Hydrochloric Acid → HCID 136252987, compound

HRID 1027242Notes

Reaction equation

HRID 1027242 reaction equation
FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]2[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[CH:19][CH:20]=2)=[C:9]([OH:33])[CH:8]=1)(=O)=O.[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:14][O:13][C:11]1[C:10]([C:15]2[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]3[CH2:27][C:26]([CH3:28])([CH3:29])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)=[CH:19][CH:20]=2)=[C:9]([OH:33])[CH:8]=[C:7]([C:40]2[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=2)[CH:12]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 887MethanolHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 136377153HCID 136377153, compound2×

Product 1

HCID 136252987HCID 136252987, compoundYield 63.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 18180031Water 1,2-dimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3-hydroxy-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 6-2, 100 mg, 0.193 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 0.579 mmol), and sodium carbonate (102 mg, 0.964 mmol) in 3:1 DME/water (1.9 mL) was degassed with a stream of dry nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.014 mmol) was added and the mixture was heated under microwave irradiation at 90° C. for one hour. The mixture was partitioned between water and dichloromethane and the organic phase acidified with HCl in MeOH (4 equivalents) and concentrated to dryness. The crude material was loaded onto an SCX column (1 g, preconditioned with MeOH), washed with MeOH, and eluted with 7 N ammonia in MeOH. The eluent was concentrated to dryness and purification by flash chromatography (12 g silica, 1-12% 7 N ammonia in MeOH gradient, in DCM) provided 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-phenol as a light yellow solid (55 mg). LCMS Rt=0.44 min [Method Q], MS (M+1)=451.5. 1H NMR (400 MHz, METHANOL-d4) δ 8.25 (d, J=10.11 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.22 (d, J=10.11 Hz, 1H), 6.74-6.85 (m, 2H), 5.05 (t, J=12.38 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.01 (s, 3H), 1.65-1.75 (m, 2H), 1.50-1.64 (m, 2H), 1.39 (s, 6H), 1.24 (s, 6H).

Workup

  1. customwas degassed with a stream of dry nitrogen for 5 minutes
  2. customThe mixture was partitioned between water and dichloromethane
  3. concentrationconcentrated to dryness
  4. washwashed with MeOH
  5. washeluted with 7 N ammonia in MeOH
  6. concentrationThe eluent was concentrated to dryness and purification by flash chromatography (12 g silica, 1-12% 7 N ammonia in MeOH gradient, in DCM)

Sources & evidence

ORD record
ord-1f855b0d240b4928a609ce49b3218056
Source dataset
uspto-grants-2014_05
Patent number
US08729263B2

Reaction notes

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