 64.3° C. during 60 min
  10. temperature(reflux) and 26.1 kg of a solution of 1.2 kg sodium hydroxide in 30.6 kg water
  11. additionwas added at 64.5-65.3° C. during 90 min
  12. temperature(reflux; exotherm)
  13. stirringThe resulting beige suspension was stirred at 65.2-66.9° C. during 45 min
  14. temperaturecooled 58-60° C.
  15. aliquotsampled for pH-control (pH 11)
  16. temperatureThe suspension was cooled to 24.8° C. during 1 h 55 min
  17. stirringstirred at this temperature during 13 h
  18. filtrationThe suspension was transferred into the centrifuge (filter cloth type: Lanz Anliker PP20)
  19. additionThe 250 L reactor was charged with 20.0 kg water and 16.0 kg of Methanol
  20. stirringstirred at 23.0° C. during 10 min
  21. washThe filter cake was washed with the methanol mixture
  22. customdried at 52.2° C.

Sources & evidence

ORD record
ord-818c0253bacb4af4be8e2f0da4f96473
Source dataset
uspto-grants-2014_10
Patent number
US08865913B2

Reaction notes

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