Sodium Carbonate → 5-{3-[(3,5-Dimethoxybenzyl)oxy]phenyl}-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

HRID 1972783Notes

Reaction equation

HRID 1972783 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:5]3[C:10]=2[C:9]([NH2:11])=[N:8][CH:7]=[N:6]3)[CH:31]=[CH:30][CH:29]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 162177063-(3,5-Dimethoxybenzyloxy)phenylboronic acidHCID 585298065-Bromo-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Product 1

HCID 585298125-{3-[(3,5-Dimethoxybenzyl)oxy]phenyl}-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineYield 28%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 5-bromo-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (70 mg, 0.21 mmol), 3-(3,5-dimethoxybenzyloxy)phenyl boronic acid (179 mg, 0.62 mmol), and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.021 mmol) in degassed DME (1.5 mL) was added aqueous Na2CO3 solution (2 M, 310 μL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic phase was washed dried (Na2SO4) and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 20% to 70% acetonitrile followed by preparative TLC eluting with 9:1 ethyl acetate/methanol (with 1% concentrated ammonium hydroxide) to obtain 29 mg (28%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1 H), 7.36 (t, 1 H), 7.07-7.04 (m, 1 H), 7.03-6.96 (m, 2 H), 6.60 (d, 2 H), 6.55 (s, 1 H), 6.43 (t, 1 H), 5.07 (s, 2 H), 3.73 (s, s H), 2.88 (t, 2 h), 2.56-2.48 (m, 6 H), 1.78-1.65 (m, 6 H), 1.60-1.49 (m, 2 H); ES-MS m/z 502.2 [M+H]+, HPLC RT (min) 2.27.

Workup

  1. temperaturecooled to rt
  2. customThe mixture was partitioned between ethyl acetate (25 mL) and water (25 mL)
  3. customThe layers were separated
  4. washthe organic phase was washed
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated to dryness
  7. customThe residue was purified by preparative HPLC
  8. washa gradient elution from 20% to 70% acetonitrile
  9. washeluting with 9:1 ethyl acetate/methanol (with 1% concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-093e950921144ffabbe708dcad7c48d9
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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