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

HRID 1910098Notes

Reaction equation

HRID 1910098 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.[Cl: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]([Cl: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 66823555tert-Butyl 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline-1-carboxylate

Product 1

HCID 668239601,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2,3-dihydro-1H-indole-1-carboxylateYield 79.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (510 mg, 2.246 mmol), 1,1-dimethylethyl 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (853 mg, 2.246 mmol), Pd2(dba)3 (103 mg, 0.112 mmol) and Potassium Phosphate (K3PO4) (954 mg, 4.49 mmol) and (t-Bu)3PHBF4 (6.52 mg, 0.022 mmol) in 1,4-Dioxane (10 mL) and Water (3.3 mL) in a sealed tube was heated at 100° C. on a stirrer hot plate. At this time, LCMS analysis indicated good conversion, so the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL), and the combined organics dried over sodium sulfate and concentrated. The residue was dissolved in DCM (ca. 100 mL), concentrated to minimum volume (ca. 40 mL), then purified by flash chromatography (0-100% EtOAc in hexanes, 40-g silica gel column) to afford 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-chloro-2,3-dihydro-1H-indole-1-carboxylate (0.716 g) as a yellow solid. LC-MS (ES) m/z=400 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 9H), 3.14 (t, J=8.59 Hz, 2H), 3.74 (s, 3H), 3.96-4.07 (m, 2H), 5.73-6.04 (m, 2H), 7.15-7.26 (m, 2H), 7.57-7.80 (m, 1H), 8.13 (s, 1H).

Workup

  1. extractionextracted with ethyl acetate (3×100 mL)
  2. dry with materialthe combined organics dried over sodium sulfate
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in DCM (ca. 100 mL)
  5. concentrationconcentrated to minimum volume (ca. 40 mL)
  6. custompurified by flash chromatography (0-100% EtOAc in hexanes, 40-g silica gel column)

Sources & evidence

ORD record
ord-50a78bdd85bb4d628f5d43ebe1b03a07
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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