Potassium Phosphate, Tribasic → (R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea

HRID 588171Notes

Reaction equation

HRID 588171 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:18][CH2:19][CH3:20])=[N:9][N:10](C(OC(C)(C)C)=O)[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([NH2:33])=[O:32])[CH3:29])=[CH:24][CH:23]=1.CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([O:18][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:33][C:31]([NH:30][C@@H:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH3:29])=[O:32])=[CH:3][C:4]=2[NH:10][N:9]=1)[CH3:20]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 11547931BippyPhosHCID 117601722(R)-1-(1-(4-fluorophenyl)ethyl)urea2×HCID 118272033tert-butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate

Product 1

HCID 118272034(R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

tert-Butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (77 mg, 0.259 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 15B; 60 mg, 0.329 mmol), bippyphos (15.6 mg, 0.031 mmol), Pd2(dba)3 (9.6 mg, 10.48 μmol), and tripotassium phosphate (82 mg, 0.388 mmol) were taken up in DME (1.3 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 18 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL) and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. For C17H18FN5O2 [M+1]+ 344. found 344. 1H NMR (500 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 7.76 (br s, 1H), 7.46 (s, 1H), 7.39-7.33 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.89-4.82 (m, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.41-1.34 (m, 6H).

Workup

  1. customThe vial was evacuated
  2. additionback-filled with N2 (×3)
  3. customRoom temperature
  4. filtrationthe reaction mixture was filtered through Celite
  5. washeluting with MeOH
  6. concentrationthe filtrate was concentrated in vacuo
  7. dissolutionThe residue was dissolved in TFA (2 mL)
  8. stirringthe solution stirred at room temperature for 3 h
  9. customThe solvent was removed in vacuo, saturated NaHCO3
  10. additionwas added
  11. extractionthe products extracted into EtOAc (×2)
  12. washThe combined organic extracts were washed with brine
  13. dry with materialdried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customPurification of the residue by flash chromatography (0-100% EtOAc-DCM)

Sources & evidence

ORD record
ord-4df8e83e439f48f5bc1116a88fe3848a
Source dataset
uspto-grants-2016_01
Patent number
US09226922B2

Reaction notes

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