Potassium Phosphate, Tribasic → 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate

HRID 1910042Notes

Reaction equation

HRID 1910042 reaction equation
Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:11][C:9]1[C:10]2[C:2]([C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:17][CH2:16]4)=[CH:3][N:4]([CH3:12])[C:5]=2[N:6]=[CH:7][N:8]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 665609385-Bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineHCID 66823308Tert-butyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate

Product 1

HCID 668236891,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylateYield 63.3%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (413 mg, 1.817 mmol), 1,1-dimethylethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (660 mg, 1.817 mmol), Pd2(dba)3 (83 mg, 0.091 mmol) and Potassium Phosphate (K3PO4) (771 mg, 3.63 mmol) and (t-Bu)3PHBF4 (52.7 mg, 0.182 mmol) in 1,4-Dioxane (7.5 mL) and Water (2.5 mL) was stirred at 100° C. overnight on a stirrer hot-plate. The reaction mixture was allowed to cool to room temperature, at which point a yellow crystalline precipitate was observed. The organic layer removed, the aqueous was diluted with water (10 mL) and extracted with one portion of ethyl acetate (1×30 mL) and two portions of DCM-MeOH (9:1, x x 30 mL) to solubilize the solids. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was adsorbed onto silica and purified by flash chromatography (0-100% EtOAc in hexanes→0-10% MeOH in DCM, 40-g silica gel column) to afford 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (441 mg, 63.3% yield) as an off-white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H), 3.15 (t, J=8.46 Hz, 2H), 3.75 (s, 3H), 4.03 (t, J=8.59 Hz, 2H), 5.88-6.12 (m, 2H), 7.12-7.22 (m, 1H), 7.25 (s, 1H), 7.44-7.72 (m, 1H), 8.15 (s, 1H).

Workup

  1. temperatureto cool to room temperature, at which point a yellow crystalline precipitate
  2. customThe organic layer removed
  3. additionthe aqueous was diluted with water (10 mL)
  4. extractionextracted with one portion of ethyl acetate (1×30 mL) and two portions of DCM-MeOH (9:1, x x 30 mL)
  5. dry with materialThe combined organics were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. custompurified by flash chromatography (0-100% EtOAc in hexanes→0-10% MeOH in DCM, 40-g silica gel column)

Sources & evidence

ORD record
ord-e8efbf3500024f6ba28b8291285f31e9
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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