Benzoyl isothiocyanate → (+/-)-(4aR*,8aS*)-8a-(2,2-difluorobenzo[1,3]dioxol-4-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine

HRID 218004Notes

Reaction equation

HRID 218004 reaction equation
C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@:13]1([C:21]2[C:29]3[O:28][C:27]([F:31])([F:30])[O:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)[C@H:18]([CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14]1>ClCCl>[F:30][C:27]1([F:31])[O:26][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C@@:13]34[N:12]=[C:10]([NH2:9])[S:11][CH2:19][C@@H:18]3[CH2:17][CH2:16][O:15][CH2:14]4)[C:29]=2[O:28]1

Participants

4

Reactant 2

HCID 68284Benzoyl isothiocyanateHCID 58405977(+/-)-[(3S*,4R*)-3-amino-3-(2,2-difluorobenzo[1,3]dioxol-4-yl)tetrahydropyran-4-yl]methanol

Product 1

HCID 58405987(+/-)-(4aR*,8aS*)-8a-(2,2-difluorobenzo[1,3]dioxol-4-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Benzoyl isothiocyanate (372 μl) was added to a solution of (±)-[(3S*,4R*)-3-amino-3-(2,2-difluorobenzo[1,3]dioxol-4-yl)tetrahydropyran-4-yl]methanol (661 mg) in dichloromethane (9.53 ml). The mixture was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in methanol (20 ml). Concentrated hydrochloric acid (five drops) was added and the mixture was heated under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml) and DBU (700 μl) was added, followed by heating under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (350 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43-1.48 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J=2.8, 12.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.98 (dd, J=4.4, 12.4 Hz, 1H), 3.69 (ddd, J=2.4, 11.6, 12.8 Hz, 1H), 3.79 (d, 11.2 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 4.10 (dd, J=5.2, 11.2 Hz, 1H) 6.99 (dd, J=2.0, 7.2 Hz, 1H), 7.03-7.09 (m, 2H).

Workup

  1. customthe solvent was evaporated under reduced pressure
  2. customThe residue was purified by silica gel column chromatography
  3. dissolutionThe resulting intermediate was dissolved in methanol (20 ml)
  4. additionConcentrated hydrochloric acid (five drops) was added
  5. temperaturethe mixture was heated
  6. temperatureunder reflux for five hours
  7. temperatureThe reaction solution was cooled to room temperature
  8. customthe solvent was evaporated under reduced pressure
  9. dissolutionThe residue was dissolved in methanol (20 ml)
  10. additionDBU (700 μl) was added
  11. temperatureby heating
  12. temperatureunder reflux for five hours
  13. temperatureThe reaction solution was cooled to room temperature
  14. customthe solvent was evaporated under reduced pressure
  15. customThe residue was purified by NH-silica gel column chromatography

Sources & evidence

ORD record
ord-619705392ac4487eb6249955d93b6051
Source dataset
uspto-grants-2012_06
Patent number
US08198269B2

Reaction notes

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