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

HRID 1622898Notes

Reaction equation

HRID 1622898 reaction equation
Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH:19]1([N:4]2[C:5]3=[N:6][C:7]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[CH:8][CH:9]=[C:10]3[C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][C:23]3=[O:22])=[CH:3]2)[CH2:21][CH2:20]1

Participants

7

Reactant 4

HCID 8070N,N'-Dimethylethylenediamine2×HCID 62657Potassium Phosphate, Tribasic2×HCID 13190471Ethyl 3-oxopiperazine-1-carboxylate2×HCID 678142033-bromo-1-cyclopropyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 67814478ethyl 4-[1-cyclopropyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylateYield 11.8%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 3-bromo-1-cyclopropyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.263 g, 765 μmol), ethyl 3-oxopiperazine-1-carboxylate (0.158 g, 0.918 mmol), N,N′-dimethylethane-1,2-diamine (33.8 μL, 0.313 mmol), copper(I) iodide (32 mg, 168 μmol), potassium phosphate (tribasic, n-hydrate) (0.179 g, 841 μmol) in DMF (10 mL) is heated at 120° C. for 15 h. The mixture is cooled to room temperature and further copper(I) iodide (0.145 g, 765 μmol), potassium phosphate (tribasic, n-hydrate) (0.536 g, 2.52 mmol) and N,N′-dimethylethane-1,2-diamine (165 μL, 1.53 mmol) are added, followed by ethyl 3-oxopiperazine-1-carboxylate (0.132 g, 0.765 mmol). After further heating for 24 h under nitrogen at 100° C., the mixture is concentrated in vacuo, diluted with MeOH and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is concentrated in vacuo and purified by column chromatography on silica, eluting with 0 to 100% EtOAc in isohexane, to give the title compound as a yellow oil (40 mg, 0.09 mmol). MS (m/z): 436 (M+1). 1H-NMR (400 MHz, CDCl3): 0.89-0.99 (m, 4H), 1.31 (t, 3H), 3.31-3.37 (m, 1H), 3.76-3.78 (m, 2H), 3.82-3.88 (m, 2H), 4.22 (q, 2H), 4.33 (s, 2H), 5.60 (s, 2H), 6.72 (d, 1H), 7.00 (s, 1H), 7.18-7.22 (m, 1H), 7.48-7.52 (m, 1H), 7.64-7.69 (m, 2H), 8.59-8.61 (m, 1H).

Workup

  1. temperatureThe mixture is cooled to room temperature
  2. temperatureAfter further heating for 24 h under nitrogen at 100° C.
  3. concentrationthe mixture is concentrated in vacuo
  4. additiondiluted with MeOH
  5. additionpoured onto a SCX-2 ion-exchange column
  6. washThis is washed with 3 column volumes of MeOH
  7. customthe product collected in the subsequent one column volume
  8. customflush of 7 M methanolic ammonia
  9. concentrationThe solution is concentrated in vacuo
  10. custompurified by column chromatography on silica
  11. washeluting with 0 to 100% EtOAc in isohexane

Sources & evidence

ORD record
ord-b1be81ffdc644edb9c0ebfadef4d3c53
Source dataset
uspto-grants-2014_07
Patent number
US08778946B2

Reaction notes

Loading…