Nitrogen → 1,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate

HRID 1910016Notes

Reaction equation

HRID 1910016 reaction equation
[NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([N:33]2[C:41]3[C:36](=[CH:37][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:40]=3)[CH2:35][CH2:34]2)=[O:32])[CH:27]=[CH:28][CH:29]=1.C([O-])(O)=O.[Na+].N#N>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:33]([C:31](=[O:32])[CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:34][CH2:35]4)=[CH:9][N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 516892Sodium BicarbonateHCID 668235231,1-dimethylethyl 3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylateHCID 668241231-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole

Product 1

HCID 668234481,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylateYield 67.4%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To 1,1-dimethylethyl 3-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (200 mg, 0.543 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (246 mg, 0.652 mmol) dissolved in 1,4-Dioxane (4 mL) was added Sat NaHCO3 (2 mL). The mixture was then bubbled N2 gas for 10 minutes then added Pd(Ph3P)4 (62.8 mg, 0.054 mmol) then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was let cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to give an amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane using a gradient of 0 to 10% MeOH in DCM for 30 minutes to isolate 1,1-dimethylethyl 3-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-azetidinecarboxylate (197 mg, 0.366 mmol, 67.3% yield) as a amber color solid. LC-MS (ES) m/z=539.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.11-8.18 (m, 2H), 7.60 (s, 1H), 7.37 (s, 1H), 7.28 (d, J=8.34 Hz, 1H), 7.20-7.26 (m, 1H), 7.06-7.15 (m, 3H), 5.76 (s, 1H), 5.46-5.56 (m, 1H), 4.33 (d, J=8.08 Hz, 4H), 4.21 (t, J=8.46 Hz, 2H), 3.93 (s, 1H), 3.83 (s, 2H), 3.22 (t, J=8.21 Hz, 2H), 2.31 (s, 3H), 1.43 (s, 9H).

Workup

  1. customThen reaction
  2. customwas then capped
  3. temperatureThe mixture was let cool
  4. extractionthen extracted with EtOAc (3×20 ml)
  5. washwashed with brine
  6. customdried over MgSo4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give an amber color oil
  10. customThe oil was then purified on a 25 g Biotage SNAP column
  11. customfor 30 minutes

Sources & evidence

ORD record
ord-3fe0965ed15d4bf39c89d861f81b7279
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

Loading…