Dimethylformamide → HCID 58529899, compound

HRID 1972911Notes

Reaction equation

HRID 1972911 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]([CH:27]4[CH2:32][CH2:31]NCC4)[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.CCN=C=NCCCN(C)C.Cl.C1[CH:46]=[CH:47][C:48]2N(O)N=[N:51][C:49]=2C=1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]([CH:67]=[O:68])[CH3:66]>>[NH2:51][CH2:49][C:48]1([C:67]([N:65]2[CH2:66][CH2:31][CH2:32][CH:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)[CH2:64]2)=[O:68])[CH2:46][CH2:47]1

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 757711-Hydroxybenzotriazole2×HCID 81531Diisopropylethylamine2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 16066662HCID 16066662, compound

Product 1

HCID 58529899HCID 58529899, compoundYield 8%

Procedure

A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), 1-(Boc-aminomethyl)-cyclopropyl-1-carboxylic acid (61 mg, 0.28 mmol), EDCl (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), and N, diisopropylethylamine (123 μL, 0.71 mmol) in DMF (1.5 mL) was stirred at rt for 17 h. Additional 1-(Boc-aminomethyl)-cyclopropyl-1-carboxylic acid (30 mg), EDCl (25 mg), HOBt (18 mg) and N,N-diisopropylethylamine (62 μL) were added and the mixture continued to stir at rt for 16 hr. 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 64 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 to afford 9 mg (8%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1 H), 7.78-7.88 (m, 2 H), 7.65 (s, 1 H), 7.29-7.37 (m, 5 H), 7.22 (dd, 1 H), 6.66 (s, 1 H), 5.65 (s, 2 H), 4.69-4.82 (m, 1 H), 4.44 (br s, 1 H), 3.37-3.51 (m, 1 H), 3.05 (dd, 1 H), 2.94 (br s, 2 H), 2.75 (d, 1 H), 2.21 (d, 1 H), 1.83-2.03 (m, 2 H), 1.60-1.75 (m, 1 H), 0.72-1.06 (m, 4 H); ES-MS m/z 521.21 [M+H]+, HPLC RT (min) 2.30.

Workup

  1. stirringto stir at rt for 16 hr
  2. customThe crude mixture was purified by preparative HPLC
  3. washa gradient elution from 15% to 45% 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. additionTo a solution of the residue in MeOH (1 mL) was added 4M HCl in dioxane (500 μL)
  9. stirringThe mixture was stirred at rt for 64 h
  10. concentrationThe mixture was concentrated
  11. dissolutionthe residue was dissolved in 3:1 CHCl3/isopropanol (15 mL)
  12. washThe mixture was washed with saturated, aqueous NaHCO3 (15 mL), brine
  13. dry with materialdried (Na2SO4)
  14. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-3ec2510dbc524bdb9ad79e9fa0f255e3
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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