Potassium Carbonate → 5-[5-(1-Azetidinylsulfonyl)-2-thienyl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide

HRID 387336Notes

Reaction equation

HRID 387336 reaction equation
[O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:31]1[S:35][C:34]([S:36]([N:39]2[CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:39]1([S:36]([C:34]2[S:35][C:31]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:4][CH2:3][S:2](=[O:29])(=[O:1])[CH2:7][CH2:6]3)=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:40][CH2:41][CH2:42]1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 593327113-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamideHCID 593327961-[(5-Bromo-2-thienyl)sulfonyl]azetidine

Product 1

HCID 593326995-[5-(1-Azetidinylsulfonyl)-2-thienyl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamideYield 48.2%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (21 mg, 0.050 mmol), 1-[(5-bromo-2-thienyl)sulfonyl]azetidine (28.3 mg, 0.100 mmol), and K2CO3 (20.81 mg, 0.151 mmol) in 1,4-dioxane (0.22 mL) and water (0.110 mL) was degassed with argon in a Biotage microwave vial for 10 min. PdCl2(dppf) (3.67 mg, 5.02 μmol) was added, the vial was sealed, and the reaction was heated at 100° C. for 5 min in a Biotage microwave at high absorption. Additional PdCl2(dppf) (3.67 mg, 5.02 μmol) was added, and the reaction was heated at 130° C. in a Biotage microwave for 30 min on high absorption. The aqueous layer was removed via pipette, and the reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g), eluting with 1:1 DCM/MeOH (10 mL). The crude product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 11.9 mg of impure product. The impure product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC(YMC C18 S-5 mm/12 nm 50×20 mm preparatory column), eluting at 20 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) over 10 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 6.1 mg (25%) of the title compound.

Workup

  1. customwas degassed with argon in a Biotage microwave vial for 10 min
  2. customthe vial was sealed
  3. temperaturethe reaction was heated at 130° C. in a Biotage microwave for 30 min on high absorption
  4. customThe aqueous layer was removed via pipette
  5. filtrationthe reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g)
  6. washeluting with 1:1 DCM/MeOH (10 mL)
  7. dissolutionThe crude product was dissolved in DMSO (1.2 mL)
  8. custompurified on a Gilson HPLC (XBridge
  9. wash5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient
  10. concentrationThe desired fractions were concentrated under a stream of nitrogen at 50° C.

Sources & evidence

ORD record
ord-8e240b3aacad45f782305659db972c06
Source dataset
uspto-grants-2013_02
Patent number
US08372875B2

Reaction notes

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