Methyl iodide → Bexlosteride

HRID 1901989Notes

Reaction equation

HRID 1901989 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH3:17]I>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:17])[C:9](=[O:14])[CH2:8][CH2:7]3

Participants

4

Reactant 2

HCID 6328Methyl iodideHCID 100599928-Chloro-1,4,4a,5,6,10b-hexahydro-2H-benzo[f]quinolin-3-one

Product 1

HCID 166562BexlosterideYield 104.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Two hundred L of THF was added to a reactor, and 24.6 kg of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was added. Then 35 kg of methyl iodide was added, rinsed in with 10 L of THF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15°-25°, rinsed in with 40 L of THF. The mixture was stirred at 36°-39° for 13 hours, and was then cooled to 15°-25°. The layers were allowed to separate, and the water/THF phase was neutralized to pH 7 with hydrochloric acid and heated to reflux. Distillate was removed until the temperature reached 77°. A total of 154 kg of water was added from time to time. The solution was cooled over 3 hours to 3°-10°, and was then stirred vigorously at that temperature until solids began to form. Then the slurry was stirred gently at constant temperature for 3 hours. The slurry was filtered, and the vessel and filter cake were washed with cold water. The cake was air dried at 25°-35° for 75 hours to obtain 27.3 kg of the desired product, potency 85.1% by liquid chromatographic analysis.

Workup

  1. washrinsed in with 10 L of THF
  2. additionA 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15°-25°
  3. washrinsed in with 40 L of THF
  4. temperaturewas then cooled to 15°-25°
  5. customto separate
  6. temperatureheated to reflux
  7. customDistillate was removed until the temperature
  8. customreached 77°
  9. additionA total of 154 kg of water was added from time to time
  10. temperatureThe solution was cooled over 3 hours to 3°-10°
  11. stirringwas then stirred vigorously at that temperature until solids
  12. customto form
  13. stirringThen the slurry was stirred gently at constant temperature for 3 hours
  14. filtrationThe slurry was filtered
  15. filtrationthe vessel and filter cake
  16. washwere washed with cold water
  17. customdried at 25°-35° for 75 hours

Sources & evidence

ORD record
ord-12e15eacb75d4fd3846a92f469d63fed
Source dataset
uspto-grants-1996_11
Patent number
US05578724

Reaction notes

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