Hydrochloric Acid → 5-(4-(1-Carbamoylcyclobutyl)phenyl)-6-chloro-1H-indazole-3-carboxylic acid

HRID 1054828Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1054828
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([NH2:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[Cl:46])[NH:42][N:41]=[C:40]2[C:47]([OH:49])=[O:48].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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].O.CCO>[C:12]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][C:45]=3[Cl:46])[NH:42][N:41]=[C:40]4[C:47]([OH:49])=[O:48])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)(=[O:13])[NH2:14]

Komponenten

11

Edukt 6

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 471521671-(4-Bromophenyl)cyclobutanecarboxamideHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Produkt 1

HCID 866988205-(4-(1-Carbamoylcyclobutyl)phenyl)-6-chloro-1H-indazole-3-carboxylic acidAusbeute 3,2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Katalysator2×HCID 702EthanolLösungsmittelHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

A suspension of 1-(4-bromophenyl)cyclobutanecarboxylic acid amide (101 mg, 0.37 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg, 0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg, 0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1 hour. Water (3 mL) was added to the reaction mixture, followed by 1 N HCl solution to adjust the pH to 2. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 10.5 min, HOLD at 0% H2O/100% MeCN to 12.0 min. Flow: 25 mL/min) to afford the title compound (4.3 mg, 3% yield). MS (ES+) 343.1 (M+H)+. Retention time=2.45 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Aufarbeitung

  1. customwas sealed in a pressure tube
  2. customThe mixture was sealed
  3. temperatureheated to 130° C. for 1 hour
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with EtOAc (3×5 mL)
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 10.5 min, HOLD at 0% H2O/100% MeCN to 12.0 min. Flow: 25 mL/min)

Quellen und Nachweise

ORD-Eintrag
ord-a165ba73eb834c26a7fa3788eb7e6ff9
Quelldatensatz
uspto-grants-2016_07
Patentnummer
US09394285B2

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