Nitrogen → 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 1910034Notes

Reaction equation

HRID 1910034 reaction equation
Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].C([O-])(O)=O.[Na+].N#N>O.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.O1CCOCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:3]=3)=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)=[O:27]

Participants

8

Reactant 4

HCID 947Nitrogen2×HCID 516892Sodium BicarbonateHCID 668235701-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indoleHCID 668236955-bromo-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Product 1

HCID 668240015-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 20.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To 5-bromo-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.352 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (183 mg, 0.457 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled N2 gas for 10 minutes then Pd(Ph3P)4 (40.7 mg, 0.035 mmol) was added. The mixture was again bubbled N2 gas for 5 minutes then capped and the reaction was heated at 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (3×mL). The organics were combined and washed with brine, dried over Mg2SO4, filtered and concentrated. The resulting amber color oil was dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 7% ACN/H2O, 0.1% TFA to 37% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added to saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then it was transferred into a 40 mL vial with MeCN then added water and freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(dimethylamino)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (35 mg). LC/MS (ES) m/z=477.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.33 (s, 2H), 7.15-7.30 (m, 4H), 6.06 (br. s., 2H), 4.24-4.33 (m, 4H), 3.95 (s, 2H), 3.24-3.30 (m, 2H), 2.72 (br. s., 2H), 2.24 (br. s., 6H).

Workup

  1. customfor 5 minutes
  2. customthen capped
  3. extractionthen extracted with EtOAc (3×mL)
  4. washwashed with brine
  5. dry with materialdried over Mg2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe resulting amber color oil was dissolved in 3 mL of DMSO
  9. custompurified by HPLC
  10. custom7.3-minute
  11. customto remove most of the MeCN
  12. waitThe water left behind
  13. additionwas added to saturated NaHCO3
  14. extractionextracted with EtOAc (3×15 mL)
  15. washThe organic was combined wash with saturated NaCl solution
  16. dry with materialdried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated
  19. dry with materialadded water and freeze-dried

Sources & evidence

ORD record
ord-b87ad27040ee40eab8fc2a37e32523ea
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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