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Hydrochloric Acid → 6-Chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indazole-3-carboxylic acid

HRID 338482
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 338482
Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][C:42]=1[Cl:43])[NH:39][N:38]=[C:37]2[C:44]([OH:46])=[O:45].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>[Cl:43][C:42]1[CH:41]=[C:40]2[C:36]([C:37]([C:44]([OH:46])=[O:45])=[N:38][NH:39]2)=[CH:35][C:34]=1[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

11

Edukt 6

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 991682-(p-Bromophenoxy)ethanolHCID 517044Potassium AcetateHCID 2734316Bis(neopentyl glycolato)diboronHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Produkt 1

HCID 86698818
6-Chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indazole-3-carboxylic acid
Ausbeute 19,3 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 44119782Bis(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 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg, 0.025 mmol) and potassium acetate (135 mg, 1.38 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), 2N 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 1N 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% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to afford the title compound (23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)+. Retention time=2.19 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% Formic acid in water (v/v); Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H2O/25.0% MeCN for 1.0 min. 75.0% H2O/25.0% MeCN linear to 45.0% H2O/55.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min)

Quellen und Nachweise

ORD-Eintrag
ord-080160d3e2ae40ed82bf405b1dd6f32c
Quelldatensatz
uspto-grants-2014_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08889730B2

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