Dichloromethane → 2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-6-(5-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine

HRID 1052313Notes

Reaction equation

HRID 1052313 reaction equation
Br[C:2]1[N:24](S(C2C=CC=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[F:23])[N:9]=[C:4]2[CH:3]=1.[CH3:34][C:35]1[C:39](B(O)O)=[CH:38][NH:37][N:36]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([F:23])[C:12]=1[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][NH:36][C:35]=3[CH3:34])[NH:24][C:5]2=[N:6][CH:7]=1

Participants

9

Reactant 5

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 899635876-bromo-2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazineHCID 178434488HCID 178434488, compound

Product 1

HCID 730542352-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-6-(5-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazineYield 46%

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-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (15 mg, 28 μmol), (3-methyl-1H-pyrazol-4-yl)boronic acid (4.2 mg, 33 μmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexed with dichloromethane (1:1) (1.8 mg, 2.2 μmol), and potassium phosphate (9.5 mg, 45 mmol) in water (0.2 mL)/1,4-dioxane (1 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL). Potassium carbonate (7.7 mg, 56 μmol) was added and the reaction mixture was warmed up to 60° C. After 0.5 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 (5.1 mg, 46%) as its TFA salt. LCMS calculated for C20H20F2N5O2 (M+H)+: m/z=400.2. Found: 400.2.

Workup

  1. customthe volatiles were removed under vacuum
  2. dissolutionthe residue was dissolved in methanol (1 mL)
  3. temperaturethe reaction mixture was warmed up to 60° C
  4. waitAfter 0.5 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-5c060d9a9eee4f50a3582977c518e727
Source dataset
uspto-grants-2016_07
Patent number
US09388185B2

Reaction notes

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