Dimethylformamide → HCID 58529740, compound

HRID 1972902Notes

Reaction equation

HRID 1972902 reaction equation
[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=N[CH2:37][CH2:38][CH2:39][N:40](C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN([CH:66]=[O:67])C>>[NH2:40][C:39]1([C:66]([N:29]2[CH2:30][CH2:31][CH:26]([C:18]3[N:19]4[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]4)=[C:16]([C:11]4[CH:12]=[CH:13][C:14]5[C:9]([CH:10]=4)=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:15]=5)[CH:17]=3)[CH2:27][CH2:28]2)=[O:67])[CH2:37][CH2:38]1

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 58529814HCID 58529814, compound

Product 1

HCID 58529740HCID 58529740, compoundYield 8%

Procedure

A mixture 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.29 mmol), 1-(Boc-amino)-cyclopropyl-1-carboxylic acid (65 mg, 0.32 mmol), EDCl (62 mg, 0.32 mmol), HOBt (44 mg, 0.32 mmol), and N,N-diisopropylethylamine (115 μL, 0.85 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% 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. To a solution of the residue in MeOH (1 mL) was added 4M HCl in dioxane (500 μL). The mixture was stirred at rt for 16 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (15 mL). The mixture was washed with saturated aqueous NaHCO3 (15 mL), brine, dried (Na2SO4) and concentrated to dryness. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% 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 to afford 11 mg (8%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.10 (d, 2 H), 7.93 (s, 1 H), 7.84 (d, 1 H), 7.69 (s, 1 H), 7.54-7.64 (m, 2 H), 7.45 (t, 1 H), 7.22 (dd, 1 H), 6.68 (s, 1 H), 3.36-3.51 (m, 1 H), 3.01-3.06 (m, 2 H), 2.21-2.37 (m, 2 H), 1.98-2.09 (m, 2 H), 1.51-1.72 (m, 2 H), 0.77-0.88 (m, 2 H), 0.59-0.74 (m, 2 H); ES-MS m/z 493.36 [M+H]+, HPLC RT (min) 2.07.

Workup

  1. customThe crude mixture was purified by preparative HPLC
  2. washa gradient elution from 15% to 45% acetonitrile in water
  3. filtrationfollowed by filtration through an acidic resin
  4. washwashing with MeOH
  5. washThe product was eluted with 2M NH3 in MeOH
  6. concentrationthe filtrate was concentrated
  7. additionTo a solution of the residue in MeOH (1 mL) was added 4M HCl in dioxane (500 μL)
  8. concentrationThe mixture was concentrated
  9. dissolutionthe residue was dissolved in 3:1 CHCl3/isopropanol (15 mL)
  10. washThe mixture was washed with saturated aqueous NaHCO3 (15 mL), brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated to dryness
  13. customThe crude mixture was purified by preparative HPLC
  14. washa gradient elution from 15% to 45% acetonitrile in water
  15. filtrationfollowed by filtration through an acidic resin
  16. washwashing with MeOH
  17. washThe product was eluted with 2M NH3 in MeOH
  18. concentrationthe filtrate was concentrated

Sources & evidence

ORD record
ord-172b43cb3ec449c3ace25f3822a8f0d8
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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