Diisopropylethylamine → HCID 58529527, compound

HRID 1972951Notes

Reaction equation

HRID 1972951 reaction equation
Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3]1.Br[CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>C1COCC1>[NH2:16][C:11]1[C:10]2=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=[C:7]([CH2:6][CH:4]3[CH2:5][N:2]([CH2:34][CH2:35][OH:36])[CH2:3]3)[N:15]2[N:14]=[CH:13][N:12]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 3608067(2-Bromoethoxy)-tert-butyldimethylsilaneHCID 69304364HCID 69304364, compound

Product 1

HCID 58529527HCID 58529527, compoundYield 6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in THF (1.5 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (53 μL, 0.25 mmol) and N,N-diisopropylethylamine (117 μl, 0.67 mmol). The reaction was heated (60° C.) for 17 h and then cooled to rt. 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 remaining aqueous mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to afford 6 mg (6%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1 H), 8.17 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.26-7.39 (m, 5 H), 7.14 (d, 1 H), 6.77 (d, 1 H), 5.66 (s, 2 H), 4.11-4.27 (m, 2 H), 3.89-4.02 (m, 3 H), 3.53-3.63 (m, 2 H), 3.33-3.42 (m, 1 H), 3.10-3.30 (m, 4 H); ES-MS m/z 454.46 [M+H]+, HPLC RT (min) 1.96.

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. additionwith the addition of saturated, aqueous NaHCO3 solution
  9. customwas evaporated
  10. customto remove volatiles
  11. extractionThe remaining aqueous mixture was extracted with ethyl acetate (3×15 mL)
  12. washthe combined organic layers were washed with brine
  13. dry with materialdried (Na2SO4)
  14. concentrationconcentrated
  15. customThe residue was triturated with Et2O

Sources & evidence

ORD record
ord-f65181a176da4329ae329396a6392226
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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