Cesium fluoride → 8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

HRID 1969691Notes

Reaction equation

HRID 1969691 reaction equation
Br[C:2]1[C:10]2[N:9]3[CH:11]=[N:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[C:35]([Sn](CCCC)(CCCC)CCCC)[CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:26]1.[Li+].[Cl-].[F-].[Cs+]>[Cu]I.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>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:32]=[C:33]([C:2]3[C:10]4[N:9]5[CH:11]=[N:12][N:13]=[C:8]5[CH:7]=[N:6][C:5]=4[N:4]([S:14]([C:17]4[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=4)(=[O:16])=[O:15])[CH:3]=3)[CH:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 433294Lithium ChlorideHCID 585573288-bromo-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineHCID 585576732-(4-Methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine

Product 1

HCID 585574828-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineYield 69.9%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

A vial containing 8-bromo-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.030 g, 0.076 mmol, prepared using D from Preparation #BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH), 2-(4-methylpiperazin-1-yl)-4-(tributylstannyl)pyrimidine (0.054 g, 0.12 mmol, Preparation #39), LiCl (0.010 g, 0.24 mmol), CuI (0.003 g, 0.02 mmol), CsF (0.017 g, 0.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) under nitrogen was evacuated and then back-filled with nitrogen. 1,4-Dioxane (0.5 mL) was added and nitrogen was bubbled through the mixture for about 30 min. The reaction vessel was sealed and the mixture was warmed to about 80° C. After about 4 h, the mixture was allowed to cool to ambient temperature. The mixture was diluted with water (5 mL) and EtOAc (5 mL) and then filtered through a syringe filter. The layers were separated and the aqueous phase was extracted with EtOAc (5 mL). The combined organics were concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM over 40 min to afford 8-(2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.026 g, 69%): LC/MS (Table 1, Method n) Rt=0.56 min; MS m/z 490 (M+H)+.

Workup

  1. customwas evacuated
  2. additionback-filled with nitrogen
  3. addition1,4-Dioxane (0.5 mL) was added
  4. customnitrogen was bubbled through the mixture for about 30 min
  5. customThe reaction vessel was sealed
  6. temperatureto cool to ambient temperature
  7. additionThe mixture was diluted with water (5 mL) and EtOAc (5 mL)
  8. filtrationfiltered through a syringe
  9. filtrationfilter
  10. customThe layers were separated
  11. extractionthe aqueous phase was extracted with EtOAc (5 mL)
  12. concentrationThe combined organics were concentrated under reduced pressure
  13. customThe residue was purified by silica gel chromatography
  14. washeluting with a gradient of 0-10% MeOH in DCM over 40 min

Sources & evidence

ORD record
ord-b8a0224e69cc4cfca0ea78ec6edc144f
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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