5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole → tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate

HRID 1529418Notes

Reaction equation

HRID 1529418 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2I.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([Sn](C)(C)C)[N:34]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:43][CH2:42]2)[N:32]=1>CN(C=O)C.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.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C:35]1[CH:36]=[C:31]([O:30][CH3:29])[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:43][CH2:42]2)[N:34]=1

Participants

6

Reactant 2

HCID 679602665-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indoleHCID 86709790Tert-butyl (1-(4-methoxy-6-(trimethylstannyl)pyrimidin-2-yl)piperidin-4-yl)carbamate

Product 1

HCID 86709789tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamateYield 43.5%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole (0.107 g, 0.2 mmol) and tert-butyl (1-(4-methoxy-6-(trimethylstannyl)pyrimidin-2-yl)piperidin-4-yl)carbamate (0.1 g, 0.2 mmol) in DMF (2 mL) was added Pd(PPh3)4 (23 mg, 0.02 mmol) and CuI (42 mg, 0.22 mmol) and argon gas was bubbled for 15 min. The reaction was heated at 90° C. for 1 h then quenched with water. The suspension was extracted with EtOAc and the organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified with basic alumina chromatography (eluting with 50% EtOAc in petroleum ether) to give tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (60 mg, 41%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 8.71 (s, 1H), 8.61 (s, 1H), 8.10-8.20 (m, 3H), 7.42-7.52 (m, 4H), 7.20-7.25 (m, 3H), 6.76 (m, 1H), 4.56 (d, J=12.9 Hz, 2H), 3.87 (s, 3H), 3.32 (d, J=9 Hz, 3H), 3.03 (m, 2H) 2.33 (s, 3H), 1.74 (d, J=12.9 Hz, 2H), 1.3 (s, 9H).

Workup

  1. customwas bubbled for 15 min
  2. customthen quenched with water
  3. extractionThe suspension was extracted with EtOAc
  4. dry with materialthe organic layer was dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified with basic alumina chromatography (eluting with 50% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-9ab187c6562a42b4a705f2afaec88881
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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