Dimethylamine → 5-{5-[(Dimethylamino)methyl]-3-thienyl}-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamide

HRID 656162

Reaction equation

HRID 656162 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]1.[CH:22]([C:24]1[S:28][CH:27]=[C:26](B(O)O)[CH:25]=1)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:38][NH:39][CH3:40].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCOCC1.O.CC(O)=O.CS(C)=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]>[CH3:38][N:39]([CH2:22][C:24]1[S:28][CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:14][CH:15]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]2)[CH:25]=1)[CH3:40]

Participants

12

Reactant 6

HCID 674DimethylamineHCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 110841152-Formylthiophene-4-boronic acidHCID 593326215-Bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamide

Product 1

HCID 593327775-{5-[(Dimethylamino)methyl]-3-thienyl}-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamideYield 82.3%

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 176Acetic AcidSolventHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamide (120 mg, 0.323 mmol), (5-formyl-3-thienyl)boronic acid (76 mg, 0.485 mmol, 1.5 eq), PdCl2(dppf) (23.65 mg, 0.032 mmol, 0.1 eq), potassium carbonate (134 mg, 0.970 mmol, 3 eq) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL), in a 2-5 mL biotage microwave reaction tube. The mixture was degassed by bubbling nitrogen through for 5 minutes and was then heated in a microwave at high absorption for 15 minutes at 120° C. The reaction was filtered through a thiol SPE cartridge (polymer labs) and was concentrated. Then a solution of 2 M dimethylamine in THF (553 mg, 1.242 mmol, 10 eq), HOAc (1 mL), NaBH(OAc)3 (263 mg, 1.242 mmol, 10 eq) were added in DMSO) (2 mL, and the reaction mixture was stirred at room temperature overnight. Then the solvent was evaporated, EtOAc and water were added, the layers were separated, and the aqueous layer extracted with EtOAc. The combined layers were washed with satured NaCl, dried, concentrated and purified by Gilson HPLC with trifluoroacetic acid buffer. The desired product fractions were combined and concentrated in an EZ2 Genevac evaporator, giving 35.3 mg (82.3%) of the title compound.

Workup

  1. customThe mixture was degassed
  2. customby bubbling nitrogen through for 5 minutes
  3. filtrationThe reaction was filtered through a thiol SPE cartridge (polymer labs)
  4. concentrationwas concentrated
  5. customThen the solvent was evaporated
  6. additionEtOAc and water were added
  7. customthe layers were separated
  8. extractionthe aqueous layer extracted with EtOAc
  9. washThe combined layers were washed with satured NaCl
  10. customdried
  11. concentrationconcentrated
  12. custompurified by Gilson HPLC with trifluoroacetic acid buffer
  13. concentrationconcentrated in an EZ2 Genevac evaporator

Sources & evidence

ORD record
ord-11c50123244f42afad5511886c70adad
Source dataset
uspto-grants-2011_12
Patent number
US08071584B2

Linked notes

Loading…