Hydrochloric Acid → HCID 178434243, Verbindung

HRID 1162149

Reaktionsgleichung

Reaktionsgleichung von HRID 1162149
C([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[N:9]1)(OC(C)(C)C)=O.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)[Cl:43].C(OC([N:52]1[CH2:57][CH2:56][CH2:55][CH:54]([NH:58][C:59]2[CH:60]=[CH:61][C:62]3[N:63]([C:65](Br)=[CH:66][N:67]=3)[N:64]=2)[CH2:53]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[ClH:75]>CN(C=O)C.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>[ClH:43].[ClH:75].[ClH:43].[CH3:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:65]3[N:63]4[N:64]=[C:59]([NH:58][CH:54]5[CH2:55][CH2:56][CH2:57][NH:52][CH2:53]5)[CH:60]=[CH:61][C:62]4=[N:67][CH:66]=3)[CH:12]=2)[NH:8][N:9]=1

Komponenten

11

Edukt 7

HCID 313Hydrochloric AcidHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 53408115tert-butyl 5-bromo-3-methyl-1H-indazole-1-carboxylateHCID 686482023-(3-Bromo-imidazo[1,2-b]pyridazine-6-yl-amino)-piperidine-1-carboxylic acid tert-butyl ester

Produkt 1

HCID 178434243HCID 178434243, VerbindungAusbeute 34 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

A solution of 1-BOC-3-methyl-5-bromo-indazole (0.24 g, 0.76 mmol), in DMF (10 mL) at room temperature, under nitrogen and treated with potassium acetate (0.40 g, 4 mmol), bis(pinacolato)diboron (0.38 g, 1.5 mmol) and Pd(dppf)Cl2.CH2Cl2 (80 mg, 0.1 mmol). This suspension was degassed with four cycles of vacuum and nitrogen. The suspension was heated at 80° C. for two hours and then cooled to room temperature. The suspension was treated with 3-(3-bromo-imidazo[1,2-b]pyridazine-6-yl-amino)-piperidine-1-carboxylic acid tert-butyl ester (0.31 g, 0.76 mmol) and potassium carbonate (0.40 g) and water (2 mL), degassed (vacuum and then nitrogen×4) and heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried with anhydrous magnesium sulfate, filtered and evaporated. After chromatography with silica gel and a gradient of hexane/ethyl acetate a mixture of mono and di-BOC protected material was obtained as shown by MS m/z 448 and 548. This mixture was treated with aqueous HCl (20%, double distilled, 5 mL) at room temperature overnight. Then the reaction mixture was evaporated to give [3-(3-methyl-1H-indazol-5-yl)-imidazo[1,2-b]pyridazine-6-yl]-piperidin-3-yl-amine trihydrochloride as an yellow solid (0.12 g, 34%); this material was purified by reversed phase chromatography (20.9 mg): mp decomposed above 250° C.; MS [M+H]+ m/z 348. Anal. (C19H21N7.3HCl.1.08H2O), C, H, N.

Aufarbeitung

  1. customThis suspension was degassed with four cycles of vacuum and nitrogen
  2. temperaturecooled to room temperature
  3. customdegassed (vacuum
  4. temperaturenitrogen×4) and heated at 100° C. for 2 hours
  5. temperatureThe reaction mixture was cooled to room temperature
  6. customquenched with saturated aqueous sodium bicarbonate (100 mL)
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. dry with materialdried with anhydrous magnesium sulfate
  9. filtrationfiltered
  10. customevaporated
  11. additionAfter chromatography with silica gel and a gradient of hexane/ethyl acetate a mixture of mono and di-BOC protected material
  12. customwas obtained
  13. customThen the reaction mixture was evaporated

Quellen und Nachweise

ORD-Eintrag
ord-0b49b258c10945e2be73127e5d5df026
Quelldatensatz
uspto-grants-2010_10
Patentnummer
US07820670B2

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