Potassium Carbonate → 6-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl]-N-(methylsulfonyl)-1H-indole-3-carboxamide

HRID 338546Notes

Reaction equation

HRID 338546 reaction equation
BrC1C=C2C(=CC=1Cl)NC=C2C=O.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][C:23]=1[Cl:24])[NH:20][CH:19]=[C:18]2[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26].CC1(C)COB([C:39]2[CH:44]=[CH:43][C:42]([C:45]([CH3:49])([CH3:48])[CH2:46][OH:47])=[C:41]([O:50][CH3:51])[CH:40]=2)OC1.BrC1C=CC(C(C)(C)CO)=C(OC)C=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)C.C1(C)C=CC=CC=1>[Cl:24][C:23]1[CH:22]=[C:21]2[C:17]([C:18]([C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26])=[CH:19][NH:20]2)=[CH:16][C:15]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH3:49])([CH3:48])[CH2:46][OH:47])=[C:41]([O:50][CH3:51])[CH:40]=1

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 866985665-bromo-6-chloro-1H-indole-3-carbaldehydeHCID 866987222-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-olHCID 866988625-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamideHCID 866988642-[4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol

Product 1

HCID 866988636-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl]-N-(methylsulfonyl)-1H-indole-3-carboxamide

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
110 °C

Procedure

A round bottomed flask was charged with a 1:1 mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde and 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27 mmol) as prepared in step 1, 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol (40 mg, 0.14 mmol) (prepared from 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar to Example 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL), toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassed with nitrogen for 5 minutes. PddppfCl2 was then added and the reaction heated to 110° C. for 3 hours. The reaction was then cooled to rt, diluted with water and ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate×3. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was then dissolved in DMSO and purified by reverse phase HPLC to provide the title compound as an ammonium salt (8.0 mg). MS (ES−): 449.1 (M−H)—HPLC retention time: 1.86 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.

Workup

  1. customthen degassed with nitrogen for 5 minutes
  2. additionPddppfCl2 was then added
  3. temperatureThe reaction was then cooled to rt
  4. additiondiluted with water and ethyl acetate
  5. customThe layers were separated
  6. extractionthe aqueous extracted with ethyl acetate×3
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. dissolutionThe crude residue was then dissolved in DMSO
  11. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-7c9744e0c8e14c5f881bd9609fd68faf
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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