Cesium carbonate → 3-(4-methyl-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-yl)urea

HRID 590829Notes

Reaction equation

HRID 590829 reaction equation
Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.FC1C=CC([C@H]([NH:48][C:49]([NH2:51])=[O:50])[C@H](O)C)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([SiH](CC)CC)C>O1CCOCC1.C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:8][C:6]1[C:5]2[C:9]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:10][NH:11][C:4]=2[CH:3]=[C:2]([NH:48][C:49](=[O:50])[NH2:51])[N:7]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 12052TriethylsilaneHCID 1181839711-((1S,2R)-1-(4-fluorophenyl)-2-hydroxypropyl)ureaHCID 1182716944-(6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine

Product 1

HCID 1317344973-(4-methyl-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-yl)urea

Reagents, catalysts & solvents 3

HCID 25112666BrettPhos PalladacycleCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

4-(6-Chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (75 mg, 0.152 mmol), 1-((1S,2R)-1-(4-fluorophenyl)-2-hydroxypropyl)urea, (48.2 mg, 0.227 mmol), BrettPhos palladacycle (12.10 mg, 0.015 mmol), cesium carbonate (128 mg, 0.394 mmol) 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (8.13 mg, 0.015 mmol) were dissolved in dioxane (1 mL) and purged under agron for five minutes. The reaction mixture was heated to 90° C. and stirred for six hrs. The reaction mixture was filtered through celite, rinsed with methanol, and concentrated in vacuo. The crude residue was dissolved in TFA (1 mL) and triethylsilane (0.036 mL, 0.227 mmol) was added. The reaction mixture was stirred at rt for 30 min then diluted with DCM and concentrated in vacuo. The reaction mixture was diluted with DMF (1 mL), filtered, and purified by mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give 1-(1S,2R)-1-(4-fluorophenyl)-2-hydroxypropyl)-3-(4-methyl-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C21H26FN6O3 [M+H]+ 429. found 429. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.11 (s, 1H), 7.31 (dd, J=5.6 Hz, 8.7 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H), 7.06 (s, 1H), 4.91 (s, 1H), 4.69 (dd, J=4.2 Hz, 8.5 Hz, 1H), 3.90 (s, 1H), 3.77-3.73 (m, 5H), 3.08 (d, J=4.2 Hz, 4H), 2.68 (s, 3H), 0.93 (d, J=6.4 Hz, 3H).

Workup

  1. custompurged under agron for five minutes
  2. filtrationThe reaction mixture was filtered through celite
  3. washrinsed with methanol
  4. concentrationconcentrated in vacuo
  5. dissolutionThe crude residue was dissolved in TFA (1 mL)
  6. stirringThe reaction mixture was stirred at rt for 30 min
  7. concentrationconcentrated in vacuo
  8. additionThe reaction mixture was diluted with DMF (1 mL)
  9. filtrationfiltered
  10. custompurified by mass-triggered reverse-phase HPLC
  11. additionFractions containing pure compound
  12. filtrationwere filtered through a PS-HCO3 cartridge
  13. concentrationthe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-49195725982e47c38e23221bceb309b9
Source dataset
uspto-grants-2016_01
Patent number
US09233979B2

Reaction notes

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