Potassium Carbonate → 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

HRID 1806330Notes

Reaction equation

HRID 1806330 reaction equation
[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:12]=[C:11]([C:23]3[CH:24]=[C:25]4[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=3)[NH:28][CH:27]=[C:26]4[CH:35]3[CH2:36][CH2:37][N:38]([S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])[CH2:39][CH2:40]3)[CH:10]=[N:9][CH:8]=2)[CH2:2][CH2:3]1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 113844275-bromo-3-[1-(ethanesulfonyl)-4-piperidinyl]-1H-indole-7-carboxamideHCID 574157101-cyclopropyl-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl)methanamine

Product 1

HCID 577327605-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
150 °C

Procedure

To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H2O (0.25 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. 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 (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C. 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 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65° C. to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).

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 (6 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. concentrationconcentration for 30 sec
  7. additionThe fractions containing product
  8. filtrationwere filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies)
  9. customto remove TFA
  10. concentrationconcentrated under a stream of nitrogen at 65° C.

Sources & evidence

ORD record
ord-36d07b112adb4d9da902057fcc17cb96
Source dataset
uspto-grants-2013_01
Patent number
US08354406B2

Reaction notes

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