Methane → Branaplam Hydrochloride

HRID 1027311Notes

Reaction equation

HRID 1027311 reaction equation
[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:13]3[N:14]=[N:15][C:16]([O:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)=[CH:17][CH:18]=3)=[C:10]([OH:12])[CH:11]=2)[CH:3]=[N:2]1.[ClH:30].O.C>[Pd].CCO>[ClH:30].[NH:2]1[CH:3]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:13]3[N:14]=[N:15][C:16]([O:19][CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)=[CH:17][CH:18]=3)=[C:10]([OH:12])[CH:11]=2)[CH:5]=[N:1]1

Participants

7

Reactant 4

HCID 297MethaneHCID 313Hydrochloric AcidHCID 962WaterHCID 135565042Branaplam

Product 1

HCID 135565041Branaplam HydrochlorideYield 49.6%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Conditions

Temperature
78 °C

Procedure

To a 2-L flask was added 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol (50 g, 127 mmol), 37% HCl (21 mL, 254 mmol), H2O (1 L) and EtOH (1 L). SMOPEX-234 (10 g, Pd scavenger) and activated charcoal (10 g) were also added. The mixture was heated at reflux (78° C.) for 3 hours. The resulting black mixture was allowed to cool to 60° C., and the Pd scavenging agents were filtered off at 50-60° C. The filtrate was cooled to 15° C. gradually over 1 h, and a pale yellow precipitate formed. After 2 h, the solid was collected by filtration, washed with EtOH (50 mL), and dried under vacuum at 50° C. to give 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride (27.2 g, 63 mmol). HRMS m/z 394.2222 [M+H]; 1H-NMR: (DMSO-d6, 400 MHz) δ 13.09 (br, 2H), 9.41 (d, J=12 Hz, 1H), 8.61 (d, J=12 Hz, 1H), 8.49 (d, J=Hz, 1H), 8.15 (br, 2H), 7.95 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.26 (d, J=8 Hz, 2H), 5.72 (m, 1H), 2.33 (dd, Ja=3.2 Hz, Jb=13.2 Hz, 2H), 1.86-1.92 (m, Ja=8 Hz, 2H), 1.23 (s, 6H), 1.10 (s, 6H); 13C-NMR: (DMSO-d6, 100 MHz) δ 162.34, 158.51, 156.41, 136.29, 128.72, 127.94, 120.40, 119.95, 116.37, 115.18, 113.45, 67.94, 56.69, 29.23, 25.10; XRPD: 13.47505, 14.29462, 14.99017, 16.55045, 17.60726, 19.69314, 21.89296, 23.89703, 25.82989, 27.13969, 28.47844, 36.94252, 43.77528.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto cool to 60° C.
  3. filtrationthe Pd scavenging agents were filtered off at 50-60° C
  4. temperatureThe filtrate was cooled to 15° C. gradually over 1 h
  5. customa pale yellow precipitate formed
  6. filtrationthe solid was collected by filtration
  7. washwashed with EtOH (50 mL)
  8. customdried under vacuum at 50° C.

Sources & evidence

ORD record
ord-a0eadca2da204f428f7cb82f6c61a460
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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