Binap, (A+-)- → 2-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methoxy)-4-((2-methylthiazol-5-yl)methylamino)pyridazin-3(2H)-one

HRID 530791Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 530791
[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14]N=2)=[CH:5][C:4]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26]C(C)=C[N:23]=2)=[N:3]1.C[C:30]1SC(CN)=C[N:34]=1.[CH:37]1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(#N)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][CH:37]=2)=[CH:5][C:4]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26][N:34]([CH3:30])[N:23]=2)=[N:3]1

Komponenten

9

Edukt 4

HCID 634876Binap, (A+-)-HCID 19046689(2-Methyl-1,3-thiazol-5-yl)methanamineHCID 23676156Sodium t-butoxideHCID 904543862-methyl-4-((5-methyl-1,3,4-thiadiazol-2-yl)methylamino)-6-(((1S,2S)-2-(5-methyl pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one

Produkt 1

HCID 904543882-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methoxy)-4-((2-methylthiazol-5-yl)methylamino)pyridazin-3(2H)-one

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittel2×HCID 1140TolueneLösungsmittelHCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

To the solution of 4-bromo-2-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclo propyl)methoxy)pyridazin-3(2H)-one (made according to Example 1, by replacing ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol with ((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methanol, 27 mg, 0.08 mmol) in toluene (2 mL) under N2, (2-methylthiazol-5-yl)methanamine (13 mg, 0.096 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), BINAP (7 mg, 0.012 mmol) and NaOtBu (9 mg, 0.096 mmol) were added. After the reaction mixture was stirred at 85° C. for 4 h, 15 mL water was added. The mixture was extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% acetonitrile in water with 10 mmol NH4HCO3 modifier) to afford the title compound as an oil. 1H NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 7.42 (d, 1H), 5.96 (d, 1H), 5.89 (s, 1H), 4.59 (s, 2H), 4.15-5.11 (m, 1H), 4.04-4.01 (m, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 2.66 (s, 3H), 1.95-1.89 (m, 1H), 1.61-1.53 (m, 1H), 1.01-0.95 (m, 2H); LRMS m/z (M+H) 387.1 found, 387.15 required.

Aufarbeitung

  1. extractionThe mixture was extracted with EtOAc (3×10 mL)
  2. dry with materialThe combined organics were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-190e2045a1704dc59ffceca9812852c4
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09353104B2

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