N,N'-Dimethylethylenediamine → ethyl 4-[5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylate

HRID 1622901Notes

Reaction equation

HRID 1622901 reaction equation
Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:20])[CH:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]1)=[O:25])[CH3:22].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[F:11][C:8]1[CH:9]=[C:10]2[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:27][C:28]3=[O:32])=[CH:3][N:4]([CH3:20])[C:5]2=[N:6][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1

Participants

7

Reactant 4

HCID 8070N,N'-Dimethylethylenediamine2×HCID 62657Potassium Phosphate, TribasicHCID 13190471Ethyl 3-oxopiperazine-1-carboxylateHCID 678144933-bromo-5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 67818492ethyl 4-[5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-oxopiperazine-1-carboxylateYield 20.9%

Reagents, catalysts & solvents 2

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

Procedure

3-Bromo-5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.233 g, 0.693 mmol), 3-oxo-piperazine-1-carboxylic acid ethyl ester (0.131 g, 0.762 mmol), N,N′-dimethylethane-1,2-diamine (0.031 mL, 0.284 mmol), copper(I) iodide (0.029 g, 0.152 mmol), potassium phosphate (tribasic, n-hydrate) (0.162 g, 0.762 mmol), and 1,4-dioxane (15 mL) are added together under a nitrogen atmosphere, and heated to reflux overnight with stirring. Further copper (I) iodide (0.120 g, 0.630 mmol) and N,N′-dimethylethane-1,2-diamine (0.120 mL, 1.099 mmol) are then added and the reaction kept at 105° C. for a further 5 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 3×30 mL). The combined organic extracts are diluted with MeOH, and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is then concentrated in vacuo to give a brown oil. This is purified by supercritical fluid chromatography (RT=4.7 minutes (UV); SFC Column. Benzenesulphonamide 21.2 mm×500 mm 5 μm; CO2 Gradient: 15-30% MeOH w/0.2% DMEA in 5.5 mins and then ramped up to 50% MeOH and held for 3.5 mins; Column Temp: 40° C.; Flow Rate: 50.0 ml/min) to give an orange solid. This is then further purified by HPLC chromatography (RT=4.67 minutes (UV); LC Column. Waters Xbridge C18 100 mm×30 mm 5 μm; H2O w/0.2% NH4HCO3 Gradient: 9-100% ACN w/0.2% NH4HCO3 in 6.0 min then held at 100% for 3.0 min; Column Temp: 50° C.; Flow Rate: 3.0 ml/min) to give the title compound as a white solid (0.0621 g, 0.145 mmol). MS (m/z): 428 (M+1). 1H-NMR (300.13 MHz, CDCl3): δ 1.32 (t, 3H), 3.72 (s, 3H), 3.73-3.80 (br, 2H), 3.84-3.89 (br, 2H), 4.22 (q, 2H), 4.34 (br, 2H), 5.66 (s, 2H), 7.03 (s, 1H), 7.21 (t, 1H), 7.49 (d, 1H), 7.51-7.55 (m, 1H), 7.70 (td, 1H), 8.60 (d, 1H).

Workup

  1. temperatureheated
  2. temperatureto reflux overnight
  3. temperatureThe reaction is cooled
  4. additionpoured onto brine (ca. 50 mL)
  5. extractionthe product extracted with CHCl3 (ca. 3×30 mL)
  6. additionThe combined organic extracts are diluted with MeOH
  7. additionpoured on to a SCX2 ion-exchange column
  8. customThis is flushed with one column volume of MeOH
  9. customthe product collected in the subsequent one column volume
  10. customflush of 7 M methanolic ammonia
  11. concentrationThe solution is then concentrated in vacuo
  12. customto give a brown oil
  13. customThis is purified by supercritical fluid chromatography (RT=4.7 minutes (UV)
  14. customin 5.5 mins
  15. waitheld for 3.5 mins
  16. custom40° C.
  17. customFlow Rate: 50.0 ml/min) to give an orange solid
  18. customThis is then further purified by HPLC chromatography (RT=4.67 minutes (UV)
  19. customin 6.0 min
  20. waitthen held at 100% for 3.0 min
  21. custom50° C.

Sources & evidence

ORD record
ord-3e05d94b5be14c90a45354c0feb1d860
Source dataset
uspto-grants-2014_07
Patent number
US08778946B2

Reaction notes

Loading…