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

HRID 1910027Notes

Reaction equation

HRID 1910027 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]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30].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:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([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]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:3]=3)=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30]

Participants

8

Reactant 4

HCID 947NitrogenHCID 516892Sodium BicarbonateHCID 668235701-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indoleHCID 668240265-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Product 1

HCID 668235525-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 47.8%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To 5-bromo-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.307 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (159 mg, 0.399 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 gas for 10 minutes then Pd(Ph3P)4 (35.4 mg, 0.031 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 (3×5 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue was then dissolved in 3 ml of DMSO and purified on 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 32% 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. To the water left behind was added 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 isolated 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-morpholinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 47.8% yield) as a white solid. LC-MS (ES) m/z=519.5 [M+H]+.

Workup

  1. customThe mixture was then bubbled with N2 gas for 10 minutes
  2. customfor 5 minutes
  3. customthen capped
  4. extractionthen extracted with EtOAc (3×5 ml)
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. dissolutionThe residue was then dissolved in 3 ml of DMSO
  10. custompurified on HPLC
  11. custom7.3-minute
  12. customto remove most of the MeCN
  13. waitTo the water left behind
  14. additionwas added saturated NaHCO3
  15. extractionextracted with EtOAc (3×15 mL)
  16. washThe organic was combined wash with saturated NaCl solution
  17. dry with materialdried over MgSO4
  18. filtrationfiltered
  19. concentrationconcentrated
  20. dry with materialadded water and freeze-dried

Sources & evidence

ORD record
ord-a255a14e807d485c8199c9dc653d2e9c
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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