Hydroxylamine → Belinostat

HRID 239812Notes

Reaction equation

HRID 239812 reaction equation
[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.C(OC(C)C)(=O)C.S(Cl)(Cl)=O.[NH2:44][OH:45]>O>[OH:45][NH:44][C:19](=[O:21])/[CH:18]=[CH:17]/[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1.[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

8

Reactant 5

HCID 787HydroxylamineHCID 7915Isopropyl AcetateHCID 24386Thionyl ChlorideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 224924412-Propenoic acid, 3-[3-[(phenylaMino)sulfonyl]phenyl]-, (2E)-2×

Product 2

HCID 6918638BelinostatHCID 224924412-Propenoic acid, 3-[3-[(phenylaMino)sulfonyl]phenyl]-, (2E)-

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
5 °C

Procedure

To the 30 gallon (˜136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCl2) (960 mL; density ˜1.631 g/mL; 118.97 g/mol; ˜13 mol) was added to the reaction mixture and the batch was stirred at 20-30° C. overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the 30 gallon (˜136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (˜136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; ˜1.078 g/mL; 33.03 g/mol; ˜214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the 30 gallon (˜136 L) reactor and the mixture was stirred and cooled to 0-10° C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10° C. during the addition. The batch was then allowed to warm to 20-30° C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 30° C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30° C. overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55° C. under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.

Workup

  1. stirringthe batch was stirred at 20-30° C. overnight
  2. aliquotthe batch was sampled
  3. washwas rinsed with isopropyl acetate (IPAc) and water
  4. additionDeionized water (28.9 L) was then added to the 30 gallon (˜136 L) reactor
  5. washto rinse the lines
  6. additionTetrahydrofuran (THF) (6.64 L) was then charged to the 30 gallon (˜136 L) reactor
  7. stirringthe mixture was stirred
  8. additionThe acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour
  9. temperaturemaintaining a batch temperature of 0-10° C.
  10. additionduring the addition
  11. temperatureto warm to 20-30° C
  12. customThe aqueous layer was separated
  13. temperaturewhile maintaining a batch temperature of less than 30° C
  14. distillationto distill out 10-13 L of solvent
  15. additionA larger volume of isopropyl acetate (IPAc) (16.6 L) was added
  16. distillationabout 6 L of solvent was distilled out
  17. customThe batch had precipitated
  18. additionheptanes (24.9 L) were added
  19. waitthe batch was held at 20-30° C. overnight
  20. filtrationThe batch was filtered
  21. washthe residue was washed with heptanes (6.64 L)
  22. customthe residue was dried at 45-55° C. under vacuum with a slight nitrogen

Sources & evidence

ORD record
ord-fce4e09be977434d84dbfe6b0a6756a2
Source dataset
uspto-grants-2014_02
Patent number
US08642809B2

Reaction notes

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