Sodium Bicarbonate → 1,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate

HRID 1910005Notes

Reaction equation

HRID 1910005 reaction equation
[NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[CH2:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)=[O:35].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:41]3[CH:40]=[C:39]4[C:44](=[CH:43][CH:42]=3)[N:36]([C:34](=[O:35])[CH2:33][C:27]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=3[F:25])[CH2:37][CH2:38]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1

Participants

6

Reactant 3

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 668237951,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate

Product 1

HCID 668236061,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylateYield 78.2%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (138 mg, 0.348 mmol), and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (167 mg, 0.418 mmol) were dissolved in 1,4-Dioxane (5. mL) then added saturated NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 min then Pd(Ph3P)4 (40.2 mg, 0.035 mmol) was added, and then the mixture was bubbled for 5 additional minutes. The reaction was then capped and heated at 100° C. for 4 hr. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organic were combined, washed with brine, dried over MgSO4, filtered and concentrated to isolated a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane eluting with a gradient of 0 to 10% MeOH in DCM for 30 min. to give 1,1-dimethylethyl 4-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (160 mg, 0.272 mmol, 78% yield) as a amber color oil. LC/MS (ES) m/z=589.6 [M+H]+.

Workup

  1. customThe mixture was then bubbled with N2 gas for 10 min
  2. customthe mixture was bubbled for 5 additional minutes
  3. customThe reaction was then capped
  4. temperatureto cool
  5. additionthen diluted with water (10 mL)
  6. extractionthen extracted with EtOAc (3×20 ml)
  7. washwashed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto isolated a amber color oil
  12. customThe oil was then purified on a 25 g Biotage SNAP column

Sources & evidence

ORD record
ord-9a023f002c2f42639861e98932b97d08
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

Loading…