Tetrahydrofuran → HCID 58529404, compound

HRID 1972912Notes

Reaction equation

HRID 1972912 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](C4CCNCC4)[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.BrCCO[Si]([C:40]([CH3:43])([CH3:42])C)(C)C.[CH:44]([N:47]([CH2:51]C)[CH:48](C)C)(C)[CH3:45].C1C[O:56]CC1>>[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]([CH:42]3[CH2:40][CH2:43][CH2:51][N:47]([CH2:44][CH2:45][OH:56])[CH2:48]3)[N:20]2[N:21]=[CH:22][N:23]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 81531Diisopropylethylamine2×HCID 3608067(2-Bromoethoxy)-tert-butyldimethylsilane2×HCID 16066662HCID 16066662, compound

Product 1

HCID 58529404HCID 58529404, compound

Conditions

Temperature
60 °C

Procedure

To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.22 mmol) in THF (1.5 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (51 μL, 0.24 mmol) and N,N-diisopropylethylamine (114 μl, 0.65 mmol). The reaction was heated at 60° C. for 17 h and then cooled to rt. Additional (2-bromoethoxy)-tert-butyldimethylsilane (51 μL) and N,N-diisopropylethylamine (114 μl) were added and the mixture continued to stir at 60° C. for 64 h. The crude mixture was purified by preparative HPLC using a gradient elution from 20% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated. A solution of the residue in 1% HCl in 95:5 EtOH/H2O (4 mL) was stirred at rt for 16 h. The mixture was basified (pH 9) with the addition of saturated, aqueous NaHCO3 solution and was evaporated to remove volatiles. The aqueous mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated.

Workup

  1. temperaturecooled to rt
  2. customThe crude mixture was purified by preparative HPLC
  3. washa gradient elution from 20% to 50% acetonitrile in water
  4. filtrationfollowed by filtration through an acidic resin
  5. washwashing with MeOH
  6. washThe product was eluted with 2M NH3 in MeOH
  7. concentrationthe filtrate was concentrated
  8. stirringA solution of the residue in 1% HCl in 95:5 EtOH/H2O (4 mL) was stirred at rt for 16 h
  9. additionwith the addition of saturated, aqueous NaHCO3 solution
  10. customwas evaporated
  11. customto remove volatiles
  12. extractionThe aqueous mixture was extracted with ethyl acetate (3×15 mL)
  13. washthe combined organic layers were washed with brine
  14. dry with materialdried (Na2SO4)
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-5d1abf05a10d4cf4ad2ea0992066531d
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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