Dichloromethane → 1-(4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol

HRID 1052254Notes

Reaction equation

HRID 1052254 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20](C4C=CC(N5CCN(C)CC5)=CC=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClCCl.[CH3:38][C:39]([OH:56])([CH3:55])[CH2:40][N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:44]4[CH:43]=[N:42][N:41]([CH2:40][C:39]([CH3:55])([OH:56])[CH3:38])[CH:45]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 582041312-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-olHCID 727924822-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine

Product 1

HCID 730562411-(4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-olYield 23.9%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
88 °C

Procedure

A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 5, 15.0 mg, 29.8 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complexed with dichloromethane (1:1) (1.30 mg, 1.59 μmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (8.5 mg, 31.8 μmol), and potassium phosphate (13.5 mg, 63.7 μmol) in water (0.2 mL)/1,4-dioxane (0.4 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residues were dissolved in methanol (1.0 mL). Potassium carbonate (8.3 mg, 59.7 μmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.0 mg) as its TFA salt. LCMS calculated for C23H28N5O3 (M+H)+: m/z=422.2. Found: 422.3.

Workup

  1. customthe volatiles were removed under vacuum
  2. dissolutionthe residues were dissolved in methanol (1.0 mL)
  3. temperaturethe reaction mixture was warmed up to 60° C
  4. waitAfter 1 hour
  5. temperaturethe reaction mixture was cooled to ambient temperature
  6. customwas purified on RP-HPLC (XBridge C18 column
  7. washeluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-0580488a3ad14751a1051d3c21c05f34
Source dataset
uspto-grants-2016_07
Patent number
US09388185B2

Reaction notes

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