Ammonium Hydroxide → Dabrafenib Hydroxy

HRID 239555Notes

Reaction equation

HRID 239555 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>O.C(OCC)(=O)C>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 2

HCID 14923Ammonium HydroxideHCID 57989895HCID 57989895, compound

Product 1

HCID 57989740Dabrafenib HydroxyYield 81%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (450 mg, 0.811 mmol) and saturated aqueous ammonium hydroxide (6.0 mL) were heated in a microwave reactor to 90° C. for 90 minutes. The reaction mixture was diluted with water, solution layered with ethyl acetate and pH of the mixture adjusted to 7 giving a gummy residue. The liquors were decanted and set aside; the gum was dissolved in mixture of warm ethyl acetate, dichloromethane and methanol and the solution added to the earlier liquors. The pH of this mixture was re-adjusted to 7.0. Organic phase was separated, dried (MgSO4), filtered and evaporated to give an orange colored foam which was dissolved in ethyl acetate (5 mL). Drop-wise addition of this solution to rapidly stirring hexanes (100 mL) gave a creamy white suspension which was filtered, filter pad washed with fresh hexanes, then air-dried to afford the title compound as a light yellow solid (370 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H) 7.97 (d, J=5.05 Hz, 1H) 7.64-7.77 (m, 1H) 7.40-7.48 (m, 1H) 7.33-7.39 (m, 1H) 7.18-7.32 (m, 4H) 6.75 (s, 2H) 5.84 (d, J=5.05 Hz, 1H) 5.09 (t, J=5.43 Hz, 1H) 3.51 (d, J=5.31 Hz, 2H) 1.33 (s, 6H). MS (ESI): 536.0 [M+H]+.

Workup

  1. customThe liquors were decanted
  2. dissolutionthe gum was dissolved in mixture of warm ethyl acetate, dichloromethane and methanol
  3. additionthe solution added to the earlier liquors
  4. customOrganic phase was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. customevaporated
  8. customto give an orange colored foam which
  9. customgave a creamy white suspension which
  10. filtrationwas filtered
  11. filtrationfilter pad
  12. washwashed with fresh hexanes
  13. customair-dried

Sources & evidence

ORD record
ord-d8b27994c3f7454cae4cee15ab0ec4bf
Source dataset
uspto-grants-2014_02
Patent number
US08642759B2

Reaction notes

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