N,N'-Dimethylethylenediamine → ethyl 4-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate

HRID 1622895Notes

Reaction equation

HRID 1622895 reaction equation
[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:30]2[C:25](=[N:26][C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:29]=2)[N:24]([CH3:39])[CH:23]=1.CNCCNC>O1CCOCC1.[Cu]I.O>[CH3:39][N:24]1[C:25]2=[N:26][C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:28][CH:29]=[C:30]2[C:22]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:23]1

Participants

8

Reactant 4

HCID 8070N,N'-Dimethylethylenediamine2×HCID 62657Potassium Phosphate, TribasicHCID 13190471Ethyl 3-oxopiperazine-1-carboxylateHCID 678161163-Bromo-1-methyl-6-(2-pyridylmethoxy)pyrrolo[2,3-b]pyridine2×

Product 1

HCID 67817855ethyl 4-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylateYield 45.5%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Ethyl 3-oxo-piperazine-1-carboxylate (161.4 g, 937.2 mmol), copper(I) iodide (27.65 g, 145.20 mmol) and potassium phosphate (tribasic, n-hydrate) (205.1 g, 937.2 mmol) is charged into a glass reactor at room temperature under nitrogen. A solution of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (210 g, 660.0 mmol) in 1,4-dioxane (2.73 L) is added, followed by N,N′-dimethylethane-1,2-diamine (24.34 g; 270.6 mmol). The reaction mixture is heated to 100° C. and stirred for 20 h. Further copper(I) iodide (10.06 g, 52.80 mmol) and N,N′-dimethylethane-1,2-diamine (10.95 g, 105.6 mmol) is added and the reaction stirred for a further 23 h. The reaction mixture is combined with a smaller batch made in a similar manner starting with 23.68 g of 3-bromo-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine. The mixture is cooled to room temperature, then poured into water (4.2 L) and extracted with EtOAc (3×1.7 L). The organic extracts are combined and washed with 3% w/w aqueous ammonia (3×400 mL), then water (2×2 L), then brine (600 mL), and dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica, eluting with 50 to 100% EtOAc in isohexane. The appropriate fractions are combined, evaporated and recrystallized from ethanol (525 mL). The solid is dried to give the title compound (125.6 g, 0.3 mol). MS (m/z): 410.1 (M+1). 1H-NMR (400 MHz, CDCl3): δ 1.31 (t, 3H), 3.72 (s, 3H), 3.80-3.78 (t, 2H), 3.86 (t, 2H), 4.22 (q, 2H), 4.34 (s, 2H), 5.59 (s, 2H), 6.71 (d, 1H), 7.01 (s, 1H), 7.20 (dd, 1H), 7.49 (d, 1H), 7.70-7.66 (m, 2H), 8.60 (d, 1H). DSC (onset) mp=143.42° C.

Workup

  1. stirringthe reaction stirred for a further 23 h
  2. temperatureThe mixture is cooled to room temperature
  3. extractionextracted with EtOAc (3×1.7 L)
  4. washwashed with 3% w/w aqueous ammonia (3×400 mL)
  5. dry with materialwater (2×2 L), then brine (600 mL), and dried over sodium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue is purified by column chromatography on silica
  9. washeluting with 50 to 100% EtOAc in isohexane
  10. customevaporated
  11. customrecrystallized from ethanol (525 mL)
  12. customThe solid is dried

Sources & evidence

ORD record
ord-12da2ccd0b9746b6a619e42163580096
Source dataset
uspto-grants-2014_07
Patent number
US08778946B2

Reaction notes

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