1,4-Dioxane → (R)-1-(3-(ethylamino)-7-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea

HRID 590816Notes

Reaction equation

HRID 590816 reaction equation
Br[C:2]1[C:3]2[NH:22][N:21]=[C:20]([NH:23][CH2:24][CH3:25])[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].O1CCOC[CH2:27]1.C[Zn]C>CN1C(=O)CCC1>[CH2:24]([NH:23][C:20]1[C:4]2[CH:5]=[N:6][C:7]([NH:8][C:9]([NH:11][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])=[O:10])=[C:2]([CH3:27])[C:3]=2[NH:22][N:21]=1)[CH3:25]

Participants

5

Reactant 3

HCID 312751,4-DioxaneHCID 118272346(R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)ureaHCID 178477796HCID 178477796, compound

Product 1

HCID 73504798(R)-1-(3-(ethylamino)-7-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

An oven-dried 5 mL microwave vial was charged with (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (100 mg, 0.198 mmol), PdOAc2 (8.5 mg, 0.038 mmol), and PCy3-BF4H (30 mg, 0.08 mmol). The reaction mixture was sealed under N2, then charged with dioxane (1.0 mL) and NMP (0.25 mL), followed by drop-wise addition of dimethylzinc (1.653 mL, 1.984 mmol, 1.2 M in toluene). The reaction was heated to 100° C. and stirred for 17 h. The reaction was quenched with TFA until gas evolution ceased and then poured into sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-20% MeOH/DCM) followed by purification via 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 (R)-1-(3-(ethylamino)-7-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C18H22N6O [M+1]+ 339. found 339. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.42-7.19 (m, 5H), 5.01 (q, J=6.9 Hz, 1H), 3.36 (m, 2H), 2.29 (s, 3H), 1.53 (d, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H).

Workup

  1. customThe reaction mixture was sealed under N2
  2. customThe reaction was quenched with TFA until gas evolution
  3. additionpoured into sat. aq. NaHCO3
  4. extractionThe aqueous layer was extracted with EtOAc (×3)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography (0-20% MeOH/DCM)
  9. customfollowed by purification via mass-triggered reverse-phase HPLC
  10. additionFractions containing pure compound
  11. filtrationwere filtered through a PS-HCO3 cartridge
  12. concentrationthe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-f6032a17c9ef4804b8bf9f9d30c1a22e
Source dataset
uspto-grants-2016_01
Patent number
US09233979B2

Reaction notes

Loading…