Pyridine → HCID 23653609, compound

HRID 423213Notes

Reaction equation

HRID 423213 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14].N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:26]=1)[O:7][CH2:8][C:9]1[N:25]=[CH:24][CH:23]=[CH:22][C:10]=1/[C:11]/2=[C:12](\[C:15]1[CH:16]=[C:17]([NH:21][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[CH:19][CH:20]=1)/[CH2:13][CH3:14]

Participants

5

Reactant 3

HCID 1049PyridineHCID 31297Methanesulfonyl chlorideHCID 59242946HCID 59242946, compound

Product 1

HCID 23653609HCID 23653609, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. (E)-3-[1-(8-chloro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1800 g, 4.96 mol) (prepared essentially as described for Intermediate 10 using the Alternate Procedure) dichloromethane (18 L) and pyridine (588.5 g, 7.44 mol) are added to the flask. The reaction mixture is cooled to 0 to 5° C. and neat methanesulfonyl chloride (681.8 g, 5.952 mol) is added dropwise over about 20-30 min, maintaining the temperature ≦5° C. After the addition is complete, the reaction mixture is stirred at 0 to 5° C. for one hour. The cooling bath is removed and the reaction stirred at room temperature for a minimum of 12 h. The progress of the reaction is followed by TLC (straight EtOAc). Once the reaction is deemed complete, the reaction mixture is washed with a 10% aqueous citric acid solution (14 L) using a 40 L separatory funnel. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 10% aqueous citric acid solution (2 L). The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a 15% aqueous sodium chloride solution (5 L) and the aqueous layer back extracted with dichloromethane (1.5 L). The combined organic layers are washed with a half saturated aqueous sodium bicarbonate solution (5 L). The sodium bicarbonate wash should be performed for a minimum of 30 min. The aqueous layer is back extracted with dichloromethane (1.5 L). The combined organic layers are dried over sodium sulfate and filtered. A 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet, thermocouple and drying tube placed in a cooling tub. The dichloromethane solution containing the product is charged to the flask, followed by trithiocyanuric acid, trisodium salt (630 g, 0.35 g/g of starting material), sodium sulfate (3.6 kg, 2 g/g of starting material) and charcoal (180 g, 0.1 g/g of starting material) to the flask. The suspension is stirred for 12 h at room temperature. The suspension is filtered and the filter cake slurried with dichloromethane (3×3 L). The filtrates are combined and concentrated to an off white solid. The product is dried in a vacuum oven at 40° C. overnight.

Workup

  1. customthermocouple and drying tube
  2. additionare added to the flask
  3. temperaturemaintaining the temperature ≦5° C
  4. additionAfter the addition
  5. customThe cooling bath is removed
  6. stirringthe reaction stirred at room temperature for a minimum of 12 h
  7. washthe reaction mixture is washed with a 10% aqueous citric acid solution (14 L)
  8. extractionThe aqueous layer is back extracted with dichloromethane (1.5 L)
  9. washThe combined organic layers are washed with a 10% aqueous citric acid solution (2 L)
  10. extractionThe aqueous layer is back extracted with dichloromethane (1.5 L)
  11. washThe combined organic layers are washed with a 15% aqueous sodium chloride solution (5 L)
  12. extractionthe aqueous layer back extracted with dichloromethane (1.5 L)
  13. washThe combined organic layers are washed with a half saturated aqueous sodium bicarbonate solution (5 L)
  14. washThe sodium bicarbonate wash should
  15. custombe performed for a minimum of 30 min
  16. extractionThe aqueous layer is back extracted with dichloromethane (1.5 L)
  17. dry with materialThe combined organic layers are dried over sodium sulfate
  18. filtrationfiltered
  19. customA 50 L three neck round bottom flask is equipped with a mechanical stirrer, nitrogen inlet
  20. customthermocouple and drying tube
  21. additionThe dichloromethane solution containing the product
  22. additionis charged to the flask
  23. stirringThe suspension is stirred for 12 h at room temperature
  24. filtrationThe suspension is filtered
  25. concentrationconcentrated to an off white solid
  26. customThe product is dried in a vacuum oven at 40° C. overnight

Sources & evidence

ORD record
ord-5c42b70184a54e23a0fcd3a7332ac85f
Source dataset
uspto-grants-2012_01
Patent number
US08101760B2

Reaction notes

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