Water → HCID 58529438, compound

HRID 1972958Notes

Reaction equation

HRID 1972958 reaction equation
[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:45](=[O:48])[CH2:46][CH3:47])[CH2:32][CH2:31]3)[N:20]2[N:21]=[CH:22][N:23]=1

Participants

6

Reactant 4

HCID 962WaterHCID 62324Propionyl chlorideHCID 81531DiisopropylethylamineHCID 58529963HCID 58529963, compound

Product 1

HCID 58529438HCID 58529438, compoundYield 42.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

5-(2-benzyl-2H-indazol-6-yl)-7-(3-piperazin-1-yl-propyl)pyrrolo-[2,1-f][1,2,4]triazin-4-ylamine (75 mg, 0.16 mmol) was dissolved in anhydrous DMF (3.2 mL) and treated with EtN(iPr)2 (44 μL, 0.32 mmol) followed by the addition of propionyl chloride (22 μL, 0.24 mmol). The mixture was heated to 50° C. for 18 h, cooled to rt and poured into water. The aqueous layer was extracted with 3×10 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (35.5 mg, 42%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.88 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.36 to 7.28 (m, 5H), 7.13 (dd, 1H), 6.60 (s, 1H), 5.63 (s, 2H), 3.41-3.31 (m, 4H), 2.89 (t, 2H), 2.38 to 2.24 (m, 8H), 1.90 to 1.84 (m, 2H), 0.93 (t, 3H); ES-MS m/z 523.3 [M+H]+, RT (min) 2.15.

Workup

  1. temperaturecooled to rt
  2. extractionThe aqueous layer was extracted with 3×10 mL of EtOAc
  3. washthe combined organic phases were washed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude was purified via preparative HPLC
  8. additionThe product containing fractions
  9. customwere collected
  10. customthe TFA from the eluent was removed via filtration through an acidic resin
  11. washby washing with acetonitrile
  12. washThe product was then eluted with 2M NH3 in MeOH
  13. concentrationThe filtrate was concentrated
  14. customthe residue was crystallized from DCM-ether

Sources & evidence

ORD record
ord-f27a837d9b234f6392ca8bcca83b91d3
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

Loading…