Trifluoroacetic acid → 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea

HRID 571384Notes

Reaction equation

HRID 571384 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C@H:44]([N:46]=[C:47]=[O:48])[CH3:45])=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[F:37][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]([NH:46][C:47]([NH:17][C:15]2[N:14]=[CH:13][C:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][NH:10][C:11]=3[CH:16]=2)=[O:48])[CH3:45])=[CH:42][CH:43]=1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 7018263(R)-(+)-1-(4-Fluorophenyl)ethyl isocyanateHCID 895258183-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine2×

Product 1

HCID 715553131-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]ureaYield 31%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (intermediate 5a; 50 mg, 0.107 mmol) and 1-fluoro-4-[(1R)-1-isocyanatoethyl]-benzene (75 mg, 0.454 mmol) in 1,4-dioxane (1 mL) was heated to 60° C. overnight, then cooled down to RT and concentrated in vacuo. The residue was suspended in DCM and purified by chromatography on silica gel (0-50% MeOH/DCM) to yield a solid, which was directly dissolved in DCM (1 mL) and treated with TFA (1 mL). The mixture was stirred at RT for 3 h, then concentrated in vacuo and purified via reverse phase HPLC over a gradient of 20-55% MeCN with 0.1% TFA. The collected fractions were then partitioned between DCM/MeOH and 1N NaOH. The organic layer was dried (Na2SO4) and concentrated in vacuo to provide 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea as a solid (13 mg, 0.033 mmol, 31%). MS ESI calc'd. for C21H20N6OF. [M+1]+ 391, found 391.

Workup

  1. temperaturecooled down to RT
  2. concentrationconcentrated in vacuo
  3. custompurified by chromatography on silica gel (0-50% MeOH/DCM)
  4. customto yield a solid, which
  5. concentrationconcentrated in vacuo
  6. custompurified via reverse phase HPLC over a gradient of 20-55% MeCN with 0.1% TFA
  7. customThe collected fractions were then partitioned between DCM/MeOH and 1N NaOH
  8. dry with materialThe organic layer was dried (Na2SO4)
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0a17170495814319b6751bc7e5fd0279
Source dataset
uspto-grants-2015_05
Patent number
US09023865B2

Reaction notes

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