Potassium Carbonate → 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

HRID 1806321Notes

Reaction equation

HRID 1806321 reaction equation
[CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH2:30][CH2:31]2)=[CH:7][CH:6]=1)[CH3:2]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 113844275-bromo-3-[1-(ethanesulfonyl)-4-piperidinyl]-1H-indole-7-carboxamideHCID 66722882{5-[(Ethylamino)methyl]-2-thienyl}boronic acid

Product 1

HCID 577327795-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamideYield 10%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
150 °C

Procedure

To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. (This run was aborted prior to 30 min due to excessive pressure build-up). The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 60° C. to give 8.8 mg of the title compound (10%).

Workup

  1. filtrationThe reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH)
  2. washeluting in sequence with H2O (3 mL), MeOH (9 mL)
  3. dry with materialThe NH3/MeOH fraction was dried under a stream of nitrogen at 40° C.
  4. custompurified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm)
  5. washeluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA)
  6. waita linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min
  7. concentrationconcentration for 30 sec
  8. additionThe fractions containing product
  9. filtrationwere filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies)
  10. customto remove TFA (2 columns used per fraction)
  11. concentrationconcentrated under a stream of nitrogen at 60° C.

Sources & evidence

ORD record
ord-4e43b16f8d094aacb51281d8fa1dac5d
Source dataset
uspto-grants-2013_01
Patent number
US08354406B2

Reaction notes

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