Hydrochloric Acid → Branaplam Hydrochloride

HRID 1027193Notes

Reaction equation

HRID 1027193 reaction equation
C1(O)C=CC=CC=1.C1(S)C=CC=CC=1.C[O:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:20]=[CH:19][C:18]=1[C:28]1[N:29]=[N:30][C:31]([O:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+].[ClH:51].O1CCOCC1>CN1C(=O)CCC1>[ClH:51].[NH:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([C:28]3[N:29]=[N:30][C:31]([O:34][CH:35]4[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]4)=[CH:32][CH:33]=3)=[C:17]([OH:16])[CH:22]=2)[CH:24]=[N:25]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 996PhenolHCID 7969Thiophenol2×HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 867105883-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]-6-(2,2,6,6-tetramethylpiperidin-4-yl)oxypyridazine

Product 1

HCID 135565041Branaplam HydrochlorideYield 9%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol, 3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (0.58 mg, 1.41 mmol) was treated with thiophenol (0.15 mg, 1.36 mmol) and K2CO3 (0.23 mg, 1.64 mmol) in NMP (9 mL) for 15 min at 190° C. After purification (0.1% trifluoroacetic acid as modifier), desired fractions were free based by catch and release using SiliaBond Propylsulfonic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was evaporated under reduced pressure. The resulting beige solid was dissolved in CH3CN/H2O/MeOH (6/1/6 mL) and SiliaMetS® DMT (2.7 g, 1.4 mmol) was added and the mixture was shaken 18 h. The mixture was then filtered through a small celite plug and the filtrate was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (4/1 mL). 4 N HCl in 1,4-dioxane (4 equivalents) was added and solvent was concentrated in vacuo to afford a yellow solid (59 mg, 9%). LCMS RT=0.51 min (LCMS method Q); [M+H]: 394.2225; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=12.0 Hz, 1H), 8.49 (d, J=9.5 Hz, 1H), 8.36 (d, J=12.0 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.21-7.28 (m, 2H), 5.63-5.87 (m, 1H), 2.34 (dd, J=13.0, 4.0 Hz, 2H), 1.81 (dd, J=13.0, 10.5 Hz, 2H), 1.53 (s, 6H), 1.50 (s, 6H).

Workup

  1. customAfter purification (0.1% trifluoroacetic acid as modifier)
  2. customThe solvent was evaporated under reduced pressure
  3. dissolutionThe resulting beige solid was dissolved in CH3CN/H2O/MeOH (6/1/6 mL)
  4. additionSiliaMetS® DMT (2.7 g, 1.4 mmol) was added
  5. filtrationThe mixture was then filtered through a small celite plug
  6. customthe filtrate was purified by catch and release
  7. concentrationThe solvent was concentrated in vacuo
  8. concentrationsolvent was concentrated in vacuo

Sources & evidence

ORD record
ord-b0280c0100d948a6b248ec04c93b668d
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

Loading…