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

HRID 387400

Reaktionsgleichung

Reaktionsgleichung von HRID 387400
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]

Komponenten

12

Edukt 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

Produkt 1

HCID 593327775-{5-[(Dimethylamino)methyl]-3-thienyl}-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamideAusbeute 82,3 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 176Acetic AcidLösungsmittelHCID 679Dimethyl SulfoxideLösungsmittelHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

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 saturated 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.

Aufarbeitung

  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 saturated NaCl
  10. customdried
  11. concentrationconcentrated
  12. custompurified by Gilson HPLC with trifluoroacetic acid buffer
  13. concentrationconcentrated in an EZ2 Genevac evaporator

Quellen und Nachweise

ORD-Eintrag
ord-399f73cb2e65414e9d590c532d23a00e
Quelldatensatz
uspto-grants-2013_02
Patentnummer
US08372875B2

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