Potassium Carbonate → (R)-1-(3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea

HRID 588167Notes

Reaction equation

HRID 588167 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[N:9][N:10](C(OCC)=O)[C:4]=2[CH:3]=1.[C:21]1([C@H:27]([NH:29][C:30]([NH2:32])=[O:31])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=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+].C([O-])([O-])=O.[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]>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:32][C:30]([NH:29][C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])=[O:31])=[CH:3][C:4]=2[NH:10][N:9]=1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 11547931BippyPhosHCID 13013340(R)-1-(1-phenylethyl)ureaHCID 118272255Ethyl 6-chloro-3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate

Product 1

HCID 76071810(R)-1-(3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

Ethyl 6-chloro-3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (100 mg, 0.334 mmol), (R)-1-(1-phenylethyl)urea (68.5 mg, 0.417 mmol), bippyphos (15.21 mg, 0.030 mmol), Pd2(dba)3 (7.4 mg, 8.08 μmol), and tripotassium phosphate (106 mg, 0.500 mmol) were taken up in DME (1.6 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 16 h. Room temperature was attained, the reaction mixture filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was taken up in MeOH (3 mL) and K2CO3 (118 mg, 0.854 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was filtered through Celite and the filtrate concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (0-10% MeOH-DCM) followed by purification by mass triggered, reverse phase prep-HPLC. The fractions containing pure product were concentrated in vacuo, lyophilized, and dissolved in MeOH. The solution was filtered through a PS—HCO3 cartridge, eluting with MeOH. The filtrate was concentrated in vacuo to give (R)-1-(3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.75 (br s, 1H), 7.48 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 4.88-4.82 (m, 1H), 4.81-4.39 (m, 2H), 3.71-3.69 (m, 2H), 3.30 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).

Workup

  1. customThe vial was evacuated
  2. additionback-filled with N2 (×3)
  3. customRoom temperature
  4. filtrationthe reaction mixture filtered through Celite
  5. washeluting with MeOH
  6. concentrationthe filtrate was concentrated in vacuo
  7. stirringThe resulting mixture was stirred at room temperature for 3 h
  8. filtrationThe mixture was filtered through Celite
  9. concentrationthe filtrate concentrated in vacuo
  10. customThe crude reaction mixture
  11. customwas purified by flash chromatography (0-10% MeOH-DCM)
  12. customfollowed by purification by mass
  13. additionThe fractions containing pure product
  14. concentrationwere concentrated in vacuo
  15. dissolutiondissolved in MeOH
  16. filtrationThe solution was filtered through a PS—HCO3 cartridge
  17. washeluting with MeOH
  18. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-17c2554a531f4c4bab98b72f0c57acb1
Source dataset
uspto-grants-2016_01
Patent number
US09226922B2

Reaction notes

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