Lithium Hexamethyldisilazide → N-(1-methylpiperidin-3-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-amine

HRID 1520085Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1520085
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[C:15]2[C:21]1[N:22]=[N:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[CH:25]=1.Cl.Cl.[NH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][N:45]([CH3:49])[CH2:44]1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1COCC1.CN(C=O)C.C(Cl)Cl>[CH3:49][N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([NH:42][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[N:22]=[N:23][N:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[CH:25]=2)[CH2:44]1

Komponenten

8

Edukt 4

HCID 2733832Lithium Hexamethyldisilazide2×HCID 177503421-Methylpiperidin-3-amine dihydrochloride2×HCID 25112535Brettphos2×HCID 574046585-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

Produkt 1

HCID 57405170N-(1-methylpiperidin-3-yl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-amineAusbeute 5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) was added to a degassed suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (200 mg; 0.44 mmol; 1.0 eq.), 3-Amino-1-methylpiperidine dihydrochloride, 98% (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II), (7.0 mg; 0.01 mmol; 0.02 eq.) and dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) in DMF (500 μl). The reaction mixture was then heated at 70° C. O/N. As the reaction was not completed, further 3-Amino-1-methylpiperidine dihydrochloride (99 mg; 0.53 mmol; 1.2 eq.), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (7.0 mg; 0.01 mmol; 0.02 eq.), dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-biphenyl-2-yl)-phosphane (5.0 mg; 0.01 mmol; 0.02 eq.) and LiHMDS (1.99 mL of a 1.0 M in THF; 1.99 mmol; 4.5 eq.) were added and the reaction mixture was heated again at 70° C. for 12 h. It was diluted with DCM and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a brown solid (10 mg; 5%). 1H NMR (300 MHz, DMSO-d6-d6): 12.96 (brs, 1H), 9.26 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.36-7.33 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (m, 1H), 3.64-3.55 (m, 1H), 3.00 (m, 1H), 2.73 (m, 1H), 2.23 (m, 3H), 1.99-1.59 (m, 3H), 1.30 (m, 1H). HPLC (max plot) 94.3%; Rt % 1.99 min. UPLC/MS: (MS+) 487.3, (MS−) 485.3.

Aufarbeitung

  1. addition4.5 eq.) were added
  2. temperaturethe reaction mixture was heated again at 70° C. for 12 h
  3. washwashed with water
  4. dry with materialThe organic phase was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by preparative HPLC

Quellen und Nachweise

ORD-Eintrag
ord-6329a50216db48818b3a6e6978e863fa
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09073892B2

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